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"abstract": "Molecular subgroups of pediatric brain tumors associated with divergent biological, clinical, and prognostic features have been identified. However, data regarding the impact of subgroup affiliation on the outcome of children with malignant brain tumors treated with radiation-sparing protocol is limited. We report long-term clinical outcomes and the molecular subgroups of malignant brain tumors in young children whose first-line treatment was high-dose chemotherapy without irradiation.\n\n\n\nTumor subclassification was performed using the Illumina HumanMethylation450 BeadChip (450k) genome-wide methylation array profiling platform. Clinical information was obtained from chart review.\n\n\n\nMethylation array profiling yielded information on molecular subgroups in 22 children. Median age at surgery was 26 months (range 1-119 months). Among medulloblastomas (MB), all 6 children in the infant sonic hedgehog (SHH) subgroup were long-term survivors, whereas all 4 children in subgroup 3 MB died. There was one long-term survivor in subgroup 4 MB. One out of five children with ependymoma was a long-term survivor (RELPOS). Both children with primitive neuroectodermal tumors died. One child with ATRT TYR and one child with choroid plexus carcinoma were long-term survivors.\n\n\n\nThe efficacy of high-dose chemotherapy radiation-sparing treatment appears to be confined to favorable molecular subgroups of pediatric brain tumors, such as infant SHH MB. Identification of molecular subgroups that benefit from radiation-sparing therapy will aid in the design of prospective, \"precision medicine\"-driven clinical trials.",
"affiliations": "Division of Pediatric Neurosurgery, Department of Neurosurgery, Hassenfeld Children's Hospital, NYU Langone Health, New York, USA. [email protected].;Department of Pathology, NYU Langone Health, New York, USA.;Division of Pediatric Neurosurgery, Department of Neurosurgery, Hassenfeld Children's Hospital, NYU Langone Health, New York, USA.;Division of Pediatric Neurosurgery, Department of Neurosurgery, Hassenfeld Children's Hospital, NYU Langone Health, New York, USA.;Department of Pathology, NYU Langone Health, New York, USA.;Department of Pathology, NYU Langone Health, New York, USA.;Pediatric Neuro-Oncology, Department of Pediatrics, Hassenfeld Children's Hospital, NYU Langone Health, New York, USA.;Pediatric Neuro-Oncology, Department of Pediatrics, Hassenfeld Children's Hospital, NYU Langone Health, New York, USA.",
"authors": "Hidalgo|Eveline Teresa|ET|0000-0002-0053-8658;Snuderl|Matija|M|;Orillac|Cordelia|C|;Kvint|Svetlana|S|;Serrano|Jonathan|J|;Wu|Peter|P|;Karajannis|Matthias A|MA|;Gardner|Sharon L|SL|",
"chemical_list": "D053823:Hedgehog Proteins",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-019-04305-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "36(1)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Clinical outcome; Molecular subgroups; Pediatric brain tumor",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D001932:Brain Neoplasms; D002528:Cerebellar Neoplasms; D002648:Child; D002675:Child, Preschool; D053823:Hedgehog Proteins; D006801:Humans; D007223:Infant; D008527:Medulloblastoma; D011446:Prospective Studies",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "133-144",
"pmc": null,
"pmid": "31375903",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23175756;11481352;2709111;25965575;15758008;19274783;25689980;26919435;24101739;16234523;27040285;1634751;3309606;25348790;24789527;26092413;27194148;15611503;29778738;23670100;6704921;26950375;23508296;8040673;18293379;23079654;29539639;6118478;23476028;3703257;2319316;15020603;28379644;23934933;25752754;27269943;18381756;28895660;23598174;25262207;16874765;27145464;23099653;26923874;8388548;16943538;20526792;27960086;666614",
"title": "Subgroup-specific outcomes of children with malignant childhood brain tumors treated with an irradiation-sparing protocol.",
"title_normalized": "subgroup specific outcomes of children with malignant childhood brain tumors treated with an irradiation sparing protocol"
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{
"abstract": "A 59-year-old man received a single-lung transplantation due to interstitial pneumonitis. Severe anastomotic pulmonary artery stenosis (PAS) resulting in hypoxia and respiratory symptoms was found in the immediate postoperative period. A scintigraphy showed severe hypoperfusion of the left transplanted lung with 7% of the total pulmonary blood flow. On postoperative days (POD) 29 and 64, the patient underwent serial balloon angioplasties without any complications. Based on the balloon selection criteria for PAS after heart surgery in children, a high-pressure large balloon was used with resultant improvement in respiratory signs and symptoms without any complications. The patient was discharged on POD 92. A follow-up scintigraphy on POD 169 revealed 58% of blood distribution to the left lung. The patient has been doing clinically well and remained asymptomatic one year after the transplantation. Balloon angioplasty with a high-pressure large balloon without stent implantation during an early postoperative period may be a safe and effective strategy. The balloon selecting criteria used in pediatric patients may be applied in the adult lung transplant recipients. <Learning objective: Anastomotic pulmonary artery stenosis (PAS) in a single-lung transplant recipient is a critical complication. A balloon angioplasty with a high-pressure large balloon should be a first choice for anastomotic PAS, because it is safer than stent implantation especially for transplant recipients. And the balloon selecting criteria used in children with congenital heart disease may be applied in the adult lung transplant recipients.>.",
"affiliations": "The University of Tokyo Hospital, Department of Pediatrics, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;The University of Tokyo Hospital, Department of Pediatrics, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;The University of Tokyo Hospital, Department of Cardiology, Tokyo, Japan.;The Children's Hospital of Philadelphia, Division of Cardiology, Philadelphia, USA.;The University of Tokyo Hospital, Department of Pediatrics, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;The University of Tokyo Hospital, Department of Pediatrics, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;The University of Tokyo Hospital, Department of Cardiology, Tokyo, Japan.;The University of Tokyo Hospital, Department of Thoracic Surgery, Tokyo, Japan.;The University of Tokyo Hospital, Department of Cardiac Surgery, Tokyo, Japan.;The University of Tokyo Hospital, Department of Pediatrics, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.",
"authors": "Shiraga|Kazuhiro|K|;Hirata|Yoichiro|Y|;Saito|Akihito|A|;Ozcelik|Nazire|N|;Asakai|Hiroko|H|;Inuzuka|Ryo|R|;Soma|Katsura|K|;Sato|Masaaki|M|;Hirata|Yasutaka|Y|;Oka|Akira|A|",
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"delete": false,
"doi": "10.1016/j.jccase.2020.03.008",
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"issn_linking": "1878-5409",
"issue": "22(1)",
"journal": "Journal of cardiology cases",
"keywords": "Anastomotic pulmonary artery stenosis; Balloon pulmonary angioplasty; Balloon selection criteria; Catheter intervention; High pressure large balloon; Lung transplantation",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "22-25",
"pmc": null,
"pmid": "32636964",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "25851200;8539661;10618351;10612386;9270100;8273631;18639464;15227331;23788195",
"title": "Successful angioplasties using high pressure large balloons in a patient with severe anastomotic pulmonary artery stenosis soon after single-lung transplantation.",
"title_normalized": "successful angioplasties using high pressure large balloons in a patient with severe anastomotic pulmonary artery stenosis soon after single lung transplantation"
} | [
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"abstract": "BACKGROUND\nSecondary hyperparathyroidism (SHPT) is a common complication in patients receiving chronic dialysis therapy. Although cinacalcet can control parathyroid function and bone turnover, preventing ectopic calcification remains challenging. Cinacalcet can also suppress PTH secretion due to parathyroid carcinoma in the same way as it does for parathyroid hyperplasia in the uremic condition. We present a case of parathyroid carcinoma partially controlled by cinacalcet, in which tumorous calcinosis was successfully resolved by total parathyroidectomy.\n\n\nMETHODS\nA female patient in her forties who had received dialysis for 12 years was referred to our hospital for painful ectopic calcifications on her right hip joint and both knees. Although she had been treated with alfacalcidol and cinacalcet for 2 years, this therapy had been discontinued 6 months earlier as a result of hypercalcemia. The patient exhibited normocalcemia (2.37 mmol/L) and hyperphosphatemia (2.42 mmol/L) with elevated intact parathyroid hormone (707,000 μg/L). Ultrasonography revealed an enlarged parathyroid gland on the left lower side of the thyroid gland. The otolaryngologist surgeons had to perform an en bloc excision to remove this parathyroid gland because of tight adhesions. Histological examination revealed that parathyroid cells had invaded the surrounding skeletal muscle through fibrous capsules, consistent with parathyroid carcinoma. Her joint pain disappeared 2 weeks after parathyroidectomy, and the tumorous calcinosis had largely resolved after 1 year.\n\n\nCONCLUSIONS\nParathyroid carcinoma is a rare cause of hyperparathyroidism in end-stage kidney disease. Our case indicates that the use of cinacalcet hinders the diagnosis of parathyroid carcinoma in a chronic dialysis patient. When uncontrolled hypercalcemia and/or hyperphosphathemia develop during cinacalcet administration, parathyroidectomy should be considered to prevent a vicious exacerbation of ectopic calcification.",
"affiliations": "Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto, Japan. [email protected].;Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto, Japan.;Department of Otorhinolaryngology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Otorhinolaryngology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto, Japan.",
"authors": "Takada|Daisuke|D|;Tsukamoto|Tatsuo|T|;Fuse|Miho|M|;Kada|Shinpei|S|;Yanagita|Motoko|M|",
"chemical_list": "D057966:Calcimimetic Agents; D000069449:Cinacalcet",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-017-0733-0",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 73310.1186/s12882-017-0733-0Case ReportThe use of cinacalcet hinders the diagnosis of parathyroid carcinoma in a chronic dialysis patient: a case report Takada Daisuke [email protected] 12Tsukamoto Tatsuo [email protected] 12Fuse Miho [email protected] 3Kada Shinpei [email protected] 3Yanagita Motoko [email protected] 11 0000 0004 0372 2033grid.258799.8Department of Nephrology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo, Kyoto, Japan 2 0000 0004 0378 7849grid.415392.8Department of Nephrology & Dialysis, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan 3 0000 0004 0372 2033grid.258799.8Department of Otorhinolaryngology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan 18 10 2017 18 10 2017 2017 18 31515 12 2016 28 9 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSecondary hyperparathyroidism (SHPT) is a common complication in patients receiving chronic dialysis therapy. Although cinacalcet can control parathyroid function and bone turnover, preventing ectopic calcification remains challenging. Cinacalcet can also suppress PTH secretion due to parathyroid carcinoma in the same way as it does for parathyroid hyperplasia in the uremic condition. We present a case of parathyroid carcinoma partially controlled by cinacalcet, in which tumorous calcinosis was successfully resolved by total parathyroidectomy.\n\nCase presentation\nA female patient in her forties who had received dialysis for 12 years was referred to our hospital for painful ectopic calcifications on her right hip joint and both knees. Although she had been treated with alfacalcidol and cinacalcet for 2 years, this therapy had been discontinued 6 months earlier as a result of hypercalcemia. The patient exhibited normocalcemia (2.37 mmol/L) and hyperphosphatemia (2.42 mmol/L) with elevated intact parathyroid hormone (707,000 μg/L). Ultrasonography revealed an enlarged parathyroid gland on the left lower side of the thyroid gland. The otolaryngologist surgeons had to perform an en bloc excision to remove this parathyroid gland because of tight adhesions. Histological examination revealed that parathyroid cells had invaded the surrounding skeletal muscle through fibrous capsules, consistent with parathyroid carcinoma. Her joint pain disappeared 2 weeks after parathyroidectomy, and the tumorous calcinosis had largely resolved after 1 year.\n\nConclusions\nParathyroid carcinoma is a rare cause of hyperparathyroidism in end-stage kidney disease. Our case indicates that the use of cinacalcet hinders the diagnosis of parathyroid carcinoma in a chronic dialysis patient. When uncontrolled hypercalcemia and/or hyperphosphathemia develop during cinacalcet administration, parathyroidectomy should be considered to prevent a vicious exacerbation of ectopic calcification.\n\nKeywords\nCinacalcetParathyroid carcinomaHemodialysisSecondary hyperparathyroidismEctopic calcificationCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nSecondary hyperparathyroidism (SHPT) is a common complication in patients undergoing chronic dialysis therapy. A recent medical advance has enabled suppression of the parathyroid function using cinacalcet (a calcimimetic drug). Combined with vitamin D, cinacalcet has successfully controls parathyroid function and bone turnover in many SHPT patients. Nevertheless, preventing ectopic calcification, such as tumorous calcinosis and vascular calcification, remains a challenge [1]. These two conditions can be caused by an excess load of calcium and phosphate into the soft tissue, including the blood vessels associated with a trans-differentiation of vascular smooth muscle cells and fibroblasts to the osteoblastic phenotype in the uremic condition [2, 3]. Since a non-calcium-containing phosphate binder can suppress the progression of calcification, ensuring a negative balance of calcium and phosphate in the body to reduce the load into the soft tissue is a reasonable therapeutic strategy [4, 5]. There remains a limitation in the cinacalcet and vitamin D combination therapy to control SHPT, however, especially in cases with severe ectopic calcification. Parathyroidectomy (PTx) could be considered the final choice to resolve such issues [6, 7].\n\nParathyroid carcinoma is a rare cause of hyperparathyroidism [8]. The use of cinacalcet to treat hypercalcemia due to parathyroid carcinoma has recently been reported [9]. Here we present a case of parathyroid carcinoma partially controlled by cinacalcet, in which the tumorous calcinosis was successfully resolved by total PTx.\n\nCase presentation\nA female patient in her forties who had received regular hemodialysis (4 h, 3 times a week) for 12 years with good adherence was referred to our hospital for multiple ectopic calcifications. The cause of her end-stage kidney disease was chronic glomerulonephritis (membranoproliferative glomerulonephritis). For 2 months she had experienced progressive pain in her right hip joint and left knee while walking. X-ray examinations revealed massive calcifications in these regions (Fig. 1a). Although her SHPT was well controlled with an adequate intact parathyroid hormone (iPTH) level, her calcium level had gradually increased (Fig. 2). Although she had been treated daily with 0.5 μg alfacalcidol and 50 mg cinacalcet for 2 years, this treatment had been discontinued 6 months earlier due to hypercalcemia and hyperphosphatemia. Calcium carbonate and lanthanum carbonate were used as a phosphate binder. Even after the calcium carbonate was discontinued, she remained hypercalcemic and eventually developed joint pain. Her iPTH level increased another 500,000 μg/L before the referral. She also had unstable angina, and had received percutaneous coronary intervention with stenting for noticeably calcified coronary arteries. She had also been prescribed telmisartan, trandopril, sodium polystyrene sulfonate, aspirin, clopidogrel sulfate, eicosapentaenoic acid, omeprazole, and pravastatin.Fig. 1 Images. Panel a and b; X-ray images of the right hip joint before (a) and after 6 months of total parathyroidectomy (b). Note that the massive calcifications around the right hip joint mostly disappeared after parathyroidectomy. Panel c; An enlarged parathyroid gland at the left lower side of the thyroid with a long axis of 21 mm, near the muscle layer of the esophagus. Panel d; Structural atypia in histological findings of the resected parathyroid gland at low (×40) magnification\n\n\nFig. 2 Clinical course of laboratory data (serum calcium, phosphorus, and intact-parathyroid hormone) and medication before and after parathyroidectomy\n\n\n\n\nOn admission, the patient was 158.5 cm tall and weighed 49 kg. Her blood pressure was 144/88 mmHg. She had no palpable neck masses. Laboratory findings were as follows: calcium (Ca) 2.22 mmol/L; inorganic phosphate (iP) 2.42 mg/dL; alkaline phosphatase (ALP) 248 U/L; and iPTH 707,000 μg/L (Table 1). Ultrasonography of the neck showed an enlarged parathyroid gland on the left lower side of the thyroid with a long axis of 21 mm. No other parathyroid glands were identified by ultrasonography (Fig. 1c). Computed tomography of the chest detected no ectopic parathyroid in the mediastinum or lung.Table 1 Laboratory data on admission\n\nComplete blood count\t\t\t\n White blood cell\t8600\t/μL\t\n Red blood cell\t403 × 104\n\t/μL\t\n Hemoglobin\t102\tg/L\t\n Platelet\t27.1 × 104\n\t/μL\t\nBlood chemistry\t\n Aspartate aminotransferase\t13\tIU/L\t\n Alanine aminotransferase\t5\tIU/L\t\n Lactate dehydrogenase\t188\tIU/L\t\n Alkaline phosphatase.\t284\tIU/L\t\n γ-glutamyltransferase\t10\tIU/L\t\n Total protein\t72\tg/L\t\n Albumin\t34\tg/L\t\n Blood urea nitrogen\t23.6\tmmol/L\t\n Uric acid\t434\tμmol/L\t\n Creatinine\t910\tμmol/L\t\n Sodium\t136\tmmol/L\t\n Potassium\t6.6\tmmol/L\t\n Chloride\t97\tmmol/L\t\n Calcium\t2.22\tmmol/L\t\n Phosphorus\t2.42\tmmol/L\t\n Magnesium\t0.99\tmmol/L\t\n C-reactive protein\t2000\tμg/L\t\n Intact parathyroid hormone\t707,000\tμg/L\t\n Bone type alkaline phosphatase\t18.6\tIU/L\t\n Tartrate-resistant acid phosphatase 5b\t818\tmU/dL\t\n\n\n\nWe resected one large nodule and three normal-size parathyroid glands. As the largest gland had macroscopically invaded the left sympathetic nerve and clearly invaded muscle layer of the esophagus, we employed an en bloc excision. Histopathological analysis revealed that the parathyroid cells had contiguously invaded beyond the fibrous capsules into the surrounding skeletal muscle tissue (Fig. 1d). Thus, a diagnosis of parathyroid carcinoma was made.\n\nTwo weeks after the surgery, the patient’s pain while walking had disappeared. To prevent postoperative hungry bone syndrome, calcium carbonate and alfacalcidol were administered for 2 months and then tapered off. X-ray films showed a significant decrease in the tumoral calcinosis of the right hip joint and left knee after 3 months (Fig. 1b). Her chest pain during mild exercise disappeared. Her phosphate level was controlled below 1.94 mmol/L with a non-calcium-containing phosphate binder and longer dialysis time (4.5–5.0 h). Her iPTH level was 0 to 2000 μg/L under a relatively low calcium level (2.00–2.12 mmol/L), indicating that a total PTx was successfully achieved in this case.\n\nDiscussion\nThis case clearly indicated that the use of cinacalcet hinders the diagnosis of parathyroid carcinoma in a chronic dialysis patient. Cinacalcet is a calcimimetic drug that reduces PTH secretion by increasing the sensitivity of the calcium-sensing receptor (Ca-SR), which is specifically expressed in parathyroid cells [10, 11]. Cinacalcet affects parathyroid adenoma and carcinoma, which express Ca-SR on the cell surface, decreases the Ca level, and suppresses tumor growth [9, 12, 13]. Although cinacalcet is used extensively in the treatment of SHPT in chronic dialysis patients worldwide, clinical trials have not determined if cinacalcet would reduce cardiovascular events and improve mortality [14, 15].\n\nParathyroid carcinoma accounts for between 0.5% and 5% of all cases of primary hyperthyroidism [16, 17]. Approximately 700 parathyroid carcinoma cases have been reported, 20 of which occurred in chronic dialysis patients [16]. A Japanese retrospective study reported 3.14% parathyroid carcinomas in 826 parathyroidectomies [18]. As it is difficult to distinguish parathyroid carcinoma from parathyroid hyperplasia (which is the most common cause of SHPT) by routine image diagnosis, cinacalcet might cause a delay in the diagnosis of parathyroid carcinoma when it is used to control the PTH level in chronic dialysis patients.\n\nClassically, the clinical features of parathyroid carcinoma include hypercalcemia, palpable neck mass, high serum PTH, and osteitis fibrosa cystica [19–21]. The principle histological features were reported by Castleman et al. to be: 1) a trabecular pattern, 2) mitotic figures, 3) thick fibrous bands, and 4) capsular and blood vessel invasion [22]. Since these features have also occasionally been noted in parathyroid adenoma and hyperplasia, two criteria were added later; the first is the local invasion of contiguous structures, and the second is lymph node or distant metastasis [23]. Our case did not have the typical clinical features described above, although the parathyroid cells invaded beyond the fibrous capsules pathologically and spread into the surrounding muscle also macroscopically, resulting in tight adhesion. Indeed, we had to perform an en bloc excision to resect the tumor during surgery. As the patient had not undergone treatment with other interventions for her parathyroid gland (such as percutaneous ethanol injection therapy), which could be a cause of secondary parathyromatosis, the surgical and histological findings strongly support the diagnosis of the largest parathyroid gland with carcinoma [24–26]. The recurrence rate for parathyroid carcinoma is reported to be 27, 82, and 91% after 1, 5, and 10 years, respectively [27]. Thus, the iPTH level should be monitored in order to ensure early detection of a recurrence.\n\nA non-calcium-containing phosphate binder can suppress the progression of ectopic calcification, such as vascular calcification and tumorous calcinosis [5]. The combination of cinacalcet with Vitamin D might, however, lead to a decrease in bone turnover as a result of the decrease in PTH. Under these conditions, hypercalcemia with hyperphosphatemia due to the decreased buffering effect of bone could result in a positive load of calcium and phosphate into the soft tissue, resulting in ectopic calcification [28]. PTx can trigger hungry bone syndrome, which accelerates the draw of calcium and phosphate from the lesions of ectopic calcification sites and squeezes them into the bone [4].\n\nIn our case, the PTx allowed us to both treat the ectopic calcification and diagnose it as parathyroid carcinoma, and the serum calcium and PTH dropped when parathyroid carcinoma was removed. The iPTH value of SHPT patients who should be treated with PTx is recommended as 500,000 μg/L by the Japanese guideline [7]. Most symptomatic patients who receive chronic dialysis and who undergo PTx have a serum iPTH level of more than 800,000 μg/L [29]. Asymptomatic patients are, however, commonly referred for parathyroidectomy when they have a sustained PTH of more than 1000,000 μg/L [7, 30]. Indeed, cinacalcet came on the market in Japan in 2008, and the number of PTx in Japan decreased strikingly as a result [15, 18, 31]. Earlier PTx should be considered before a vicious exacerbation of ectopic calcification. Further study is required to determine the new indications of PTx in patients receiving chronic dialysis therapy and cinacalcet treatment.\n\nConclusions\nWe successfully treated a chronic dialysis patient for parathyroid carcinoma with tumoral calcinosis by total PTx. The use of cinacalcet hinders the diagnosis of parathyroid carcinoma in a chronic dialysis patient.\n\nAbbreviations\nALPalkaline phosphatase\n\nCacalcium\n\nCa-SRcalcium-sensing receptor\n\niPinorganic phosphate\n\niPTHintact parathyroid hormone\n\nPTxparathyroidectomy\n\nSHPTsecondary hyperparathyroidism\n\nAcknowledgements\nWe thank Dr. Yoshiki Mikami (Department of Pathology, Kyoto University Graduate School of Medicine) for helpful discussion about the histopathology of resected parathyroid tissue.\n\nFunding\nNone.\n\nAvailability of data and materials\nRecords and data pertaining to this case are in the patient’s secure medical records in the Kyoto University Hospital.\n\nAuthors’ contributions\nDT was an attending doctor for this patient under the supervision of TT, and wrote this paper. SK and MF performed total parathyroidectomy. MY helped DT draft the manuscript. All authors discussed the results and implications, commented on the manuscript at all stages, and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient, as well as for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Goodman WG Goldin J Kuizon BD Yoon C Gales B Sider D Wang Y Chung J Emerick A Greaser L Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis N Engl J Med 2000 342 20 1478 1483 10.1056/NEJM200005183422003 10816185 \n2. Shroff R Long DA Shanahan C Mechanistic insights into vascular calcification in CKD J Am Soc Nephrol 2013 24 2 179 189 10.1681/ASN.2011121191 23138485 \n3. Paloian NJ Giachelli CM A current understanding of vascular calcification in CKD Am J Physiol Renal Physiol 2014 307 8 F891 F900 10.1152/ajprenal.00163.2014 25143458 \n4. Peacock M Calcium metabolism in health and disease Clin J Am Soc Nephrol 2010 5 Suppl 1 S23 S30 10.2215/CJN.05910809 20089499 \n5. Patel L Bernard LM Elder GJ Sevelamer versus calcium-based binders for treatment of Hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials Clin J Am Soc Nephrol 2016 11 2 232 244 10.2215/CJN.06800615 26668024 \n6. Cunningham J Locatelli F Rodriguez M Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options Clin J Am Soc Nephrol 2011 6 4 913 921 10.2215/CJN.06040710 21454719 \n7. Fukagawa M Yokoyama K Koiwa F Taniguchi M Shoji T Kazama JJ Komaba H Ando R Kakuta T Fujii H Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder Ther Apher Dial 2013 17 3 247 288 10.1111/1744-9987.12058 23735142 \n8. Wei CH Harari A Parathyroid carcinoma: update and guidelines for management Curr Treat Options in Oncol 2012 13 1 11 23 10.1007/s11864-011-0171-3 \n9. Silverberg SJ Bone HG 3rd Marriott TB Locker FG Thys-Jacobs S Dziem G Kaatz S Sanguinetti EL Bilezikian JP Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism N Engl J Med 1997 337 21 1506 1510 10.1056/NEJM199711203372104 9366582 \n10. Brown EM Clinical lessons from the calcium-sensing receptor Nat Clin Pract Endocrinol Metab 2007 3 2 122 133 10.1038/ncpendmet0388 17237839 \n11. Brennan SC Thiem U Roth S Aggarwal A Fetahu I Tennakoon S Gomes AR Brandi ML Bruggeman F Mentaverri R Calcium sensing receptor signalling in physiology and cancer Biochim Biophys Acta 2013 1833 7 1732 1744 10.1016/j.bbamcr.2012.12.011 23267858 \n12. Collins MT Skarulis MC Bilezikian JP Silverberg SJ Spiegel AM Marx SJ Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent J Clin Endocrinol Metab 1998 83 4 1083 1088 10.1210/jcem.83.4.4726 9543122 \n13. Marcocci C Cetani F Rubin MR Silverberg SJ Pinchera A Bilezikian JP Parathyroid carcinoma J Bone Miner Res 2008 23 12 1869 1880 10.1359/jbmr.081018 19016595 \n14. Raggi P Chertow GM Torres PU Csiky B Naso A Nossuli K Moustafa M Goodman WG Lopez N Downey G The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis Nephrol Dial Transplant 2011 26 4 1327 1339 10.1093/ndt/gfq725 21148030 \n15. 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Bover J Urena P Ruiz-Garcia C daSilva I Lescano P del Carpio J Ballarin J Cozzolino M Clinical and practical use of Calcimimetics in dialysis patients with secondary hyperparathyroidism Clin J Am Soc Nephrol 2016 11 1 161 174 10.2215/CJN.01760215 26224878 \n29. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.: Parathyroidectomy in patients with CKD. Am J Kidney Dis. 2003;42(Suppl 3):S127–9.\n30. Moorthi RN Moe SM CKD-mineral and bone disorder: core curriculum 2011 Am J Kidney Dis 2011 58 6 1022 1036 10.1053/j.ajkd.2011.08.009 22018457 \n31. Fukagawa M Fukuma S Onishi Y Yamaguchi T Hasegawa T Akizawa T Kurokawa K Fukuhara S Prescription patterns and mineral metabolism abnormalities in the cinacalcet era: results from the MBD-5D study Clin J Am Soc Nephrol 2012 7 9 1473 1480 10.2215/CJN.13081211 22822017\n\n",
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"keywords": "Case report; Cinacalcet; Ectopic calcification; Hemodialysis; Parathyroid carcinoma; Secondary hyperparathyroidism",
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"mesh_terms": "D000328:Adult; D057966:Calcimimetic Agents; D002277:Carcinoma; D000069449:Cinacalcet; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D007676:Kidney Failure, Chronic; D010282:Parathyroid Neoplasms; D006435:Renal Dialysis",
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"abstract": "A diabetic woman had been suffering from progressively blurry vision in the right eye for 1 year after cataract surgery. Slit lamp examination revealed bilateral band keratopathy with quiescent anteriorchamber reaction, an intumescent cataract in the left eye, and dense posterior capsular opacity in the right eye. Capsulotomy was performed, but this led to neovascular glaucoma. Because of a refractory elevation in intraocular pressure, trabeculectomy with mitomycin C treatment, vitrectomy with panretinal photocoagulation, and intravitreal injection of bevacizumab were performed. A positive rapid plasma reagin test and a positive Treponema pallidum hemagglutination assay led to the impression of syphilitic uveitis, and the patient was treated with intravenous penicillin for 2 weeks. The visual acuity of the right eye was 0.1 at the 12th-month follow up. This case shows that neovascular glaucoma may present as a complication of capsulotomy in uveitic/diabetic eyes.",
"affiliations": "Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.;Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.",
"authors": "Lin|Hong-Zin|HZ|;Lee|Yuan-Chieh|YC|",
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"fulltext": "\n==== Front\nTzu Chi Med J\nCi Ji Yi Xue Za Zhi\nTCMJ\nTzu-Chi Medical Journal\n1016-3190 2223-8956 Medknow Publications & Media Pvt Ltd India \n\nTCMJ-28-76\n10.1016/j.tcmj.2015.06.005\nCase Report\nNeovascular glaucoma following Nd:YAG laser capsulotomy in a patient with diabetes and syphilitic uveitis\nLin Hong-Zin ab Lee Yuan-Chieh abc* a Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan\nb Department of Ophthalmology and Visual Science, Tzu Chi University, Hualien, Taiwan\nc Institute of Medical Science, Tzu Chi University, Hualien, Taiwan\n* Corresponding author. Department of Ophthalmology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien, Taiwan. Tel.: +886 38561825x3253; fax: +886 38577161. E-mail address: [email protected] (Y.-C. Lee).\n\nApr-Jun 2016 \n05 9 2015 \n28 2 76 78\n03 6 2015 08 6 2015 10 6 2015 Copyright: © 2016, Buddhist Compassion Relief Tzu Chi Foundation2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A diabetic woman had been suffering from progressively blurry vision in the right eye for 1 year after cataract surgery. Slit lamp examination revealed bilateral band keratopathy with quiescent anteriorchamber reaction, an intumescent cataract in the left eye, and dense posterior capsular opacity in the right eye. Capsulotomy was performed, but this led to neovascular glaucoma. Because of a refractory elevation in intraocular pressure, trabeculectomy with mitomycin C treatment, vitrectomy with panretinal photocoagulation, and intravitreal injection of bevacizumab were performed. A positive rapid plasma reagin test and a positive Treponema pallidum hemagglutination assay led to the impression of syphilitic uveitis, and the patient was treated with intravenous penicillin for 2 weeks. The visual acuity of the right eye was 0.1 at the 12th-month follow up. This case shows that neovascular glaucoma may present as a complication of capsulotomy in uveitic/diabetic eyes.\n\nDiabetesNd:YAG laser capsulotomyNeovascular glaucomaSyphilitic uveitis\n==== Body\n1. Introduction\nOpacification of the posterior capsule (PCO) is the most common complication of cataract surgery in uveitis patients [12]. In such patients, the incidence of PCO is 14.2% to 58% with extracapsular cataract extraction [34] and 23.7% to 62% with phacoemulsification [12567]. Visual function is highly adversely affected by PCO [89]. Capsulotomy by Nd:YAG laser is the gold standard for restoring better visual acuity in patients with PCO. Capsulotomy is considered a relatively safe procedure, but it still has several complications. These include a sudden increase in intraocular pressure (IOP), long-term IOP elevation [10111213], iris hemorrhage [14], cystoid macular edema [121516], posterior vitreous detachment [17], retinal breaks/detachment [181920], and aqueous misdirection syndrome [2122]. Neovascular glaucoma (NVG) rarely occurs as a complication of capsulotomy [23]. Here, we present a case of NVG following Nd:YAG capsulotomy involving a patient with diabetes and syphilitic uveitis.\n\n2. Case Report\nA 68-year-old woman with diabetes, who had sight in one eye, visited our clinic due to progressively blurry vision in her right eye for 1 year. She had lost the vision in her left eye at the age of 17 due to an unknown cause. She had undergone cataract surgery of the right eye 1 year previously at another hospital. On examination, the corrected visual acuity was 0.05, and hand motion was at 10 cm for the left eye. Right-and left-eye IOP was 17 mmHg and 16 mmHg, respectively. Biomicroscopy showed mild band keratopathy with quiescent anterior-chamber reaction in both eyes and an intumescent cataract in the left eye. In addition, there was a superior sclerocorneal incision scar and partial iris defect with a large and up-drawn pupil in the right eye. Careful examination did not reveal even the slightest rubeosis. The intraocular lens was surrounded by a fibrotic capsule with dense PCO behind; this PCO hindered a clear and detailed fundus examination. Therefore, Nd:YAG laser capsulotomy was performed. However, blood gushed from the small capsulotomy right after the second laser shot. When the hyphema resolved 5 days later, prominent neovascularization of the iris and an elevated IOP of up to 31 mmHg were noted (Fig. 1). Gonioscopy revealed hyperpigmentation of the trabecular meshwork and some peripheral anterior synechiae. Fluorescein angiography failed to provide clear images due to the PCO with a small opening and the presence of faint vitreous hemorrhage. Topical timolol, dorzolamide, and brimonidine were prescribed, and intravitreal injection of bevacizumab was performed. Because of persistently high IOP, combined surgery, including trabeculectomy with mitomycin C, pars plana vitrectomy with panretinal photocoagulation, and intravitreal injection of bevacizumab, was performed 2 weeks after the capsulotomy. IOP returned to within normal limits postoperatively. Repeated fluorescein angiography revealed leakage of sclerotic vessels and patches of macular ischemia. A rapid plasma reagin test and a Treponema pallidum hemagglutination assay showed positive responses. Under the impression of syphilitic uveitis, the patient was treated with intravenous penicillin for 2 weeks. The visual acuity of the right eye was 0.1 at the 12th-month follow up.\n\nFig. 1 Five days after Nd:YAG laser capsulotomy, when the hyphema resolved, prominent neovascularization of the iris can be seen.\n\n3. Discussion\nNeovascular glaucoma, which usually results from diabetic retinopathy, ischemic central retinal vein occlusion, or ocular ischemic syndrome, rarely occurs following capsulotomy [23]. Capsulotomy increases the risk of NVG in diabetic eyes [242526]. A retrospective review has shown that NVG develops more often in diabetic eyes that have undergone extracapsular cataract extraction with capsulotomy than in those without capsulotomy [24]. Weinreb et al [25] reported that NVG occurred after capsulotomy in three diabetic patients who had undergone panretinal photocoagulation before uncomplicated extracapsular cataract extraction.\n\nMost of the vascular endothelial growth factors (VEGFs) in the eyes are released from the ischemic retina, and the concentration of VEGFs in the vitreous fluid is much higher than that in the aqueous humor during ocular neovascularization [27]. An intact posterior capsule acts as an anatomical barrier that confines VEGFs to the posterior segment; this confinement prevents the spread of VEGFs into the anterior segment and hence the neovascularization of the iris and angle [28]. Nd:YAG laser capsulotomy breaks this anatomical barrier and carries the risk of NVG in patients with ischemia or inflammation of the posterior segment.\n\nNVG following capsulotomy in a uveitis patient has been reported [4]. Infection with T. pallidum increases angiogenesis, which is mediated in part by an increased production of various angio-genic factors [29]. Our patient had diabetes and syphilis uveitis and thus carried a high risk of NVG. However, capsulotomy is nearly inevitable when patients develop PCO with significantly decreased visual acuity. Prevention of PCO formation might be a better way to avoid NVG following capsulotomy. Phacoemulsification instead of extracapsular cataract extraction [30]; the use of acrylic intraocular lenses [31]; the removal of any retained lens fragment [32]; posterior capsule polishing to remove any residual debris, leaving the eye as clean as possible; complete removal of viscoelastics [31]; and aggressive control of intraocular inflammation are key steps to avoiding PCO formation.\n\nFrom this case we have learned that capsulotomy may result in NVG in uveitis/diabetes patients, even in seemingly quiescent eyes. Ophthalmologists should keep this possible complication in mind. A careful ocular examination and thorough patient counseling may be essential before Nd:YAG laser capsulotomy in the treatment of uveitis/diabetes patients.\n\nConflict of interest: none.\n==== Refs\n[1] Elgohary MA McCluskey PJ Towler HM Okhravi N Singh RP Obikpo R Outcome of phacoemulsification in patients with uveitis Br J Ophthalmol 2007 91 916 21 17229800 \n[2] Ram J Gupta A Kumar S Kaushik S Gupta N Severia S Phacoemulsification with intraocular lens implantation in patients with uveitis J Cataract Refract Surg 2010 36 1283 8 20656149 \n[3] Chung YM Yeh TS Intraocular lens implantation following extracapsular cataract extraction in uveitis Ophthalmic Surg 1990 21 272 6 2362754 \n[4] Krishna R Meisler DM Lowder CY Estafanous M Foster RE Long-term follow-up of extracapsular cataract extraction and posterior chamber intraocular lens implantation in patients with uveitis Ophthalmology 1998 105 1765 9 9754189 \n[5] Suresh PS Jones NP Phacoemulsification with intraocular lens implantation in patients with uveitis Eye 2001 15 621 8 11702974 \n[6] Estafanous MF Lowder CY Meisler DM Chauhan R Phacoemulsification cataract extraction and posterior chamber lens implantation in patients with uveitis Am J Ophthalmol 2001 131 620 5 11336937 \n[7] Kawaguchi T Mochizuki M Miyata K Miyata N Phacoemulsification cataract extraction and intraocular lens implantation in patients with uveitis J Cataract Refract Surg 2007 33 305 9 17276275 \n[8] Hayashi K Hayashi H Nakao F Hayashi F Correlation between posterior capsule opacification and visual function before and after neodymium: YAG laser posterior capsulotomy Am J Ophthalmol 2003 136 720 6 14516813 \n[9] Buehl W Sacu S Findl O Association between intensity of posterior capsule opacification and visual acuity J Cataract Refract Surg 2005 31 543 7 15811742 \n[10] Richter CU Arzeno G Pappas HR Steinert RF Puliafito C Epstein DL Intraocular pressure elevation following Nd: YAG laser posterior capsulotomy Ophthalmology 1985 92 636 40 3839298 \n[11] Shani L David R Tessler Z Rosen S Schneck M Yassur Y Intraocular pressure after neodymium: YAG laser treatments in the anterior segment J Cataract Refract Surg 1994 20 455 8 7932138 \n[12] Ari S Cingu AK Sahin A Cinar Y Caca I The effects of Nd: YAG laser posterior capsulotomy on macular thickness, intraocular pressure, and visual acuity Ophthalmic Surg Lasers Imaging 2012 43 395 400 22785102 \n[13] Jahn CE Emke M Long-term elevation of intraocular pressure after neodymium: YAG laser posterior capsulotomy Ophthalmologica 1996 210 85 9 9148259 \n[14] Gardner KM Straatsma BR Pettit TH Neodymium: YAG laser posterior cap-sulotomy: the first 100 cases at UCLA Ophthalmic Surg 1985 16 24 8 3838376 \n[15] Kraff MC Sanders DR Jampol LM Lieberman HL Effect of primary capsulotomy with extracapsular surgery on the incidence of pseudophakic cystoid macular edema Am J Ophthalmol 1984 98 166 70 6476044 \n[16] Karahan E Tuncer I Zengin MO The effect of ND: YAG laser posterior capsulotomy size on refraction, intraocular pressure, and macular thickness J Ophthalmol 2014 2014 846385 \n[17] Sheard RM Goodburn SF Comer MB Scott JD Snead MP Posterior vitreous detachment after neodymium: YAG laser posterior capsulotomy J Cataract Refract Surg 2003 29 930 4 12781278 \n[18] Dardenne MU Gerten GJ Kokkas K Kermani O Retrospective study of retinal detachment following neodymium: YAG laser posterior capsulotomy J Cataract Refract Surg 1989 15 676 80 2614712 \n[19] Javitt JC Tielsch JM Canner JK Kolb MM Sommer A Steinberg EP National outcomes of cataract extraction. Increased risk of retinal complications associated with Nd: YAG laser capsulotomy. The Cataract Patient Outcomes Research Team Ophthalmology 1992 99 1487 97 1454313 \n[20] Ranta P Tommila P Kivela T Retinal breaks and detachment after neodymi-um: YAG laser posterior capsulotomy: five-year incidence in a prospective cohort J Cataract Refract Surg 2004 30 58 66 14967269 \n[21] Mastropasqua L Ciancaglini M Carpineto P Lobefalo L Gallenga PE Aqueous misdirection syndrome: a complication of neodymium: YAG posterior capsu-lotomy J Cataract Refract Surg 1994 20 563 5 7996414 \n[22] Arya SK Sonika Kochhar S Kumar S Kang M Sood S Malignant glaucoma as a complication of Nd: YAG laser posterior capsulotomy Ophthalmic Surg Lasers Imaging 2004 35 248 50 15185795 \n[23] Hayreh SS Neovascular glaucoma Prog Retin Eye Res 2007 26 470 85 17690002 \n[24] Poliner LS Christianson DJ Escoffery RF Kolker AE Gordon ME Neovascular glaucoma after intracapsular and extracapsular cataract extraction in diabetic patients Am J Ophthalmol 1985 100 637 43 2414993 \n[25] Weinreb RN Wasserstrom JP Parker W Neovascular glaucoma following neodymium-YAG laser posterior capsulotomy Arch Ophthalmol 1986 104 730 1 2423063 \n[26] Tsopelas N Kokolakis N Droutsas D Theodossiadis G Extracapsular cataract extraction in diabetic eyes. The role of YAG laser capsulotomy Doc Ophthalmol 1995 91 17 24 8861633 \n[27] Aiello LP Avery RL Arrigg PG Keyt BA Jampel HD Shah ST Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders N Engl J Med 1994 331 1480 7 7526212 \n[28] Prasad P Setna PH Dunne JA Accelerated ocular neovascularisation in diabetics following posterior chamber lens implantation Br J Ophthalmol 1990 74 313 4 1693855 \n[29] Macaron NC Cohen C Chen SC Arbiser JL Cutaneous lesions of secondary syphilis are highly angiogenic J Am Acad Dermatol 2003 48 878 81 12789178 \n[30] Pande MV Spalton DJ Kerr-Muir MG Marshall J Postoperative inflammatory response to phacoemulsification and extracapsular cataract surgery: aqueous flare and cells J Cataract Refract Surg 1996 22 770 4 9279670 \n[31] Alio JL Chipont E BenEzra D Fakhry MA International Ocular Inflammation Society, Study Group of Uveitic Cataract Surgery. Comparative performance of intraocular lenses in eyes with cataract and uveitis J Cataract Refract Surg 2002 28 2096 108 12498843 \n[32] Teo L Chee SP Retained lens fragment in the anterior segment as a cause of recurrent anterioruveitis Int Ophthalmol 2010 30 89 91 19020810\n\n",
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"issue": "28(2)",
"journal": "Ci ji yi xue za zhi = Tzu-chi medical journal",
"keywords": "Diabetes; Nd:YAG laser capsulotomy; Neovascular glaucoma; Syphilitic uveitis",
"medline_ta": "Ci Ji Yi Xue Za Zhi",
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"literaturereference": "HONG_ZIN LIN AND YUAN_CHIEH LEE. NEOVASCULAR GLAUCOMA FOLLOWING ND: YAG LASER CAPSULOTOMY IN A PATIENT WITH DIABETES AND SYPHILITIC UVEITIS. TZU CHI MEDICAL JOURNAL. 2016;28:76 TO 78",
"literaturereference_normalized": "neovascular glaucoma following nd yag laser capsulotomy in a patient with diabetes and syphilitic uveitis",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20160729",
"receivedate": "20160729",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12608519,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
}
] |
{
"abstract": "Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis.\n\n\n\nPlasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients.\n\n\n\nAt peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points.\n\n\n\nThe mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.",
"affiliations": "Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.;Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.;MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.;Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.;Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.;Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.;MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.;Department of Medical Toxicology, Banner -University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.",
"authors": "Weemhoff|James L|JL|;Woolbright|Benjamin L|BL|;Jenkins|Rosalind E|RE|;McGill|Mitchell R|MR|;Sharpe|Matthew R|MR|;Olson|Jody C|JC|;Antoine|Daniel J|DJ|;Curry|Steven C|SC|;Jaeschke|Hartmut|H|",
"chemical_list": "D015415:Biomarkers; D004272:DNA, Mitochondrial; D024243:HMGB1 Protein; D053538:Keratin-18; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D000410:Alanine Transaminase",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.13202",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "37(3)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "Hypoxic hepatitis; acetaminophen; apoptosis; biomarkers; ischaemic hepatitis; miRNA-122; necrosis",
"medline_ta": "Liver Int",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase; D017209:Apoptosis; D015415:Biomarkers; D053938:DNA Fragmentation; D004272:DNA, Mitochondrial; D005260:Female; D024243:HMGB1 Protein; D006505:Hepatitis; D006801:Humans; D000860:Hypoxia; D007511:Ischemia; D053538:Keratin-18; D016014:Linear Models; D008099:Liver; D008297:Male; D035683:MicroRNAs; D008875:Middle Aged; D008928:Mitochondria; D009336:Necrosis; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "377-384",
"pmc": null,
"pmid": "27429052",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "14532127;23403733;25092309;20361374;24991092;25636263;1637381;2069235;24440789;16313996;16896059;3099216;12488232;19439490;24012766;12657975;21948394;23571099;12106817;25046819;22266604;25039534;21745276;9435481;15897805;22229890;26159260;19246379;9309681;24458046;22378043;22089187;22045675;22334567;9531309;14663289",
"title": "Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis.",
"title_normalized": "plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis"
} | [
{
"companynumb": "US-JNJFOC-20170308959",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "019872",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETAMINOPHEN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "019872",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETAMINOPHEN."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WEEMHOFF JL, WOOLBRIGHT BL, JENKINS RE, MCGILL MR, SHARPE MR, OLSON JC, ET AL. PLASMA BIOMARKERS TO STUDY MECHANISMS OF LIVER INJURY IN PATIENTS WITH HYPOXIC HEPATITIS. LIVER INTERNATIONAL 2017;37:377?384.",
"literaturereference_normalized": "plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170320",
"receivedate": "20170320",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13349890,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170429"
}
] |
{
"abstract": "The factors associated with sustained virologic response (SVR) in chronic hepatitis C (CH-C) genotype 1 patients treated with simeprevir (SMV), pegylated interferon (Peg-IFN) plus ribavirin (RBV) triple therapy have not been fully investigated. Two hundred and twenty-nine treatment-naïve CH-C patients treated with SMV triple therapy were enrolled in this study. The overall SVR rate was 87% in per-protocol analysis. In multivariate analysis, the interleukin (IL) 28B genotype (rs8099917, TT vs. non-TT, odds ratio [OR]: 0.044, P = 0.001) and RBV dose (< 10/10-12/ ≥ 12 mg/kg/day, OR: 4.513, P = 0.041) were significant factors associated with SVR. In patients with the IL28B non-TT genotype, RBV dose affected SVR dose-dependently in stratified analysis of RBV dose (P = 0.015); it was 44% (8/18) for patients administered <10 mg/kg/day of RBV, 78% (14/18) for those administered 10-12 mg/kg/day of RBV, and 100% (3/3) for those administered ≥12 mg/kg/day of RBV, whereas in patients with the IL28B TT genotype, a significant correlation between SVR and RBV dose was not observed (P = 0.229). Regarding RBV dose reduction of less than 10 mg/kg/day, the inosine triphosphate pyrophosphatase (ITPA) genotype (rs1127354, CC vs. non-CC, OR: 0.239, P = 0.003) and age (by 1 y.o., OR: 1.084, P = 0.002) were significant independent factors. RBV dosage affected SVR dose-dependently in patients with the IL28B non-TT genotype treated with SMV triple therapy. Special attention to anemia progression and RBV dosage should be paid to aged patients with the ITPA CC genotype. J. Med. Virol. 88:1776-1784, 2016. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Osaka Rosai Hospital, Sakai, Osaka, Japan.;Osaka Police Hospital, Osaka, Osaka, Japan.;NTT West Osaka Hospital, Osaka, Osaka, Japan.;Kansai Rousai Hospital, Amagasaki, Hyogo, Japan.;National Hospital Organization, Osaka National Hospital, Osaka, Osaka, Japan.;Japan Community Health Care Organization Osaka Hospital, Osaka, Osaka, Japan.;Kaizuka City Hospital, Kaizuka, Osaka, Japan.;Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.;Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka, Japan.;Minoh City Hospital, Minoh, Osaka, Japan.;Ikeda Municipal Hospital, Ikeda, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Kansai Rousai Hospital, Amagasaki, Hyogo, Japan.;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.",
"authors": "Tahata|Yuki|Y|;Hiramatsu|Naoki|N|;Oze|Tsugiko|T|;Urabe|Ayako|A|;Morishita|Naoki|N|;Yamada|Ryoko|R|;Yakushijin|Takayuki|T|;Hosui|Atsushi|A|;Oshita|Masahide|M|;Kaneko|Akira|A|;Hagiwara|Hideki|H|;Mita|Eiji|E|;Ito|Toshifumi|T|;Yamada|Yukinori|Y|;Inada|Masami|M|;Katayama|Kazuhiro|K|;Tamura|Shinji|S|;Imai|Yasuharu|Y|;Hikita|Hayato|H|;Sakamori|Ryotaro|R|;Yoshida|Yuichi|Y|;Tatsumi|Tomohide|T|;Hayashi|Norio|N|;Takehara|Tetsuo|T|",
"chemical_list": "D000998:Antiviral Agents; C471044:IFNL3 protein, human; D016898:Interferon-alpha; D007378:Interleukins; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D007372:Interferons; D000069616:Simeprevir; D011755:Pyrophosphatases; C511829:ITPA protein, human; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
"doi": "10.1002/jmv.24528",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-6615",
"issue": "88(10)",
"journal": "Journal of medical virology",
"keywords": "chronic hepatitis C; interleukin 28B; ribavirin dose; simeprevir; sustained virologic response",
"medline_ta": "J Med Virol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; D000069616:Simeprevir; D000072230:Sustained Virologic Response; D016896:Treatment Outcome",
"nlm_unique_id": "7705876",
"other_id": null,
"pages": "1776-84",
"pmc": null,
"pmid": "26991414",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of ribavirin dosage in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin combination therapy.",
"title_normalized": "impact of ribavirin dosage in chronic hepatitis c patients treated with simeprevir pegylated interferon plus ribavirin combination therapy"
} | [
{
"companynumb": "JP-JNJFOC-20160819944",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2B"
},
"drugadditional": null,
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "60 UG TO 150 UG BASED ON BODY WEIGHT FOR 24 WEEKS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PEGINTRON"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "REDUCED AS PER THE BODY WEIGHT, AGE AND ITPA GENOTYPE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "RIBAVIRIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2A"
},
"drugadditional": null,
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "FOR 24 WEEKS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "180",
"drugstructuredosageunit": "004",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PEGASYS"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "600 TO 1000 MG DEPENDING ON BODY WEIGHT",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "RIBAVIRIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "205123",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CAPSULE",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "100",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SOVRIAD"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Psychiatric symptom",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Remission not achieved",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Liver injury",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Retinopathy",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adverse drug reaction",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood bilirubin increased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAHATA Y, HIRAMATSU N, OZE T, URABE A, MORISHITA N, YAMADA R, ET AL. IMPACT OF RIBAVIRIN DOSAGE IN CHRONIC HEPATITIS C PATIENTS TREATED WITH SIMEPREVIR, PEGYLATED INTERFERON PLUS RIBAVIRIN COMBINATION THERAPY. JOURNAL OF MEDICAL VIROLOGY 01-OCT-2016;88/10:1776-1784.",
"literaturereference_normalized": "impact of ribavirin dosage in chronic hepatitis c patients treated with simeprevir pegylated interferon plus ribavirin combination therapy",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20161212",
"receivedate": "20160826",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12690315,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "OBJECTIVE\nThe purpose of our study was to provide evidence on the treatment choices, reasons, and results of switching between biologic agents in treating patients with psoriasis.\n\n\nMETHODS\nWe conducted a retrospective database search of six tertiary referral centers for pso-riasis patients between January 2007 and May 2019. We analyzed patient and treatment characteristics of all patients in the registry.\n\n\nRESULTS\nWe enrolled 427 psoriatic patients treated with biologics, and 145 (34%) required a switch to another biologic. The reasons for discontinuing the first biologic agent were inefficacy (n = 106, 62.4%), adverse events (n = 28, 16.5%), and others (n = 36, 21.2%). At week 12, there was a 67.7% reduction in the Psoriasis Area and Severity Index (PASI) score of patients treated with their first biologic, and 51.4% reduction for the second. A drug survival analysis showed no statistically significant difference between the drug survival of first-line biologic agents, but ustekinumab had the highest survival rate among second-line biologics (log-rank p = 0.010). Multivariate analyses for overall drug discontinuation showed that the occurrence of psoriatic arthritis (OR: 1.883, 95% CI: 1.274-2.782, p = 0.001), nail involvement (OR: 2.334, 95% CI: 1.534-3.552, p < 0.001), and use of concomitant treatment (OR: 2.303, 95% CI: 1.403 -3.780, p = 0.001) are predictors for discontinuation.\n\n\nCONCLUSIONS\nDiscontinuation of treatment was most commonly due to inefficacy. Patients who switched to a different biologic agent showed a similar improvement in PASI scores compared to biologic-naive patients. Switching to a second biologic therapy due to inefficacy or adverse events caused by the first one may improve psoriasis.",
"affiliations": "Department of Dermatology, University of Health Sciences, Şişli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey, [email protected].;Department of Dermatology, University of Health Sciences, Şişli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology, University of Health Sciences, Okmeydanı Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology, University of Health Sciences, Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology, University of Health Sciences, Haseki Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology, University of Health Sciences, Haseki Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey.;Istanbul Medeniyet University, Göztepe Training and Research Hospital, Istanbul, Turkey.",
"authors": "Özkur|Ezgi|E|;Kıvanç Altunay|İlknur|İ|;Oğuz Topal|İlteriş|İ|;Aytekin|Sema|S|;Topaloğlu Demir|Filiz|F|;Özkök Akbulut|Tuğba|T|;Kara Polat|Asude|A|;Karadağ|Ayşe Serap|AS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D003879:Dermatologic Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504839",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "237(1)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": "Adalimumab; Biologic; Etanercept; Infliximab; Psoriasis; Secukinumab; Ustekinumab",
"medline_ta": "Dermatology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D002648:Child; D003879:Dermatologic Agents; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "22-30",
"pmc": null,
"pmid": "31865339",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Switching Biologics in the Treatment of Psoriasis: A Multicenter Experience.",
"title_normalized": "switching biologics in the treatment of psoriasis a multicenter experience"
} | [
{
"companynumb": "TR-AMGEN-TURSP2020000186",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "761024",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "UNKNOWN FORMULATION",
"drugdosagetext": "UNK",
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"drugindication": "PSORIASIS",
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"medicinalproduct": "ADALIMUMAB"
}
],
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"reaction": [
{
"reactionmeddrapt": "Psoriatic arthropathy",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adverse event",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "ERDAL OZKUR E.? ALTUNAY I.K.? TOPAL I.O. ET AL.. SWITCHING BIOLOGICS IN THE TREATMENT OF PSORIASIS: A MULTICENTER EXPERIENCE. DERMATOLOGY. 2019?1-9",
"literaturereference_normalized": "switching biologics in the treatment of psoriasis a multicenter experience",
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"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20200116",
"receivedate": "20200107",
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},
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"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "We report the biological and clinical impacts possibly associated with HHV-6 reactivation in autologous hematopoietic stem cell transplant (AHSCT) recipients after intensive chemotherapy regimen for lymphoma.\n\n\n\nWe retrospectively reviewed clinical, biological, radiological, treatment and outcomes of patients with positive HHV-6 DNA in whole blood following autologous hematopoietic stem cell transplantation.\n\n\n\nBlood HHV-6 reactivation was reported in 27 (8.5%) patients among 316 AHSCT recipients after high dose therapy for lymphoma. Thirteen (4.1%) patients were symptomatic with fever (100%), diarrhea (61.5%), skin rash (46.1%), and pneumonia (23.1%). Antiviral treatment was administered in 9 (69%) patients and outcome was favorable in all cases.\n\n\n\nOur study suggests a possible pathogenic role of HHV-6 in AHSCT recipients and suggests an impact of antiviral treatments on viral replication and clinical signs resolution.",
"affiliations": "Department of Infectious Diseases, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.;Department of Hemato-Oncology, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France.;Microbiology Laboratory, Inserm U941, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris Diderot University, Paris, France.;Department of Hemato-Oncology, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France.;Microbiology Laboratory, Inserm U941, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris Diderot University, Paris, France.;Department of Infectious Diseases, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. Electronic address: [email protected].",
"authors": "Colombier|M A|MA|;Amorim|S|S|;Salmona|M|M|;Thieblemont|C|C|;Legoff|J|J|;Lafaurie|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jinf.2017.05.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4453",
"issue": "75(2)",
"journal": "The Journal of infection",
"keywords": "Antiviral treatment; Autologous hematopoietic stem cell transplantation; Fever; HHV-6 reactivation; Lymphoma",
"medline_ta": "J Infect",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D005334:Fever; D018380:Hematopoietic Stem Cell Transplantation; D015654:Herpesvirus 6, Human; D006801:Humans; D016867:Immunocompromised Host; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D019349:Roseolovirus Infections; D066027:Transplant Recipients; D014775:Virus Activation",
"nlm_unique_id": "7908424",
"other_id": null,
"pages": "155-159",
"pmc": null,
"pmid": "28551368",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "HHV-6 reactivation as a cause of fever in autologous hematopoietic stem cell transplant recipients.",
"title_normalized": "hhv 6 reactivation as a cause of fever in autologous hematopoietic stem cell transplant recipients"
} | [
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{
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},
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],
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}
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},
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},
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},
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"medicinalproduct": "MELPHALAN."
}
],
"patientagegroup": null,
"patientonsetage": "66",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Mantle cell lymphoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Human herpesvirus 6 infection",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lymphoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "REPORTER KNOWN TO LICENSEE, COLOMBIER MA, AMORIM S, SALMONA M, THIEBLEMONT C, LEGOFF J, LAFAURIE M. HHV-6 REACTIVATION AS A CAUSE OF FEVER IN AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS. JOURNAL OF INFECTION 2017?75:155-159.",
"literaturereference_normalized": "hhv 6 reactivation as a cause of fever in autologous hematopoietic stem cell transplant recipients",
"qualification": "3",
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] |
{
"abstract": "Small cell lung cancer with interstitial lung disease (ILD-SCLC) is difficult to treat because of the risk of fatal pneumonitis. Our study aims to evaluate the validity of topotecan (TOP) as chemotherapy for patients with relapsed ILD-SCLC. Overall survival was compared between TOP and other drugs as second-line treatments for ILD-SCLC patients. Forty-seven patients began chemotherapy and second-line treatment was administered in 48.5% of relapsed cases. The response rate of TOP for second-line therapy was 16.7%. Hematologic toxicities were grade 4 anemia, grade 3 neutropenia and grade 3 thrombocytopenia. Mild pulmonary toxicity was observed in 1 case. Patients receiving TOP as second-line treatment showed no significant difference in survival when compared to patients who underwent other regimens (median survival time 179 vs. 76 days; p =0.76). TOP is a well tolerated drug and is a viable candidate for second-line treatment of ILD-SCLC patients.",
"affiliations": "Department of Thoracic Malignancy, Osaka Prefectural Medical Center For Respiratory And Allergic Diseases, Osaka, Japan. [email protected]",
"authors": "Suzuki|H|H|;Hirashima|T|T|;Kobayashi|M|M|;Sasada|S|S|;Okamoto|N|N|;Uehara|N|N|;Matsuura|Y|Y|;Tamiya|M|M|;Morishita|N|N|;Higashiguchi|M|M|;Tsumori|T|T|;Kawase|I|I|",
"chemical_list": "D000970:Antineoplastic Agents; D019772:Topotecan",
"country": "England",
"delete": false,
"doi": "10.1179/joc.2011.23.6.367",
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"issn_linking": "1120-009X",
"issue": "23(6)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": null,
"medline_ta": "J Chemother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma; D019772:Topotecan",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "367-70",
"pmc": null,
"pmid": "22233823",
"pubdate": "2011-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of topotecan as second-line chemotherapy for small cell lung cancer patients with interstitial lung disease.",
"title_normalized": "effect of topotecan as second line chemotherapy for small cell lung cancer patients with interstitial lung disease"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP07299",
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}
],
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"literaturereference": "SUZUKI H., HIRASHIMA T., KOBAYASHI M., SASADA S., OKAMOTO N., UEHARA N. ET AL.. EFFECT OF TOPOTECAN AS SECOND-LINE CHEMOTHERAPY FOR SMALL CELL LUNG CANCER PATIENTS WITH INTERSTITIAL LUNG DISEASE. J CHEMOTHER. 2011;23(6):367-370",
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},
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{
"abstract": "Neonatal withdrawal can be difficult to treat in infants with co-exposure to opiates and gabapentin. Because maternal self-report can underestimate exposures, we evaluated the effect of universal toxicology screening for gabapentin. Identification of co-exposure to opiates and gabapentin increased after implementation of toxicology screening, with implications for improved neonatal care.",
"affiliations": "Department of Pediatrics, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV.;NICU, Hoops Family Children's Hospital at Cabell Huntington Hospital, Huntington, WV.;Department of Neurology, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV.;Department of Psychology, Marshall University, Huntington, WV.;National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.;National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.;Marshall University Center of Excellence for Recovery, Huntington, WV. Electronic address: [email protected].",
"authors": "Loudin|Sean|S|;Haas|Jessica|J|;Payne|Mary|M|;Linz|Marianna Footo|MF|;Meaney-Delman|Dana|D|;Honein|Margaret A|MA|;Saunders|Amy|A|",
"chemical_list": "D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D053610:Opiate Alkaloids; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2019.09.029",
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"issn_linking": "0022-3476",
"issue": "217()",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005500:Follow-Up Studies; D000077206:Gabapentin; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D009357:Neonatal Abstinence Syndrome; D053610:Opiate Alkaloids; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D014903:West Virginia",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "196-198",
"pmc": null,
"pmid": "31668481",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "31216102;30655335;27889067;28768628;28557958;30377951;27265421",
"title": "Identifying Co-Exposure to Opiates and Gabapentin During Pregnancy.",
"title_normalized": "identifying co exposure to opiates and gabapentin during pregnancy"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP009591",
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},
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"medicinalproduct": "GABAPENTIN."
}
],
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "LOUDIN S, HAAS J, PAYNE M, LINZ MF, MEANEY-DELMAN D, HONEIN MA, ET AL.. IDENTIFYING CO-EXPOSURE TO OPIATES AND GABAPENTIN DURING PREGNANCY.. JOURNAL OF PEDIATRICS. 2020?217:196-198",
"literaturereference_normalized": "identifying co exposure to opiates and gabapentin during pregnancy",
"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20201110",
"receivedate": "20201110",
"receiver": {
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},
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},
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"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
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}
] |
{
"abstract": "There is a global outbreak of infections due to Mycobacterium chimaera associated with cardiac surgery. The most serious infections involve prosthetic material implantation, and all have followed surgical procedures involving cardiopulmonary bypass. We describe a cluster of four cases following cardiac surgery at a tertiary referral centre in Sydney, Australia. We report novel clinical findings, including haemolysis and kidney rupture possibly related to immune reconstitution inflammatory syndrome. The positive effect of corticosteroids on haemodynamic function in two cases and the failure of currently recommended antimicrobial therapy to sterilise prosthetic valve material in the absence of surgery despite months of treatment are also critically examined. Positron emission tomography was positive in two cases despite normal transoesophageal echocardiograms. The proportion of cases with M. chimaera infection after aortic valve replacement (4/890, 0.45%; 95% confidence interval 0.18-1.15%) was significantly higher than after all other cardiothoracic surgical procedures (0/2433, 0%; 95% confidence interval 0-0.16%).",
"affiliations": "Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Sydney, NSW, Australia.;Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Kogarah, New South Wales, Australia.;Centre for Infectious Diseases and Microbiology, Public Health, Westmead Hospital, Sydney, New South Wales, Australia.;Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Sydney, NSW, Australia.;Department of Cardiothoracic Surgery, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Cardiothoracic Surgery, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Kogarah, New South Wales, Australia.;Department of Microbiology and Infectious Diseases, Liverpool Hospital, Liverpool, New South Wales, Australia.;Department of Microbiology and Infectious Diseases, Liverpool Hospital, Liverpool, New South Wales, Australia.;Clinical Governance Unit, South Eastern Sydney Local Health District, The Sutherland Hospital, Caringbah, New South Wales, Australia.;Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Sydney, NSW, Australia.;Centre for Infectious Diseases and Microbiology, Public Health, Westmead Hospital, Sydney, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Kogarah, New South Wales, Australia.;Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia.",
"authors": "Overton|Kristen|K|https://orcid.org/0000-0001-6726-5722;Mennon|Vidthyia|V|;Mothobi|Nomvuyo|N|;Neild|Blake|B|;Martinez|Elena|E|;Masters|Jeffrey|J|;Grant|Peter|P|;Akhunji|Zakir|Z|;Su|Wei-Yuen|WY|;Torda|Adrienne|A|;Whyte|Claudia M|CM|;Lloyd|Andrew|A|;Weatherall|Chris|C|;Hofmeyr|Ann|A|;Foo|Hong|H|;Brookes|Kim|K|;Marriott|Debbie|D|;Sintchenko|Vitali|V|;Clezy|Kate|K|;Konecny|Pam|P|;Post|Jeffrey J|JJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.14093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "48(12)",
"journal": "Internal medicine journal",
"keywords": "\nMycobacterium chimaera; cardiac surgery; genome sequencing; heater-cooler unit; outbreak",
"medline_ta": "Intern Med J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001021:Aortic Valve; D001315:Australia; D005260:Female; D006349:Heart Valve Diseases; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009161:Mycobacterium; D009165:Mycobacterium Infections, Nontuberculous; D049268:Positron-Emission Tomography; D011183:Postoperative Complications; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "1514-1520",
"pmc": null,
"pmid": "30517986",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cluster of invasive Mycobacteria chimaera infections following cardiac surgery demonstrating novel clinical features and risks of aortic valve replacement.",
"title_normalized": "cluster of invasive mycobacteria chimaera infections following cardiac surgery demonstrating novel clinical features and risks of aortic valve replacement"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-195805",
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},
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{
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},
{
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"medicinalproduct": "RIFABUTIN."
}
],
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"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mitral valve disease",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haemolysis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cardiac failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mitral valve incompetence",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "OVERTON K, MENNON V, MOTHOBI N, NEILD B, MARTINEZ E, MASTERS J, ET AL. CLUSTER OF INVASIVE MYCOBACTERIA CHIMAERA INFECTIONS FOLLOWING CARDIAC SURGERY DEMONSTRATING NOVEL CLINICAL FEATURES AND RISKS OF AORTIC VALVE REPLACEMENT. INTERN MED J. 2018?APR? 48(12):1514-1520",
"literaturereference_normalized": "cluster of invasive mycobacteria chimaera infections following cardiac surgery demonstrating novel clinical features and risks of aortic valve replacement",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
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"patient": {
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"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
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{
"abstract": "BACKGROUND\nHepatitis B virus (HBV) reactivation is commonly observed in HBsAg-positive hematologic patients undergoing immunosuppressive chemotherapy. Recent guidelines recommend antiviral prophylaxis to be continued for up to 12 months after the discontinuation of the anticancer regimen.\n\n\nMETHODS\nWe report a case of a patient who underwent antiviral prophylaxis for 26 months after the discontinuation of a rituximab-containing chemotherapy regimen for a lymphoma and was admitted in the infectious diseases department with a 3-day history of jaundice, itching, and dark urine. After excluding other possible causes of acute liver damage, HBV reactivation was suspected. HBV-DNA was 4497000 IU/mL. Following reintroduction of entecavir, we observed a steady decline of ALT, AST, bilirubin and HBV-DNA serum levels, with a rapid resolution of acute hepatitis and an improvement in clinical conditions; one year after the event of HBV reactivation and beginning of antiviral therapy, the patient was virologically suppressed.\n\n\nCONCLUSIONS\nOur study demonstrates that the risk of HBV reactivation in HBsAg-positive patients with undetectable HBV-DNA can occur even after three years from the last administration of rituximab and several months after the withdrawal of prophylactic antiviral therapy in patients with hematological malignancies. This implies that a close monitoring of HBV-related markers including HBV-DNA must continue after the withdrawal of prophylactic NA therapy.",
"affiliations": "Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy. [email protected].;Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Agostino Gemelli Hospital, Catholic University, Rome, Italy.;Institute of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy.;Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Agostino Gemelli Hospital, Catholic University, Rome, Italy.",
"authors": "Ciccullo|Arturo|A|http://orcid.org/0000-0001-5941-883X;Ponziani|F R|FR|;Maiolo|E|E|;Pallavicini|F|F|;Pompili|M|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-018-1242-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "47(2)",
"journal": "Infection",
"keywords": "Entecavir; Hepatitis B; Lymphoma; Rituximab",
"medline_ta": "Infection",
"mesh_terms": "D019072:Antibiotic Prophylaxis; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D004359:Drug Therapy, Combination; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D007558:Italy; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D014775:Virus Activation",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "313-316",
"pmc": null,
"pmid": "30368733",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17338776;19075267;1983820;20597091;21054683;21520001;23918413;25199680;25447850;25514302;27088278;27291888;28427875;28951776",
"title": "Late reactivation of hepatitis B virus after rituximab-containing chemotherapy for mantle cell lymphoma: a case report.",
"title_normalized": "late reactivation of hepatitis b virus after rituximab containing chemotherapy for mantle cell lymphoma a case report"
} | [
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},
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"medicinalproduct": "ENTECAVIR."
}
],
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"reaction": [
{
"reactionmeddrapt": "Chromaturia",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Jaundice",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pruritus",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hepatomegaly",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatitis B reactivation",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201704"
}
},
"primarysource": {
"literaturereference": "CICCULLO A, PONZIANI FR, MAIOLO E, PALLAVICINI F, POMPILI M.. LATE REACTIVATION OF HEPATITIS B VIRUS AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY FOR MANTLE CELL LYMPHOMA: A CASE REPORT. INFECTION. INFECTION. 2019?47(2):313-6",
"literaturereference_normalized": "late reactivation of hepatitis b virus after rituximab containing chemotherapy for mantle cell lymphoma a case report",
"qualification": "3",
"reportercountry": "IT"
},
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}
] |
{
"abstract": "An open-label, pilot study was conducted to evaluate deferasirox/deferiprone combination chelation therapy in adult patients with transfusion-dependent thalassemia and severe iron overload. Enrollment proved difficult. Nine patients (median age, 27.4 y; ferritin, 4965 ng/mL; liver iron concentration, 28.5 mg/g dry weight; cardiac T2*, 13.3 ms) received treatment. Two were withdrawn for treatment-related adverse effects. Arthralgia (4 patients) and gastrointestinal symptoms (5 patients) were common; no episodes of neutropenia/agranulocytosis occurred. Adherence difficulties were common. Of 6 patients with 12 to 18 months follow-up, 3 showed improvement in cardiac T2* and 2 in liver iron. Combination oral chelation may be effective but adverse effects and adherence challenges may limit efficacy.",
"affiliations": "Division of Hematology.;Division of Hematology/Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago.;Division of Cardiology, Children's Hospital of Philadelphia.;Division of Hematology/Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago.;Division of Hematology.;Division of Hematology.",
"authors": "Hammond|John|J|;Thompson|Alexis A|AA|;Fogel|Mark A|MA|;Hammond|Katherine|K|;Kokroko|Jolene|J|;Kwiatkowski|Janet L|JL|",
"chemical_list": "D000077543:Deferiprone; D000077588:Deferasirox",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "41(1)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000328:Adult; D001803:Blood Transfusion; D000077588:Deferasirox; D000077543:Deferiprone; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019190:Iron Overload; D008297:Male; D010865:Pilot Projects; D013789:Thalassemia",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e47-e50",
"pmc": null,
"pmid": "30080754",
"pubdate": "2019-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Combination Oral Chelation in Adult Patients With Transfusion-dependent Thalassemia and High Iron Burden.",
"title_normalized": "combination oral chelation in adult patients with transfusion dependent thalassemia and high iron burden"
} | [
{
"companynumb": "US-APOPHARMA USA, INC.-2018AP019236",
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},
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"drugindication": "THALASSAEMIA",
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}
],
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}
],
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},
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"literaturereference": "HAMMOND J, THOMPSON AA, FOGEL MA, HAMMOND K, KOKROKO J, KWIATKOWSKI JL. COMBINATION ORAL CHELATION IN ADULT PATIENTS WITH TRANSFUSION?DEPENDENT THALASSEMIA AND HIGH IRON BURDEN. DOI: 10.1097/MPH.0000000000001269.. J PEDIATR HEMATOL ONCOL. 2018?EPUB",
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},
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},
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}
],
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"reaction": [
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"reactionmeddrapt": "Arthralgia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HAMMOND J, THOMPSON AA, FOGEL MA, HAMMOND K, KOKROKO J, KWIATKOWSKI JL. COMBINATION ORAL CHELATION IN ADULT PATIENTS WITH TRANSFUSION?DEPENDENT THALASSEMIA AND HIGH IRON BURDEN. DOI: 10.1097/MPH.0000000000001269. J PEDIATR HEMATOL ONCOL. 2018?EPUB",
"literaturereference_normalized": "combination oral chelation in adult patients with transfusion dependent thalassemia and high iron burden",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180828",
"receivedate": "20180828",
"receiver": {
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"receivertype": "6"
},
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"sender": {
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"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "The purpose was to compare the effects of 3 different dose combinations of bupivacaine and sufentanil on the onset of analgesia and the occurrence of side effects.\n\n\n\nOne hundred sixty-nine pregnant women were randomly assigned to 3 groups: the B1S5 group received 0.1% bupivacaine+5 μg sufentanil in 15 mL; the B125S5 group received 0.125% bupivacaine+5 μg sufentanil in 15 mL; and the B1S10 group received 0.1% bupivacaine+10 μg sufentanil in 15 mL. The primary outcome was the analgesic onset time, and the secondary outcomes were mode of delivery, patient satisfaction, maternal and neonatal side effects (pruritus, hypotension, sedation, motor block, decreased fetal heart rate, fever, and interference with breastfeeding).\n\n\n\nThe median (inter-quartile range) time to achieve effective analgesia was significantly faster in the B125S5 group than in the B1S5 group (10 [11-14 {4-30}] min vs. 15 [17-20 {5-30}] min, P<0.001). There was no significant difference in the analgesia onset time between the B1S10 and B125S5 groups (10 [11-14 {4-30}] min vs. 12 [13-15 {3-30}] min, P=0.202). Pruritus, hypotension, motor block, maternal satisfaction, delivery mode, decreased fetal heart rate, total bupivacaine dose and breastfeeding scores were not significantly different among the 3 groups except the sufentanil dosage and incidence of mild drowsiness and fever (the B1S10 group had significantly higher fever than the other groups).\n\n\n\nThe B125S5 combination may be superior to the B1S5 and B1S10 combinations as an initial dose for epidural analgesia to achieve rapid effective analgesia with minimal side effects.",
"affiliations": "Department of Anaesthesia, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.;Department of Anaesthesia, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.;Department of Anaesthesia, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.;Department of Anaesthesia, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.;Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN.",
"authors": "Wang|Tingting|T|;Lu|Yaojun|Y|;Zhou|Peiwen|P|;Huang|Shaoqiang|S|;Yu|Xinhua|X|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D017409:Sufentanil; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1097/AJP.0000000000000837",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-8047",
"issue": "36(8)",
"journal": "The Clinical journal of pain",
"keywords": null,
"medline_ta": "Clin J Pain",
"mesh_terms": "D015360:Analgesia, Epidural; D016362:Analgesia, Obstetrical; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D017409:Sufentanil",
"nlm_unique_id": "8507389",
"other_id": null,
"pages": "612-617",
"pmc": null,
"pmid": "32349005",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A Randomized Controlled Comparison of Epidural Analgesia Onset Time and Adverse Reactions During Labor With Different Dose Combinations of Bupivacaine and Sufentanil.",
"title_normalized": "a randomized controlled comparison of epidural analgesia onset time and adverse reactions during labor with different dose combinations of bupivacaine and sufentanil"
} | [
{
"companynumb": "CN-ACELRX PHARMACEUTICALS, INC-ACEL20210728",
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"activesubstancename": "BUPIVACAINE"
},
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"drugdosageform": "UNKNOWN",
"drugdosagetext": "0.1% BUPIVACAINE PLUS 10 MCG SUFENTANIL AS A 5 ML EPL BOLUS, AND EPL BOLUS INJECTION OF 10 ML OF 0.1",
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"medicinalproduct": "BUPIVACAINE."
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{
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},
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}
],
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},
{
"reactionmeddrapt": "Bradycardia foetal",
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}
],
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},
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},
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"drugdosageform": "UNKNOWN",
"drugdosagetext": "0.1% BUPIVACAINE PLUS 10 MCG SUFENTANIL AS A 5 ML EPL BOLUS, AND EPL BOLUS INJECTION OF 10 ML OF 0.1",
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"medicinalproduct": "SUFENTANIL"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "0.1% BUPIVACAINE PLUS 10 MCG SUFENTANIL AS A 5 ML EPL BOLUS, AND EPL BOLUS INJECTION OF 10 ML OF 0.1",
"drugenddate": null,
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"drugindication": "ANALGESIC THERAPY",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BUPIVACAINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Bradycardia foetal",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "A RANDOMIZED CONTROLLED COMPARISON OF EPIDURAL ANALGESIA ONSET TIME AND ADVERSE REACTIONS DURING LABOR WITH DIFFERENT DOSE COMBINATIONS OF BUPIVACAINE AND SUFENTANIL. CLIN J PAIN. 2020 AUG?36(8):612?617. DOI:10.1097/AJP.0000000000000837",
"literaturereference_normalized": "a randomized controlled comparison of epidural analgesia onset time and adverse reactions during labor with different dose combinations of bupivacaine and sufentanil",
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},
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},
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},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
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{
"abstract": "A 37-year-old male patient presented with metamorphopsia and unilateral visual impairment with the presence of hundreds of bilateral avascular retinal pigment epithelial detachments (PEDs). The patient suffered from allergic bronchial asthma which was treated with inhaled corticosteroids. Cessation of corticosteroid treatment resulted in flattening of larger PEDs and subsequent transition to atrophic areas over time while smaller PEDs persisted and spread peripherally over an observation period of 14½ years.",
"affiliations": "AugenAllianz-Zentren Heidenheim, Bergstr. 7-9, 89518, Heidenheim, Deutschland. [email protected].;Universitäts-Augenklinik Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Deutschland.;Universitäts-Augenklinik Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Deutschland.;Universitäts-Augenklinik Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Deutschland.",
"authors": "Bindewald-Wittich|A|A|;Milojcic|C|C|;Pfau|M|M|;Holz|F G|FG|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00347-018-0848-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-293X",
"issue": "116(9)",
"journal": "Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft",
"keywords": "Allergic bronchial asthma; Central serous chorioretinopathy; Choroidal hyperpermeability; Metamorphopsia; Multimodal retinal imaging",
"medline_ta": "Ophthalmologe",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D005451:Fluorescein Angiography; D006801:Humans; D008297:Male; D012163:Retinal Detachment; D055213:Retinal Pigment Epithelium; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "9206148",
"other_id": null,
"pages": "887-892",
"pmc": null,
"pmid": "30627764",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10482095;12431693;14986014;15187679;15350327;15805907;21386917;26026923;28673727;7777273;9331207",
"title": "Bilateral multifocal pigment epithelial detachments associated with inhaled corticosteroids.",
"title_normalized": "bilateral multifocal pigment epithelial detachments associated with inhaled corticosteroids"
} | [
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"reactionmeddraversionpt": "22.1",
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"literaturereference": "BINDEWALD-WITTICH A, MILOJCIC C, PFAU M, HOLZ FG.. BILATERAL MULTIFOCAL PIGMENT EPITHELIAL DETACHMENTS ASSOCIATED WITH INHALED CORTICOSTEROIDS.. OPHTHALMOLOGE. 2019?116(9):887-92",
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{
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"literaturereference": "BINDEWALD-WITTICH A, MILOJCIC C, PFAU M, HOLZ FG. [BILATERAL MULTIFOCAL PIGMENT EPITHELIAL DETACHMENTS ASSOCIATED WITH INHALED CORTICOSTEROIDS]. OPHTHALMOLOGE 2019?116(9):887-892.",
"literaturereference_normalized": "bilateral multifocal pigment epithelial detachments associated with inhaled corticosteroids",
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},
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}
] |
{
"abstract": "Infiltration of the liver by hematologic malignancies is an uncommon cause of liver failure. B-Cell chronic lymphocytic leukemia (cll) is a usually indolent disease that may infiltrate the liver, but based on a review of the literature, has never been reported to induce acute liver failure. Here, we describe the case of a 78-year-old woman with acute liver failure secondary to infiltration with cll being unresponsive to chemotherapy and causing death. This case is notable because of its atypical presentation and ultimate poor prognosis.",
"affiliations": "Department of Medicine, McGill University, Montreal, QC.",
"authors": "Esfahani|K|K|;Gold|P|P|;Wakil|S|S|;Michel|R P|RP|;Solymoss|S|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.v18i1.756",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "18(1)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Chronic lymphocytic leukemia; acute liver failure; fulminant hepatic failure; small lymphocytic lymphoma",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "39-42",
"pmc": null,
"pmid": "21331280",
"pubdate": "2011-01",
"publication_types": "D016428:Journal Article",
"references": "11699425;11454193;8200270;9431904;9713971;14687834;8410123;8510487;8480749;10546758;11711783;9853565;2204655;16810767;12873593;9616324;9448189;19663087;8305063;18599169;2972899;12952236;9246036;11843819;11707855",
"title": "Acute liver failure because of chronic lymphocytic leukemia: case report and review of the literature.",
"title_normalized": "acute liver failure because of chronic lymphocytic leukemia case report and review of the literature"
} | [
{
"companynumb": "CA-TEVA-2021-CA-1988412",
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] |
{
"abstract": "OBJECTIVE\nHypomagnesemia is common among hospitalized patients, particularly those who are critically ill. It can be associated with a number of potentially life-threatening cardiovascular, neurological and behavioral manifestations. As opposed to acute, chronic hypomagnesemia is often underdiagnosed and underreported and as such may pose a diagnostic and therapeutic problem.\n\n\nMETHODS\nWe describe a case of magnesium wasting in a middle-aged woman with head and neck cancer who presented with recurrent syncopal episodes complicated by a femur fracture 4 months after completing a course of carboplatin-containing chemotherapy. Fractional excretion of magnesium of 16% was consistent with renal wasting of magnesium. After ruling out all common causes of hypomagnesemia, it was concluded that she sustained carboplatin-induced renal tubular damage making her relatively resistant to magnesium supplementation.\n\n\nCONCLUSIONS\nSeveral antineoplastic agents have been linked to chronic hypomagnesemia including anti-epidermal growth factor receptor agents such as cetuximab and panitumumab, cyclosporine, and the platinum-based agents cisplatin and carboplatin. The example case presented here illustrates the importance of chronic hypomagnesemia and its possible debilitating effects following carboplatin-containing chemotherapy. A growing numbers of cancer survivors are treated with these antineoplastic agents, and are hospitalized for non-cancer-related problems. These patients may have prolonged hypomagnesemia, and hence pose a diagnostic dilemma. We review the pathophysiology, etiology, diagnosis, clinical manifestations, monitoring and treatment of hypomagnesemia, with special attention to mechanisms of renal damage caused by platinum-containing chemotherapeutic agents.",
"affiliations": "a Hospital Medicine Unit, Massachusetts General Hospital , Boston , MA , USA.;a Hospital Medicine Unit, Massachusetts General Hospital , Boston , MA , USA.;a Hospital Medicine Unit, Massachusetts General Hospital , Boston , MA , USA.",
"authors": "Velimirovic|Marko|M|;Ziperstein|Joshua Charles|JC|;Fenves|Andrew Zoltan|AZ|",
"chemical_list": "D016190:Carboplatin; D008274:Magnesium",
"country": "England",
"delete": false,
"doi": "10.1080/21548331.2017.1286924",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2154-8331",
"issue": "45(2)",
"journal": "Hospital practice (1995)",
"keywords": "Chronic hypomagnesemia; carboplatin; chemotherapy; head and neck cancer; magnesium wasting",
"medline_ta": "Hosp Pract (1995)",
"mesh_terms": "D016190:Carboplatin; D002908:Chronic Disease; D005260:Female; D005264:Femoral Fractures; D006258:Head and Neck Neoplasms; D006801:Humans; D007674:Kidney Diseases; D008274:Magnesium; D008875:Middle Aged; D017741:Survivors; D013575:Syncope",
"nlm_unique_id": "101268948",
"other_id": null,
"pages": "58-64",
"pmc": null,
"pmid": "28114816",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case of chronic hypomagnesemia in a cancer survivor.",
"title_normalized": "a case of chronic hypomagnesemia in a cancer survivor"
} | [
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}
],
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"reaction": [
{
"reactionmeddrapt": "Ventricular tachycardia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypomagnesaemia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Syncope",
"reactionmeddraversionpt": "20.0",
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},
{
"reactionmeddrapt": "Renal tubular injury",
"reactionmeddraversionpt": "20.0",
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},
{
"reactionmeddrapt": "Femoral neck fracture",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia aspiration",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
}
],
"summary": null
},
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"literaturereference": "VELIMIROVIC M, ZIPERSTEIN JC, FENVES AZ.. A CASE OF CHRONIC HYPOMAGNESEMIA IN A CANCER SURVIVOR. HOSP-PRACT-(MINNEAP). 2017;45(2):58-64",
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},
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{
"abstract": "Angioedema of tongue can be a truly emergency situation and needs rapid evaluation and intervention if airway compromise happens. It is also crucial to recognize the causality of the allergic reaction. Mostly the culprit can be identified if detailed medical regimen and exposure history have been reviewed. A rare case of gabapentin-induced angioedema of tongue is presented.",
"affiliations": "National Taiwan University Hospital Hualien Tzu Chi Hospital Hualien Taiwan.;National Taiwan University Hospital Hualien Tzu Chi Hospital Hualien Taiwan.",
"authors": "Chong|Kok-Chin|KC|;Hsu|Tzu-Heng|TH|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.6705/j.jacme.202106_11(2).0005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-5587",
"issue": "11(2)",
"journal": "Journal of acute medicine",
"keywords": "Kimchi; angioedema; gabapentin; tongue swelling",
"medline_ta": "J Acute Med",
"mesh_terms": null,
"nlm_unique_id": "101574304",
"other_id": null,
"pages": "72-73",
"pmc": null,
"pmid": "34295638",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports",
"references": "19925599;24456350;24456368;28802302",
"title": "Gabapentin-Induced Angioedema of Tongue.",
"title_normalized": "gabapentin induced angioedema of tongue"
} | [
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"reactionmeddrapt": "Obstructive airways disorder",
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},
{
"reactionmeddrapt": "Angioedema",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHONG, K.. GABAPENTIN?INDUCED ANGIOEDEMA OF TONGUE. JOURNAL OF ACUTE MEDICINE. 2021?11(2):72?73",
"literaturereference_normalized": "gabapentin induced angioedema of tongue",
"qualification": "1",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
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"receivedate": "20210813",
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},
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},
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] |
{
"abstract": "BACKGROUND\nPotential increase of cancer incidence is one of the main safety concerns of the disease-modifying therapies employed in Multiple Sclerosis (MS).\n\n\nOBJECTIVE\nDetailed description of patients who developed cancer among a prospective cohort of Spanish MS patients on dimethyl fumarate (DMF) treatment.\n\n\nMETHODS\nWe describe patients who developed cancer among a cohort of 886 MS patients on DMF treatment (2681 patient-years), with a median time of exposure of 39.5 months (IQR 23-51.5), who participated in a multicentre and prospective real-world study conducted in 16 Spanish National Health System hospitals from February 2014 to May 2019. Local researchers were periodically contacted by the investigation team to monitor safety issues. Cancer histories were collected from the medical records and the information was updated at July 30th 2020.\n\n\nRESULTS\nEight Caucasian women developed cancer, which accounts for 0.9% and an accumulated malignancy rate of 298.39 cases per 100,000 patient-years of DMF exposure. At the time of cancer diagnosis, age was between 33 to 67 years and median time on DMF treatment 16.5 months (range 1-53). Two patients had familiar history of cancer. No specific cancer lines were found (breast cancer in 2 cases, thyroid in 3, urothelial carcinoma, cervix and a progression to leiomyosarcoma from a mitotically active leiomyoma). DMF was withdrawn during cancer treatment in 6 patients and reintroduced later. All cancers except one are in complete remission. The patient with leiomyosarcoma died by cancer progression.\n\n\nCONCLUSIONS\nA relationship between cancers and DMF is unlikely because the malignancy rate was similar to that of the age-and sex-matched general population, and because of the absence of specific tumour cell lines. Nevertheless, as with other immunosuppressive DMTs, clinicians treating MS should be aware of any potential cancer symptom and demand proper testing.",
"affiliations": "Department of Neurology, Hospital Universitario Infanta Leonor, Avenida Gran Vía del Este, 80, 28031 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology, Hospital Universitario Doce de Octubre, Av. de Córdoba, s/n, 28041 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology, Hospital Universitario Doce de Octubre, Av. de Córdoba, s/n, 28041 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology, Hospital Universitario Doce de Octubre, Av. de Córdoba, s/n, 28041 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology, Hospital Universitario Puerta de Hierro, Calle Joaquín Rodrigo, 1, 28222 Majadahonda, Madrid, Spain.;Department of Neurology, Hospital Universitario Príncipe de Asturias, Carr. de Alcalá, s/n, 28805 Meco, Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology, Hospital Universitario Clínico San Carlos, Calle del Prof Martín Lagos, s/n, 28040 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology, Hospital Universitario Clínico San Carlos, Calle del Prof Martín Lagos, s/n, 28040 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology,Hospital Universitario Ramón y Cajal, M-607, km. 9, 100, 28034 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology,Hospital Universitario Ramón y Cajal, M-607, km. 9, 100, 28034 Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology,Hospital Universitario Getafe, Carr. Madrid - Toledo, Km 12,500, 28905 Getafe, Madrid, Spain.;Multiple Sclerosis Unit, Department of Neurology,Hospital Universitario Getafe, Carr. Madrid - Toledo, Km 12,500, 28905 Getafe, Madrid, Spain. Electronic address: [email protected].",
"authors": "Gómez-Moreno|Mayra|M|;Sánchez-Seco|Victoria Galán|VG|;Moreno-García|Sara|S|;Cámara|Paula Salgado|PS|;Sabin-Muñoz|Julia|J|;Ayuso-Peralta|Lucia|L|;Oreja-Guevara|Celia|C|;Díaz-Díaz|Judit|J|;Sainz de la Maza|Susana|S|;Costa-Frossard|Lucienne|L|;Pilo de la Fuente|Belén|B|;Aladro-Benito|Yolanda|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2021.102747",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "49()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Cancer; Dimethyl fumarate; Multiple sclerosis; Safety",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000368:Aged; D000069462:Dimethyl Fumarate; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D009369:Neoplasms; D011446:Prospective Studies",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102747",
"pmc": null,
"pmid": "33524928",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cancer diagnosis in a Spanish cohort of multiple sclerosis patients under dimethylfumarate treatment.",
"title_normalized": "cancer diagnosis in a spanish cohort of multiple sclerosis patients under dimethylfumarate treatment"
} | [
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},
{
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{
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"drugindication": "RELAPSING MULTIPLE SCLEROSIS",
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"medicinalproduct": "INTERFERON?BETA?1A"
}
],
"patientagegroup": "5",
"patientonsetage": "52",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Metastases to liver",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Uterine leiomyosarcoma",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201603"
}
},
"primarysource": {
"literaturereference": "GOMEZ?MORENO M, SANCHEZ?SECO VG, MORENO?GARCIA S, CAMARA PS, SABIN?MUNOZ J, AYUSO?PERALTA L, ET AL. CANCER DIAGNOSIS IN A SPANISH COHORT OF MULTIPLE SCLEROSIS PATIENTS UNDER DIMETHYLFUMARATE TREATMENT. MULT?SCLER?RELAT?DIS 2021?49:102747.",
"literaturereference_normalized": "cancer diagnosis in a spanish cohort of multiple sclerosis patients under dimethylfumarate treatment",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20210715",
"receivedate": "20210715",
"receiver": {
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"receivertype": "6"
},
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "Although pregnancy after kidney transplantation has been considered as high risk for maternal and fetal complications, it can be successful in properly selected patients. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs; however, there has been very limited information about tacrolimus pharmacokinetics during pregnancy. In this study, we evaluated the tacrolimus doses, blood levels, and the outcomes of pregnancies in kidney allograft recipients. From 2004 to 2014, we found 16 pregnancies in 12 kidney allograft recipients at our center. We reviewed the files and data reports including fetal outcomes, graft function, complications, tacrolimus trough levels, and doses. We analyzed the tacrolimus trough levels and doses before pregnancy, during pregnancy (monthly), and in the postpartum period. Throughout the pregnancy, we aimed to achieve tacrolimus trough levels between 4 and 7 ng/mL. All patients were on triple immunosuppression, including tacrolimus, azathioprine, and prednisolone. In total, 11 of 16 (68.7%) pregnancies were successful, with a mean weight gain of 12.5 ± 1.66 kg. One patient developed gestational diabetes mellitus and 2 had preeclampsia. Although 5 of 11 babies were found to have low birth weight, 4 of these were premature. Two patients lost their grafts, 1 due to acute rejection and the second due to progression of chronic allograft dysfunction. We have shown that tacrolimus doses need to be significantly increased to keep appropriate trough levels during pregnancy (the doses: before, 3.20 ± 0.9 mg/day; first trimester, 5.03 ± 1.5; second trimester, 6.50 ± 1.8; third trimester, 7.30 ± 2.3; post-partum, 3.5 ± 0.9). In conclusion, the dose of tacrolimus needs to be increased to provide safe and stable tacrolimus trough levels during pregnancy. Although pregnancy can be successful in most cases, it should be kept in mind that there is an increased risk of maternal and fetal complications, including allograft loss, low birth weight, spontaneous abortus, and preeclampsia.",
"affiliations": "Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey. Electronic address: [email protected].;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Gynecology and Obstetrics, Ankara University School of Medicine, Ankara, Turkey.;Department of Perinatology, Ankara University School of Medicine, Ankara, Turkey.;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.",
"authors": "Aktürk|S|S|;Çelebi|Z K|ZK|;Erdoğmuş|Ş|Ş|;Kanmaz|A G|AG|;Yüce|T|T|;Şengül|Ş|Ş|;Keven|K|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D001379:Azathioprine; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D000075202:Contraindications; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007223:Infant; D016030:Kidney Transplantation; D011239:Prednisolone; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D018566:Pregnancy, High-Risk; D016559:Tacrolimus",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1442-4",
"pmc": null,
"pmid": "26093738",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy After Kidney Transplantation: Outcomes, Tacrolimus Doses, and Trough Levels.",
"title_normalized": "pregnancy after kidney transplantation outcomes tacrolimus doses and trough levels"
} | [
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],
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"reaction": [
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"reactionmeddraversionpt": "19.1",
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},
{
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"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal transplant failure",
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"reactionoutcome": "6"
}
],
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},
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},
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},
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},
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{
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"reaction": [
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"reactionoutcome": "6"
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{
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "AKTURK S, CELEBI ZK, ERDOGMUS S, KANMAZ AG, YUCE T, SENGUL S, ET AL. PREGNANCY AFTER KIDNEY TRANSPLANTATION: OUTCOMES, TACROLIMUS DOSES, AND TROUGH LEVELS. TRANSPLANT PROC. 2015 JUN;47(5):1442-4.",
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},
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"receiptdate": "20150720",
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"medicinalproduct": "AZATHIOPRINE."
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"medicinalproduct": "PREDNISOLONE."
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],
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"reaction": [
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},
{
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}
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] |
{
"abstract": "IRIS is a phenomenon describing localized inflammatory reactions at BCG vaccination site and development of lymphadenopathy as immune system recovers. It is a rare entity in children following haploidentical HSCT. We represent the successful treatment of a case with fluctuating lymphadenopathy due to BCG vaccine during immune reconstitution period following ex vivo T-cell-depleted haploidentical HSCT.",
"affiliations": "Department of Pediatric Hematology/Oncology, Koç University School of Medicine, Istanbul, Turkey.;Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.;Pediatric Bone Marrow Transplantation Unit, Acibadem University School of Medicine, Istanbul, Turkey.;Pediatric Bone Marrow Transplantation Unit, Acibadem University School of Medicine, Istanbul, Turkey.;Department of Pathology, Acibadem University School of Medicine, Istanbul, Turkey.;Pediatric Bone Marrow Transplantation Unit, Acibadem University School of Medicine, Istanbul, Turkey.",
"authors": "Erbey|Fatih|F|0000-0002-4475-0407;Dur|Ayse Humeyra|AH|0000-0003-3820-0430;Atay|Didem|D|0000-0003-3040-1959;Akçay|Arzu|A|;Tecimer|Tülay|T|;Öztürk|Gülyüz|G|",
"chemical_list": "D000995:Antitubercular Agents; D001500:BCG Vaccine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(5)",
"journal": "Pediatric transplantation",
"keywords": "BCG; HSCT; Haploidentical; IRIS",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000995:Antitubercular Agents; D001500:BCG Vaccine; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007223:Infant; D008212:Lymphocyte Depletion; D016511:Severe Combined Immunodeficiency; D013601:T-Lymphocytes; D014388:Tuberculosis, Lymph Node; D014421:Turkey",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13464",
"pmc": null,
"pmid": "31081274",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful treatment of BCG-related immune reconstitution inflammatory syndrome following ex vivo T-cell-depleted haploidentical hematopoietic stem cell transplantation: A case report.",
"title_normalized": "successful treatment of bcg related immune reconstitution inflammatory syndrome following ex vivo t cell depleted haploidentical hematopoietic stem cell transplantation a case report"
} | [
{
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},
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"abstract": "Background and study aims The US FDA recently approved a cancer treatment with pembrolizumab based upon the tumor biomarker status of deficient mismatch repair (dMMR) rather than a specific disease-based approach. We sought to determine if endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) could determine dMMR and quantification of PD-L1 expression to potentially guide the delivery of tumor agnostic immunotherapy. Patients and methods Immunohistochemistry was performed on archived pancreas core biopsy specimens. Tumors with absent nuclear staining of DNA mismatch repair proteins represented dMMR. Tumors were considered to have any or high PD-L1 expression, if expressed in ≥ 1 % or ≥ 50 % of tumor cells. Results Histologic specimen adequacy for MMR status assessment was satisfactory in 97.2 % of tumors. dMMR and high PD-L1 expression was identified in 3 % and 8.1 % of the cohort. Conclusion In the setting of tumor type agnostic immunotherapy, it is projected that at least 3 % of malignant pancreas lesions will be sensitive to pembrolizumab and up to 8 % sensitive to the family of immune checkpoint inhibitors. This highlights the expanding role of EUS-FNB in the field of precision immuno-oncology.",
"affiliations": "Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, United States.;Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, United States.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States.;Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, United States.;Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, United States.;Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, United States.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States.",
"authors": "Gleeson|Ferga C|FC|;Levy|Michael J|MJ|;Roden|Anja C|AC|;Boardman|Lisa A|LA|;Sinicrope|Frank A|FA|;McWilliams|Robert R|RR|;Zhang|Lizhi|L|",
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"fulltext": "\n==== Front\nEndosc Int OpenEndosc Int Open10.1055/s-00025476Endoscopy International Open2364-37222196-9736© Georg Thieme Verlag KG Stuttgart · New York 10.1055/a-0650-4447Case reportEUS fine-needle pancreatic core biopsy can determine eligibility for tumor-agnostic immunotherapy Gleeson Ferga C. 1Levy Michael J. 1Roden Anja C. 2Boardman Lisa A. 1Sinicrope Frank A. 13McWilliams Robert R. 3Zhang Lizhi 21 Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, United States2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States3 Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, United StatesCorresponding author Ferga C. Gleeson, MD Mayo ClinicDivision of Gastroenterology & Hepatology\n200 1\nst\nSt SW\nRochester MN [email protected] 2018 08 10 2018 6 10 E1278 E1282 09 4 2018 \naccepted after revision\n14 5 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground and study aims \nThe US FDA recently approved a cancer treatment with pembrolizumab based upon the tumor biomarker status of deficient mismatch repair (dMMR) rather than a specific disease-based approach. We sought to determine if endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) could determine dMMR and quantification of PD-L1 expression to potentially guide the delivery of tumor agnostic immunotherapy.\n\n\n\nPatients and methods\n Immunohistochemistry was performed on archived pancreas core biopsy specimens. Tumors with absent nuclear staining of DNA mismatch repair proteins represented dMMR. Tumors were considered to have any or high PD-L1 expression, if expressed in ≥ 1 % or ≥ 50 % of tumor cells.\n\n\n\nResults\n Histologic specimen adequacy for MMR status assessment was satisfactory in 97.2 % of tumors. dMMR and high PD-L1 expression was identified in 3 % and 8.1 % of the cohort.\n\n\n\nConclusion\n In the setting of tumor type agnostic immunotherapy, it is projected that at least 3 % of malignant pancreas lesions will be sensitive to pembrolizumab and up to 8 % sensitive to the family of immune checkpoint inhibitors. This highlights the expanding role of EUS-FNB in the field of precision immuno-oncology.\n==== Body\nIntroduction\nDeficient DNA mismatch repair (MMR) results in a hypermutated phenotype characterized by microsatellite instability (MSI) and a higher burden of mutation-associated neoantigens that are targeted by the immune system. Deficient MMR and high frequency MSI (MSI-H) have been shown to be predictive biomarkers for immune checkpoint inhibitor drugs which block the programmed death protein-1/programmed death ligand-1 (PD-1/PD-L1) interaction between tumor cells and activated T cells. These agents include antibodies against PD-1 and PD-L1 that have significantly altered the treatment algorithm for several solid tumors. Presence and level of PD-L1 tumor expression are associated with responsiveness to these antibodies in certain malignancies that include advanced melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial cancer and Hodgkin’s lymphoma.\n\n\nIn 2017, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (KEYTRUDA) for patients with unresectable or metastatic d-MMR solid tumors based upon an assessment of 15 cancer types, among which, 149 MSI-H patients were enrolled across 5 clinical trials\n1\n. A complete or partial response was experienced by 39.6 % of patients, with responses lasting ≥ 6 months in 78 %. Based upon these data, the FDA approved a cancer treatment for the first time based upon tumor biomarker status, rather than a specific disease-based approach.\n\n\n\nVanderwalde and colleagues recently published their experience evaluating a broad spectrum of 11,348 solid tumors noting the frequency of dMMR based on having MSI-H: PD-L1 expression in endometrial cancer (17 %: 16.2 %), gastric adenocarcinoma (8.7 %: 18.5 %), colorectal adenocarcinoma (5.7 %: 7.2 %), cholangiocarcinoma (2.3 %: 18.6 %), pancreatic ductal adenocarcinoma (PDAC) (1.2 %: 21.6 %), renal cell carcinoma (0.6 %: 29.7 %) and melanoma (0 %: 42.3 %)\n2\n. The fact that dMMR is rarely present among PDAC patients was further demonstrated in a study of 833 surgically resected PDAC tumors revealing a frequency of 0.8 %, all of whom were patients found to have Lynch syndrome\n3\n.\n\n\nIn an era of evolving tumor agnostic immunotherapy, we questioned if pancreatic endoscopic ultrasound-guided fine-needle biopsy (EUS FNB) provides sufficient material for dual immunohistochemistry (IHC) for dMMR and PD-L1 status evaluations. We sought to determine the prevalence of MSI-H status and quantification of PD-L1 expression to determine their utility in guiding disease-agnostic immunotherapy based upon biomarker status.\n\nPatients and methods\nIHC was performed on consecutive archived treatment-naïve formalin-fixed paraffin-embedded EUS pancreas core biopsy specimens (2001 – 2017 IRB # 17-006528). Briefly, 4-μm-thick tissue sections were stained using the Ventana BenchMark XT automated slide-staining system using the following antibodies: Anti-PD-L1 (clone SP263, VENTANA, Tucson, AZ), MLH1 (clone G168-728, Cell Marque, Rocklin, California, United States), MSH2 (clone FE11, Biocare Medical, Concord, Massachusetts, United States), MSH6 (clone BC/44, Biocare Medical, Concord, Massachusetts, United States), and PMS2 (clone A16-4, Biocare Medical, Concord, M Massachusetts, United States). Antigen-antibody reactions were visualized using UltraView detection with diaminobenzidine as the chromogen.\n\nA minimum of 100 viable tumor cells were required on one stained slide for the specimen to be considered adequate for evaluation. Positive PD-L1 expression was defined as membranous staining. The approximate percentage of positive tumor cells versus all tumor cells provided the Tumor Proportion Score (TPS). The specimen was considered to have PD-L1 expression if PD-L1 was expressed in ≥ 1 % of tumor cells and a high level of expression if ≥ 50 %. Tumors were classified as dMMR if they exhibited absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2).\n\nResults\nClinical demographics\n\nThirty-nine treatment-naïve patients with either a primary or secondary pancreas malignancy who underwent EUS with FNB were assessed for histologic specimen adequacy for MMR and PD-L1 expression status. Age of the overall cohort was 71.2 ± 10.2 years, 61.5 % were male, and the overall mortality rate was 25.6 % at 7 months (4.9 – 15.7) following EUS diagnosis. The study cohort was composed of 21 patients with PDAC who had previously reported PD-L1 expression analysis and with patient details as follows: 72.9 ± 8.9 years; 57 % male; CA19-9 level = 143 U/mL (18 – 998); 57 % 8\nth\nAJCC Stage ≥ III)\n4\n. The study also included 18 patients (69.3 ± 11.6 years; 66 % male) with either a renal cell cancer (RCC) (n = 16) or melanoma that had metastasized to the pancreas (n = 2). Using either a 19G Trucut biopsy needle (n = 9 patients) (Quick-Core Biopsy Needle, Cook Medical, Winston-Salem, North Carolina, United States) or a 22G Sharkcore FNB needle (n = 30 patients) (SharkCore FNB needle, Medtronic, Dublin, Ireland), tumor tissue was sampled with an overall median tissue aggregate that was 19 mm (12 – 20) in length following 2 (3 – 5) EUS-FNB passes.\n\n\nDNA mismatch repair status\n\nAmong the 39 patients, 36 had specimen blocks available for retrieval from the tissue archive and 35 (97.2 %) patients (FNB passes 2\n3\n4\n5\n) had histologic specimen adequacy to assess dMMR by IHC. One patient (2.9 %) displayed loss of MLH1-PMS2 (\nFig. 1\n). The patient was a 64-year-old male with decompensated cirrhosis secondary to nonalcoholic steatohepatitis, a splenic artery pseudoaneurysm resulting in hemosuccus pancreaticus and previously resected colon cancer. He presented with cholestatic jaundice and an elevated CA19-9 (1,184 U/mL) as a consequence of a 4-cm EUS T4N0M0 PDAC head mass. The additional immunostains performed on the tumor showed that the tumor cells were positive for CK7 and focally positive for CDX2 and CK20. This immunophenotype supports the diagnosis of a primary PDAC. He was started on FOLFIRINOX. He subsequently underwent germline testing which detected Lynch syndrome and received pembrolizumab. He had stable disease on therapy, but succumbed to vascular complications, presumably from his cirrhosis, 7.7 months following EUS.\n\n\nFig. 1a – e \nLoss of MLH1-PMS2 protein expression in a PDAC EUS-FNB specimen.\n\n\nMMR status and PD-L1 expression\n\nThirty-seven patients (94.9 %) had specimens that were satisfactory for PD-L1 expression assessment (\nFig. 2\n). Expression thresholds of ≥ 1 %, ≥ 5 %, ≥ 10 %, ≥ 25 % and ≥ 50 % expression in tumor cells were identified in 16 (43.2 %), 13 (35.1 %), 7 (18.9 %), 5 (13.5 %) and 3 (8.1 %) patients, respectively (\nFig. 3\n). Tumor tissue from 33 patients underwent dual MSI and PD-L1 immunostaining (\nFig. 4\n). PD-L1 expression (> 1 %) with proficient (p) MMR or dMMR status was identified in 13 (39.4 %) and 1 (3 %) patient, respectively. The tumor from the patient with Lynch syndrome had PD-L1 expression in 10 % of tumor cells.\n\n\nFig. 2 a \nEUS-FNB malignant melanoma metastasis to the pancreas with\nb\nPD-L1 expression > 90 %.\n\n\nFig. 3 \n Patient prevalence and quantification of PD-L1 expression positivity for EUS-FNB specimens of treatment-naïve PDAC, clear cell renal cell carcinoma and malignant melanoma.\n\n\nFig. 4 \nDual MSI and PD-L1 IHC assessment yield.\n\n\nBiomarker-based immunotherapy eligibility\nBased upon the prevalence of dMMR status, 3 % of our patients would be eligible to receive pembrolizumab in the setting of a FDA-approved disease-agnostic immunotherapy approach. PD-L1 expression was high (TPS > 50 %) in 8.1 % of patients, suggesting that expression of this biomarker by their tumors may indicate potential sensitivity to immune checkpoint inhibitor therapy.\n\nDiscussion\nAmong a unique patient cohort, we determined that a paired evaluation of MMR status and PD-L1 expression by IHC is possible using specimens obtained with EUS-FNB. Our findings demonstrate the capability of using tissues obtained with EUS-FNB for molecular classification of treatment-naïve solid pancreas masses by identifying biomarkers that may guide use of checkpoint inhibitor therapy. The 3 % prevalence of dMMR in our cohort indicates that patients with these tumors are candidates for treatment with pembrolizumab. Furthermore, 8.1 % of evaluated tumors had a high level of expression of PD-L1 (TPS > 50 %), which in certain tumor types is associated with responsiveness to checkpoint inhibitor therapy.\n\n\nFollowing much debate, it has been established that endoscopic ultrasound-guided fine-need aspiration and EUS-FNB needles yield a similar satisfactory specimen for diagnostic purposes, with the caveat that fewer FNB passes are required to achieve such a yield\n5\n6\n7\n8\n9\n10\n. However, when tissue for companion diagnostic or prognostic tumor information is required for integration of molecular analyses into clinical decision-making, the optimal needle landscape changes depending upon the specific objective. Options for use of tissue specimens include IHC, genotyping using next-generation sequencing (NGS), or establishing tumor organoids in a research setting. PDACs demonstrate only 5 % to 20 % neoplastic cellularity and are characterized by a prominent desmoplastic reaction considered to be a hostile tumor microenvironment (TME) for subsequent therapy\n11\n12\n. Cytology smears are thought to be superior for multiplex gene panel NGS evaluations, as their overall cellularity, tumor fraction, and sequencing metrics are considered to be superior to that of FNB, yet, successful preclinical disease models to include organoid development require that EUS-FNB deliver tumor cells and the corresponding TME\n13\n14\n15\n.\n\n\nAs endosonographers, while we try to navigate the provision of satisfactory material for ancillary molecular analysis to improve cytologic adequacy and identify predictors of prognosis and chemosensitivity, we are now poised to assist in patient selection for precision immuno-oncology. There are a number of barriers to the utility of immunotherapy in PDAC as the mutational burden is low; the TME is characterized by dense stroma with very few T cells, collectively creating a “cold” or non-immunogenic environment and potentially making such tumors less responsive to checkpoint inhibitors. Yet, there is much need for enhanced tissue access and sampling for analysis to utilize biomarkers in patients with solid tumors, including PDAC, which can determine eligibility for checkpoint inhibitor therapy.\n\n\nTo date, the MMR/MSI status of pancreatic lesions has only been evaluated in surgically resected specimens, which represent a small proportion of patients that have earlier, less advanced disease, as patients with more advanced disease are no longer surgical candidates. MMR and PD-L1 status may be influenced by prior neoadjuvant or adjuvant therapy as has been observed in both breast and colon cancer analyses\n16\n17\n. Therefore, for primary pancreatic masses to include PDAC, it may be more desirable to perform such analysis on treatment-naïve specimens for which EUS-FNB is ideally suited to establish the molecular signature. For secondary pancreatic metastasis, we evaluated RCC and melanoma treatment-naïve lesions, which is the ideal scenario. However, from a practical perspective, patients with these lesions have usually undergone prior treatment that requires careful consideration of the molecular testing.\n\n\nConclusion\nIn conclusion, we highlight that our early experience with dual MMR IHC and PD-L1 expression analysis shows that it is technically feasible to assess biomarker-based immunotherapy eligibility with EUS-FNB specimens from solid primary and secondary pancreatic masses. Based upon the prevalence of dMMR and high PD-L1 expression, 3 % of the treatment-naïve cohort is a candidate for checkpoint inhibitor therapy and high PD-L1 expression may provide additional information regarding sensitivity to immunotherapy depending upon tumor type.\n\nCompeting interests None\n==== Refs\nReferences\n1 US Food and Drug Administration FDA approves first cancer treatment for any solid tumor with a specific genetic feature https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm\n2 Vanderwalde A Spetzler D Xiao N Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients Cancer Med 2018 7 746 756 29436178 \n3 Hu Z I Shia J Stadler Z K Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations Clin Cancer Res 2018 24 1326 1336 29367431 \n4 Gleeson F C Zhang L Roden A C EUS fine-needle biopsy can determine PD-L1 immune biomarker status in treatment naïve pancreatic ductal adenocarcinoma Clin Gastroenterol Hepatol 2018 3 10.1016/j.cgh.2018.01.001 \n5 Lee B S Cho C M Jung M K comparison of histologic core portions acquired from a core biopsy needle and a conventional needle in solid mass lesions: a prospective randomized trial Gut Liver 2017 15 559 566 \n6 Lee Y N Moon J H Kim H K Core biopsy needle versus standard aspiration needle for endoscopic ultrasound-guided sampling of solid pancreatic masses: a randomized parallel-group study Endoscopy 2014 46 1056 1062 25098611 \n7 Tian L Tang A L Zhang L Evaluation of 22G fine-needle aspiration (FNA) versus fine-needle biopsy (FNB) for endoscopic ultrasound-guided sampling of pancreatic lesions: a prospective comparison study Surg Endosc 2018 32 3533 3539 29404729 \n8 Hedenström P Demir A Khodakaram K EUS-guided reverse bevel fine-needle biopsy sampling and open tip fine-needle aspiration in solid pancreatic lesions - a prospective, comparative study Scand J Gastroenterol 2018 53 231 237 29301477 \n9 Strand D S Jeffus S K Sauer B G EUS-guided 22-gauge fine-needle aspiration versus core biopsy needle in the evaluation of solid pancreatic neoplasms Diagn Cytopathol 2014 42 751 758 24550162 \n10 Bang J Y Hebert-Magee S Trevino J Randomized trial comparing the 22-gauge aspiration and 22-gauge biopsy needles for EUS-guided sampling of solid pancreatic mass lesions Gastrointest Endosc 2012 76 321 327 22658389 \n11 Iacobuzio-Donahue C A Ryu B Hruban R H Exploring the host desmoplastic response to pancreatic carcinoma: gene expression of stromal and neoplastic cells at the site of primary invasion Am J Pathol 2002 160 91 99 11786403 \n12 Wood L D Hruban R H Pathology and molecular genetics of pancreatic neoplasms Cancer J 2012 18 492 501 23187835 \n13 Roy-Chowdhuri S Chen H Singh R R Concurrent fine needle aspirations and core needle biopsies: a comparative study of substrates for next-generation sequencing in solid organ malignancies Mod Pathol 2017 30 499 508 28084342 \n14 Wani S Muthusamy V R McGrath C M AGA White Paper: optimizing endoscopic ultrasound-guided tissue acquisition and future directions Clin Gastroenterol Hepatol 2018 16 318 327 29074447 \n15 Tiriac H Bucobo J C Tzimas D Successful creation of pancreatic cancer organoids by means of EUS-guided fine-needle biopsy sampling for personalized cancer treatment Gastrointest Endosc 2018 87 1474 1480 29325707 \n16 Goldstein J B Wu W Borras E Can microsatellite status of colorectal cancer be reliably assessed after neoadjuvant therapy? Clin Cancer Res 2017 1 5246 5254 \n17 Pelekanou V Carvajal-Hausdorf D E Altan M Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance Breast Cancer Res 2017 7 91\n\n",
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}
],
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],
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},
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"literaturereference": "GLEESON FC, LEVY MJ, RODEN AC, BOARDMAN LA, SINICROPE FA, MCWILLIAMS RR, ET AL.. EUS FINE-NEEDLE PANCREATIC CORE BIOPSY CAN DETERMINE ELIGIBILITY FOR TUMOR-AGNOSTIC IMMUNOTHERAPY. ENDOSCOPY INTERNATIONAL OPEN. 2018?06:E1278-82",
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},
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{
"abstract": "Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R- patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.",
"affiliations": "Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis MO.;Division of Hematology/Oncology and.;Blood and Marrow Transplant Program and.;Blood and Marrow Transplant Program, Northside Hospital, Atlanta, GA.;Division of Transplantation and Cellular Therapy, University of Miami, Miami, FL.;UF Health Shands Children's Hospital, Gainesville, FL.;MD Anderson Cancer Center, Houston, TX.;Center for International Blood and Marrow Transplantation Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.;Stem Cell Transplant and Cellular Therapies Service, University of California, Irvine, Orange, CA.;Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH.;Department of Hematology/Oncology, Hospital Infantil Universitario Niño Jesus, Madrid, Spain.;The Sidney Kimmel Comprehensive Cancer Center, John Hopkins, Baltimore, MD.;Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, KS.;Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.;Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.;Center for International Blood and Marrow Transplantation Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.;Hematology, Oncology, University of Miami, Miami, FL.;Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY.;University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH.;University of Chicago Medicine, Chicago, IL.;Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, and.;Adult Blood and Marrow Stem Cell Transplant Program, Knight Cancer Institute, Oregon Health and Science University, Portland, OR.;University of California, San Diego Medical Center, La Jolla, CA.;Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, IL.;Department of Blood & Marrow Transplant and Cellular Immunotherapy (BMT CI), Moffitt Cancer Center, Tampa, FL.;Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, NC.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.;Division of Infectious Diseases, City of Hope National Medical Center, Duarte, CA.;Stem Cell Transplantation Program, Dana Farber Cancer Institute, Boston, MA; and.;Center for International Blood and Marrow Transplantation Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.",
"authors": "Goldsmith|Scott R|SR|0000-0001-9216-2418;Abid|Muhammad Bilal|MB|;Auletta|Jeffery J|JJ|;Bashey|Asad|A|;Beitinjaneh|Amer|A|;Castillo|Paul|P|;Chemaly|Roy F|RF|;Chen|Min|M|;Ciurea|Stefan|S|0000-0001-8597-3271;Dandoy|Christopher E|CE|0000-0002-4001-9203;Díaz|Miguel Ángel|MÁ|;Fuchs|Ephraim|E|;Ganguly|Siddhartha|S|;Kanakry|Christopher G|CG|;Kanakry|Jennifer A|JA|;Kim|Soyoung|S|0000-0003-1404-0575;Komanduri|Krishna V|KV|;Krem|Maxwell M|MM|0000-0003-3980-480X;Lazarus|Hillard M|HM|0000-0002-1159-5607;Liu|Hongtao|H|0000-0002-3190-7807;Ljungman|Per|P|0000-0002-8281-3245;Masiarz|Richard|R|;Mulroney|Carolyn|C|;Nathan|Sunita|S|;Nishihori|Taiga|T|0000-0002-2621-7924;Page|Kristin M|KM|;Perales|Miguel-Angel|MA|0000-0002-5910-4571;Taplitz|Randy|R|0000-0002-6279-7567;Romee|Rizwan|R|;Riches|Marcie|M|0000-0003-0257-0990",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2020009362",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "137(23)",
"journal": "Blood",
"keywords": "CIMBTR; CMV; MARROW AND STEM CELL TRANSPLANTATION; haploidentical; organ specific toxicity: infectious; outcomes; posttransplant cyclophosphamide",
"medline_ta": "Blood",
"mesh_terms": null,
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3291-3305",
"pmc": null,
"pmid": "33657221",
"pubdate": "2021-06-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "30292744;30342913;31179485;28986189;24041869;18489989;29211658;32438042;20124511;15084929;31849930;27443287;16125590;31608225;26884374;30578673;26507225;25778751;26160014;6093296;12384408;22683614;27042847;18940684;31089284;30824040;21540462;24225944;27682069;22180440;16434374;23744585;27833447;24037724;9385097;24806159;20353832;26130705;23983215;32202631;31191499;8610387;30913039;25139358;20490728",
"title": "Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis.",
"title_normalized": "posttransplant cyclophosphamide is associated with increased cytomegalovirus infection a cibmtr analysis"
} | [
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"literaturereference": "Goldsmith SR, Abid MB, Auletta JJ, Bashey A, Beitinjaneh A, Castillo P, et al.. Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis.. Blood. 2021;137(23):3291-3305",
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},
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] |
{
"abstract": "An 80-year-old woman presented with a 5-week history of increasing confusion. Examination was remarkable only for deficits in short-term memory and paranoid thoughts. Blood tests revealed hyponatraemia, and further biochemical testing was consistent with syndrome of inappropriate antidiuretic hormone (SIADH). After an exhaustive diagnostic workup for causes of SIADH, the only abnormal finding was a mildly raised antivoltage-gated potassium channel (VGKC) titre of 185 pmol/L (0-69) consistent with possible anti-VGKC autoimmune limbic encephalitis. However, other diagnostic features were absent. She is currently undergoing outpatient investigation for other causes of memory loss.",
"affiliations": "Department of General and Geriatric Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Department of General and Geriatric Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.",
"authors": "Black|Nicholas|N|;Hamada|Hazim|H|",
"chemical_list": "D005938:Glucocorticoids; D024642:Potassium Channels, Voltage-Gated; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223484",
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"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "immunology; memory disorders; pituitary disorders",
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"mesh_terms": "D000369:Aged, 80 and over; D001327:Autoimmune Diseases; D003221:Confusion; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D020363:Limbic Encephalitis; D008569:Memory Disorders; D009483:Neuropsychological Tests; D024642:Potassium Channels, Voltage-Gated; D011239:Prednisolone; D057832:Watchful Waiting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29514833",
"pubdate": "2018-03-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23757422;21212700;27016871;22379457;20164214;24465150;20663977;24465165;17848866;23992774;21180634;16932578;21777830;19346313;25984214;12897340;17565425;26563934;19773352",
"title": "Possible anti-VGKC autoimmune limbic encephalitis associated with SIADH.",
"title_normalized": "possible anti vgkc autoimmune limbic encephalitis associated with siadh"
} | [
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],
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{
"abstract": "We report the successful use of electroconvulsive therapy in a 19-year-old man with autism and mild mental retardation who developed severe depression with repeated suicide attempts, multiple symptoms of catatonia, and life-threatening repetitive self-injurious behaviors. After 3 years of failed psychotropic and behavioral interventions in inpatient settings, the patient demonstrated excellent remission of symptoms with bilateral electroconvulsive therapy.",
"affiliations": "Kennedy Krieger Institute, Baltimore, MD 21209, USA. [email protected]",
"authors": "Wachtel|Lee Elizabeth|LE|;Griffin|Merrie|M|;Reti|Irving Michael|IM|",
"chemical_list": "D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
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"issn_linking": "1095-0680",
"issue": "26(1)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D001321:Autistic Disorder; D002389:Catatonia; D003131:Combined Modality Therapy; D003865:Depressive Disorder, Major; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D011595:Psychomotor Agitation; D011619:Psychotropic Drugs; D016728:Self-Injurious Behavior; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "9808943",
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"pages": "70-3",
"pmc": null,
"pmid": "19483640",
"pubdate": "2010-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electroconvulsive therapy in a man with autism experiencing severe depression, catatonia, and self-injury.",
"title_normalized": "electroconvulsive therapy in a man with autism experiencing severe depression catatonia and self injury"
} | [
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{
"abstract": "New-onset refractory status epilepticus (NORSE) is a drug-resistant status epilepticus that often has a catastrophic outcome. Our patient was diagnosed with NORSE and had an EEG reading that showed status epilepticus persisting for 8 months in general anesthesia. After autoimmune workup showed positive antiphospholipid antibodies, his seizure was controlled, and he was discharged with good condition apart from moderate cognitive impairment. However, he later developed schizophrenia. Although psychiatric disorders have been associated with antiphospholipid syndrome, to the best of our knowledge, it has not been reported to be associated with status epilepticus. We recommend vigilance of psychological complications of refractory status epilepticus patients for early psychiatric referral, diagnosis, and treatment.",
"affiliations": "Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. E-mail: [email protected].",
"authors": "Al-Khateeb|Mashael|M|;Adem|Fatima|F|;Moqbel|Amani|A|;Baz|Salah|S|",
"chemical_list": null,
"country": "Saudi Arabia",
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"doi": "10.17712/nsj.2018.3.20180014",
"fulltext": "\n==== Front\nNeurosciences (Riyadh)\nNeurosciences\nnsj\nnsj\nNeurosciences\nNeurosciences\n1319-6138\n1319-6138\nRiyadh : Armed Forces Hospital\n\n31380826\nNeurosciences-24-240\n10.17712/nsj.2018.3.20180014\nCase Report\nSchizophrenia following new-onset refractory status epilepticus secondary to antiphospholipid syndrome\nAl-Khateeb Mashael MD\nAdem Fatima MD\nMoqbel Amani MD\nBaz Salah MD\nDivision of Neurology (Al-Khateeb, Baz), Department of Neuroscience, King Faisal Specialty Hospital, and Research Center, from the College of Medicine (Moqbel, Adem), Alfaisal University, Riyadh, Kingdom of Saudi Arabia\nAddress correspondence and reprint request to: Dr. Mashael O. Al-Khateeb, Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia E-mail: [email protected] ORICID ID: https://orcid.org/0000-0001-9458-8367\n7 2019\n24 3 240244\n25 11 2018\n15 4 2019\nCopyright: © Neurosciences\n2019\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.\nNew-onset refractory status epilepticus (NORSE) is a drug-resistant status epilepticus that often has a catastrophic outcome. Our patient was diagnosed with NORSE and had an EEG reading that showed status epilepticus persisting for 8 months in general anesthesia. After autoimmune workup showed positive antiphospholipid antibodies, his seizure was controlled, and he was discharged with good condition apart from moderate cognitive impairment. However, he later developed schizophrenia. Although psychiatric disorders have been associated with antiphospholipid syndrome, to the best of our knowledge, it has not been reported to be associated with status epilepticus. We recommend vigilance of psychological complications of refractory status epilepticus’ patients for early psychiatric referral, diagnosis, and treatment.\n==== Body\nNew-onset refractory status epilepticus (NORSE) is a syndrome of new-onset drug-resistant status epilepticus that often has a catastrophic outcome. Epilepsy is usually associated with psychiatric disorders of different manifestations of which psychosis is an example.1 However, not much is found in the literature review regarding psychiatric disorders following NORSE although a recent study concluded 32% of NORSE patients ended up with altered behavioral states like aggression.2 Schizophrenia following NORSE like in the rare presentation of this case has not been reported in the literature review before, although an association between schizophrenia and autoimmune disorders like APS has been reported.3\n\nCase Report\n\nPatient information and clinical findings\n\nA 41-year-old, nonsmoker, married man works in a college with no past relevant family or medical history. He had blurry vision and headache, and after 2 hours he developed generalized tonic-clonic seizure. He was brought to the local emergency department where benzodiazepine and 2 antiepileptic drugs loading doses failed to stop his seizures. Midazolam boluses as a continuous infusion over 5 days were then administered. Although the medications’ doses were increased, his seizure was drug resistant. He was then intubated, and propofol, midazolam, fentanyl in addition to the maintenance medication valproic acid, phenobarbitone, levetiracetam, and phenytoin were administered.\n\nDiagnostic assessment and therapeutic intervention\n\nHe was given empirical antibiotics although the workup findings of CT scan and brain MRI performed at the local hospital he first presented in were normal, including the lumbar puncture which only showed slightly elevated white blood cells with normal protein and glucose levels.\n\nAfter 2 weeks, he was transferred to a tertiary center Emergency Department due to his deteriorated status. He was comatose and was having intermittent twitching of the face and upper extremity. He was transferred immediately to the intensive care unit and epilepsy service. Head CT, MRI and neck magnetic resonance angiography and venography (MRA/MRV), in addition to cerebral angiography showed no abnormality detected except for a parasagittal hematoma (Figure 1, 2) which improved after 2 weeks although the patients status remained the same. Although he was already on midazolam, propofol, and fentanyl, he had a prolonged seizure that lasted more than 10 minutes. He continued having in between seizures activities while he was being kept intubated and ventilated on tracheostomy with ketamine and thiopental. Continuous EEG showed initially generalized spikes and waves every 1-2 seconds (Figure 3) for >48 hours, and NORSE was diagnosed. Then, anesthesia induced burst suppression pattern was observed (Figure 4).\n\nFigure 1 Axial CT brain showed left (A) and right (B) parasagittal hematoma without mass effect.\n\nFigure 2 Axial FLAIR MRI with bilateral diffuse high signal intensities.\n\nFigure 3 Electroencephalography showing generalized periodic discharges.\n\nFigure 4 Electroencephalography showing suppression-burst pattern.\n\nWork-up excluded Anti-NMDA receptor encephalitis and revealed elevated Antiphospholipid antibody (APA) including antiB2 Glycoprotein I. Lumbar puncture yielded clear cerebrospinal fluid, 6 white blood cells, with normal glucose and protein content. Bacterial, fungal cultures, cryptococcal antigen, cytology and whole-body pet scan in addition to para-neoplastic work-up all showed negative findings including voltage-gated potassium channel (VGKC), AMPA, GAD 65, LGI1. The APA levels remained elevated on 2 occasions.\n\nAnti-β2 glycoprotein-I antibodies result was (50–100 U/mL) (IgG&IgA) and our normal laboratory value is <20U/mL. Antiphospholipid syndrome was diagnosed and heparin started. He continued to have episodic right arm and leg jerks with right facial twitching.\n\nMultiple intravenous doses of benzodiazepine and a loading dose of phenytoin, valproic acid, levetiracetam, midazolam, thiopental, phenobarbitone, fentanyl, and ketamine infusion were administered. Moreover, a trial of 5 days induced hypothermia ended up with insufficient seizure suppression.\n\nHe was then put on a treatment plan which included pulse intravenous steroid, immunoglobulin, plasma exchange and rituximab which showed no immediate response. The doses were as follow :- IVIg 0.4g/kg for 5 days, steroid 1g for 5 days, and Rituximab 1g/once, 2 doses given within a 2 week interval. Over the following 8 months, levetiracetam 2g intravenously twice daily, lamotrigine 200mg nasogastric twice daily, and phenobarbital 110mg twice daily were administered and suppressed the seizures completely.\n\nFollow-up and outcomes\n\nA third head CT and MRI (Figure 5) after 8 months showed complete resolution of the hematoma. All anesthetic agents were then tapered off gradually while his seizures remained controlled, and he was eventually extubated. After approximately 8 months of ICU admission, he was discharged to the regular floor.\n\nFigure 5 8 months later, a third CT brain showed complete resolution.\n\nDuring the neuropsychologist’s evaluation, the patient was neat and mostly cooperative, although slightly aggressive. The patient showed neurocognitive decline, affected temporal orientation to day, date and year, slowed motor activity, labile mood, constricted affect, distracted attention and memory, and orientation impairment. Although his speech was impoverished, he had some insight of his illness, lack of words and difficulty in articulation. Although visual hallucinations were present, he did not have any suicidal or delusional thoughts. He was then being monitored in the same tertiary center for few months and then discharged with phenobarbital, tegretol, lamictal, and levetiracetam to a rehabilitation center with residual moderate to severe cognitive decline without any focal neurological deficits.\n\nAfter 7 months of following up and being evaluated by the rheumatology and epilepsy service, he remained seizure free, and neurological examination showed nystagmus bilaterally and intact cranial nerves. However, psychiatric assessment’s remarkable findings were euphoric mood, cognitive impairment, poor planning, and macropsia with positive illusion picture.\n\nDuring his routine outpatient follow up, a mental status assessment was conducted and it was reported that his appearance was disheveled, his speech was tangential, and his eye contact was intense with slowed motor activity and labile affect. He was easily distracted and had an irritable mood. In addition, his behavior was agitated with grandiose and paranoid delusions along with visual and auditory hallucinations. Furthermore, he was aggressive, homicidal, and had self-harm thoughts with short-term memory and orientation to place, object, and person. Schizophrenia psychosis was then diagnosed in the outpatient clinic after 9 visits over the course of a year. He started treatment with regular psychiatric follow-up at the local hospital in his town.\n\nTable 1 Relevant Past Medical History and Interventions of A 41-year-old, nonsmoker, married man who works in a college with no past relevant family or medical.\n\nDates\tSummaries from initial and follow-up visits\tDiagnostic testing\tInterventions\t\nMarch 2014\tLocal ER\n- He complained of blurry vision and headache, and after 2 hours he developed generalized tonic-clonic seizure.\n- He was taken to the ER\t- CT\n- Brain MRI\n- Lumbar puncture\t- Refer to the medication table below\n- Intubation\n- Antibiotics\t\n2 weeks later and for the next 8 months\tTertiary hospital\nICU\n- Comatosed with intermittent twitching of the face and upper extremity\n- Prolonged seizure that lasted for more than 10 mins\n- Antiphospholipid syndrome diagnosed\n- Episodic right arm and leg jerk with right facial twitching\n- Seizure suppression\nWard\n- Neuropsychologists evaluation\n- Stayed in the epilepsy ward for few months\t- Head CT\n- Head MRI\n- Neck Magnetic resonance angiography and venography (MRA/MRV)\n- Cerebral angiography\n- Continuous EEG\n- Lumbar puncture\n- Antibody workup\n- Paraneoplastic workup\n- Infection workup\n- Whole body pet scan\t- Refer to the medication table below\n- Intubated and ventilated on tracheostomy\n- Induced hypothermia\t\nAfter discharge\n- 7 months of follow up by the rheumatology and epilepsy service he remained seizure free.\n- Schizophrenia developed\t\tRefer to the medication table below\t\nOutcome\n- Seizure control\n- Moderate cognitive impairment\n- Later developed Schizophrenia\t\t\t\nER - emergency room, ICU - intensive care unit, CT MRI - Computed Tomography Magnetic Resonance Imaging, MRA/MRV - Magnetic resonance angiography and venography, EEG - Electroencephalography\n\nTable 2 Medication summary table.\n\nLocal hospital emergency room\tICU medication\tAntiepileptic medications in ICU\tDischarge medications\t\nMidazolam\tMidazolam\tPrednisolone\tCarbamazepine\t\nFentanyl\tFentanyl\tLevetiracetam\tLamotrigine\t\nPropofol\tPropofol\tCarbamazepine\tLevetiracetam\t\n\tKetamine\tPhenobarbital\tPhenobarbital\t\n\tThiopental\tPhenytoin\tLorazepam\t\n\tIV Ig\tLamotrigine\tEscitalopram\t\n\tHypothermia\tRanitidine\tRisperdal\t\n\tSteroid\tRisperdal\t\t\n\tRituximab\tEscitalopram\t\t\n\tWarfarin\tWarfarin\t\t\nICU - intensive care unit, IV Ig - intravenous immunoglobulin\n\nDiscussion\n\nAutoimmune disorders result in various neurological and psychiatric presentations. Antiphospholipid syndrome (APS), an acquired autoimmune disorder, can manifest a spectrum of clinical manifestations, including pregnancy morbidities; vasculopathies; and neuropsychiatric disorders such as stroke, seizures, and psychosis.4\n\nThe pathogenic mechanisms underlying APS are mostly complex or unclear. One mechanism of the pathogenesis of epilepsy secondary to APS could be linked to the immune-mediated response and vasculopathy inherent to APS. The vasculopathy is hypothesized to occur via the activation of endothelial cells, monocytes, and platelets, resulting in the overproduction of tissue factors and thromboxane A2.4 Autoimmune epilepsies are also known to be associated with refractory status epilepticus, the outcome of which is primarily determined by the underlying etiology of the seizures, age of the patient and duration of status epilepticus.5\n\nAn association between schizophrenia and autoimmune disorders such as APS has been previously documented. Although a coagulation pathway abnormality and immune-related phenomena have been suggested, the mechanisms underlying this association remains unclear,3,6 Since APS can manifest itself in the central nervous system as psychosis, we tend to believe that the schizophrenia could be a complication of the status epilepticus secondary to APS.7 However, we cannot dismiss the fact that schizophrenia could have been triggered by multiple factors, such as the use of antiepileptic medications that can cognitively impair epileptic patients.8\n\nA recent study has shown that the pathophysiology of schizophrenia and epilepsy seems to involve a common pathway of dysfunctional glutamatergic neurotransmission.9 Moreover, there has been a proved positive genetic correlation between schizophrenia and epilepsy.10 Although an association with refractory status epilepticus is yet to be investigated, the incidence of mental health disorders such as schizophrenia is very common in epileptic individuals.10 According to our literature review, other than a case report of a schizophrenic patient developing status epilepticus, schizophrenia following status epilepticus has, to our knowledge, never previously been documented.\n\nOur patient was in the intensive care unit (ICU) for 8 months with status epilepticus under continuous EEG monitoring. The patient underwent multiple trials of anti-epileptic medications and anesthesia to electrographically and clinically suppress seizures. These were successful, yielding a relatively good outcome. After ruling out symptoms of schizoaffective and mood disorders in addition to substance abuse and medical conditions, the patient met all the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia. These included visual hallucinations, delusions, disorganized speech, grossly disorganized behavior, continuous disturbance for more than 6 months, and social and occupational dysfunction.\n\nIn conclusion, we, therefore, advocate early referral of refractory status epilepticus patients to specialized centers in order to ensure better management. In addition, we recommend consistent psychiatric monitoring both inside and outside the ICU, particularly if an autoimmune disorder is suspected\n\nAcknowledgment\n\nWe would like to thank Mrs. Lamees Al Khateeb for assisting in the writing of the manuscript. We would also like to thank Editage [http://www.editage.com] for editing and reviewing this manuscript for English language. Moreover, Dr. Riyadh Al Aqaili was the radiologist in charge of the case.\n\nDisclosure. The authors declare no conflicting interests, support or funding from any drug company.\n==== Refs\n1 Hilger E Zimprich F Pataraia E Aull-Watschinger S Jung R Baumgartner C Psychoses in epilepsy:A comparison of postictal and interictal psychoses Epilepsy Behav 2016 60 58 62 27179193\n2 Meletti S Giovannini G d'Orsi G Toran L Monti G Guha R New-Onset Refractory Status Epilepticus with Claustrum Damage:Definition of the Clinical and Neuroimaging Features Front Neurol 2017 8 111 28396650\n3 Regina P Pnina R Natur A Yair L Anti-phospholipid syndrome associated with schizophrenia description of five patients and review of the literature Immunol Res 2017 65 438 446 28102512\n4 Muscal E Brey R Neurologic manifestations of the antiphospholipid syndrome:Integrating molecular and clinical lessons Curr Rheumatol Rep 2008 10 67 73 18457615\n5 Kirmani B Barr D Robinson D Pranske Z Fonkem E Benge J Management of Autoimmune Status Epilepticus Front Neurol 2018 9 259 29867707\n6 Hoirisch-Clapauch S Amaral O Mezzasalma M Panizzutti R Nardi A Dysfunction in the coagulation system and schizophrenia Transl Psychiatry 2016 6 704\n7 Graf J Central Nervous System Manifestations of Antiphospholipid Syndrome Rheum Dis Clin North Am 2017 43 547 560 29061241\n8 Cascella N Schretlen D Sawa A Schizophrenia and epilepsy:is there a shared susceptibility? Neurosci Res 2009 63 227 235 19367784\n9 Dedeurwaerdere S Boets S Janssens P Lavreysen H Steckler T In the grey zone between epilepsy and schizophrenia:alterations in group II metabotropic glutamate receptors Acta Neurol Belg 2015 115 221 232 25539775\n10 Vonberg F Bigdeli T Genetic Correlation Between Schizophrenia and Epilepsy JAMA Neurol 2016 73 125 126 26551756\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1319-6138",
"issue": "24(3)",
"journal": "Neurosciences (Riyadh, Saudi Arabia)",
"keywords": null,
"medline_ta": "Neurosciences (Riyadh)",
"mesh_terms": "D000328:Adult; D016736:Antiphospholipid Syndrome; D006801:Humans; D008297:Male; D012559:Schizophrenia; D013226:Status Epilepticus",
"nlm_unique_id": "101252453",
"other_id": null,
"pages": "240-244",
"pmc": null,
"pmid": "31380826",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28396650;26551756;27179193;26731441;19367784;28102512;18457615;29867707;29061241;25539775",
"title": "Schizophrenia following new-onset refractory status epilepticus secondary to antiphospholipid syndrome.",
"title_normalized": "schizophrenia following new onset refractory status epilepticus secondary to antiphospholipid syndrome"
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] |
{
"abstract": "OBJECTIVE\nPoppers have become legal in France since June 2013. Is their liberalisation associated with an increase of severe side effects observed?\n\n\nMETHODS\nTo identify elevated methaemoglobinaemia related to poppers abuse, we reviewed all methaemoglobin concentrations measured in Nantes university hospital, during 12 months.\n\n\nRESULTS\nMethaemoglobin concentrations were superior to 25% in three cases of poppers consumption that occurred after the legalisation.\n\n\nCONCLUSIONS\nEvaluating the prevalence of elevated methaemoglobinaemia could help to monitor severe complications of poppers use in France.",
"affiliations": "Pharmacology department, Nantes university hospital, Hôtel-Dieu, 9, quai Moncousu, 44093 Nantes cedex, France; Inserm U1246 Sphere \"methodS in Patient-centered outcomes and HEalth ResEarch\", Nantes university, institute of health research IRS, 44200 Nantes, France. Electronic address: [email protected].;Emergency department, Nantes university hospital, Hôtel-Dieu, 9, quai Moncousu, 44093 Nantes cedex, France. Electronic address: [email protected].;Biochemistry department, Nantes university hospital, Hôtel-Dieu, 44093 Nantes cedex, France.;Biochemistry department, Nantes university hospital, Hôtel-Dieu, 44093 Nantes cedex, France.;Psychiatry department, Nantes university hospital, Hôtel-Dieu, CAPPA-Jacques-Prevert, 44093 Nantes cedex 1, France.;Pharmacology department, Nantes university hospital, Hôtel-Dieu, 9, quai Moncousu, 44093 Nantes cedex, France; Inserm U1246 Sphere \"methodS in Patient-centered outcomes and HEalth ResEarch\", Nantes university, institute of health research IRS, 44200 Nantes, France; Addictology department, Nantes university hospital, hôpital Saint-Jacques, 44093 Nantes cedex 1, France.;Psychiatry department, Nantes university hospital, Hôtel-Dieu, CAPPA-Jacques-Prevert, 44093 Nantes cedex 1, France.;Inserm U1246 Sphere \"methodS in Patient-centered outcomes and HEalth ResEarch\", Nantes university, institute of health research IRS, 44200 Nantes, France; Addictology department, Nantes university hospital, hôpital Saint-Jacques, 44093 Nantes cedex 1, France.;Pharmacology department, Nantes university hospital, Hôtel-Dieu, 9, quai Moncousu, 44093 Nantes cedex, France; Inserm U1246 Sphere \"methodS in Patient-centered outcomes and HEalth ResEarch\", Nantes university, institute of health research IRS, 44200 Nantes, France.",
"authors": "Victorri-Vigneau|Caroline|C|;Trewick|David|D|;Dejoie|Thomas|T|;Masson|Damien|D|;Bulteau|Samuel|S|;Rousselet|Morgane|M|;Sauvaget|Anne|A|;Grall-Bronnec|Marie|M|;Jolliet|Pascale|P|",
"chemical_list": "D013287:Illicit Drugs; D014665:Vasodilator Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.therap.2017.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "73(3)",
"journal": "Therapie",
"keywords": "Abuse; Elevated methaemoglobinaemia; Poppers; Regulation",
"medline_ta": "Therapie",
"mesh_terms": "D000328:Adult; D005260:Female; D005602:France; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008708:Methemoglobinemia; D008875:Middle Aged; D014665:Vasodilator Agents; D055815:Young Adult",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "217-221",
"pmc": null,
"pmid": "29150022",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Poppers regulation for public sale: No measure in France yet.",
"title_normalized": "poppers regulation for public sale no measure in france yet"
} | [
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{
"abstract": "Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV-1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein-Barr virus disease with relevant meningoencephalitis responded to rituximab.",
"affiliations": "Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany. [email protected].;Institute of Medical Virology, Helmut-Ruska-Haus, Charité-Universitätsmedizin Berlin, and Labor Berlin Charité-Vivantes GmbH, Berlin, Germany.;Institute of Medical Virology, Helmut-Ruska-Haus, Charité-Universitätsmedizin Berlin, and Labor Berlin Charité-Vivantes GmbH, Berlin, Germany.;Institute of Virology and Antiviral Therapy, German Consulting Laboratory for HSV and VZV, Jena University Hospital, Jena, Germany.;Department of Pediatric Oncology/Hematology/SCT, Charité-Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Voigt|S|S|;Hofmann|J|J|;Edelmann|A|A|;Sauerbrei|A|A|;Kühl|J-S|JS|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D017245:Foscarnet; D000069283:Rituximab; C525733:brincidofovir; D003596:Cytosine; D000077404:Cidofovir; D000212:Acyclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Epstein-Barr virus; adenovirus; brincidofovir; hematopoietic stem cell transplantation; herpes simplex virus",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000212:Acyclovir; D000256:Adenoviridae; D000258:Adenovirus Infections, Human; D019072:Antibiotic Prophylaxis; D000998:Antiviral Agents; D002675:Child, Preschool; D000077404:Cidofovir; D003596:Cytosine; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D020031:Epstein-Barr Virus Infections; D005260:Female; D017245:Foscarnet; D018380:Hematopoietic Stem Cell Transplantation; D006561:Herpes Simplex; D006562:Herpes Zoster; D018259:Herpesvirus 1, Human; D014645:Herpesvirus 3, Human; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D008590:Meningoencephalitis; D052016:Mucositis; D009190:Myelodysplastic Syndromes; D063065:Organophosphonates; D000069283:Rituximab; D019562:Viral Load",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "791-794",
"pmc": null,
"pmid": "27482652",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Brincidofovir clearance of acyclovir-resistant herpes simplex virus-1 and adenovirus infection after stem cell transplantation.",
"title_normalized": "brincidofovir clearance of acyclovir resistant herpes simplex virus 1 and adenovirus infection after stem cell transplantation"
} | [
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ACICLOVIR"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THIOTEPA"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNKNOWN ()",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "THIOTEPA."
}
],
"patientagegroup": null,
"patientonsetage": "5",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Lymphoproliferative disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Viraemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Viral load increased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disease recurrence",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adenovirus infection",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Herpes simplex",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nervous system disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Epstein-Barr virus infection",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Encephalitis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pharyngitis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes simplex",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BRINCIDOFOVIR CLEARANCE OF ACYCLOVIR-RESISTANT HERPES SIMPLEX VIRUS-1 AND ADENOVIRUS INFECTION AFTER STEM CELL TRANSPLANTATION.",
"literaturereference_normalized": "brincidofovir clearance of acyclovir resistant herpes simplex virus 1 and adenovirus infection after stem cell transplantation",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "DE",
"receiptdate": "20181011",
"receivedate": "20181011",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 15487381,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
},
{
"companynumb": "DE-BAUSCH-BL-2018-023952",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
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"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "FLUDARABINE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "018604",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "3 X 10 MG/KG/DAY OR 3 X 15 MG/KG/DAY; ON DAYS 212?233; 260?270",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACICLOVIR"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstartdateformat": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ALEMTUZUMAB"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MELPHALAN."
}
],
"patientagegroup": null,
"patientonsetage": "5",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VOIGT S, HOFMANN J, EDELMANN A, SAUERBREI A, KUHL J. BRINCIDOFOVIR CLEARANCE OF ACYCLOVIR?RESISTANT HERPES SIMPLEX VIRUS?1 AND ADENOVIRUS INFECTION AFTER STEM CELL TRANSPLANTATION.",
"literaturereference_normalized": "brincidofovir clearance of acyclovir resistant herpes simplex virus 1 and adenovirus infection after stem cell transplantation",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20180921",
"receivedate": "20180903",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15343721,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "Immunotherapy with intravesical bacillus Calmette-Guérin (BCG) is considered the most effective adjuvant to endoscopic resection of bladder urothelial carcinoma in the therapeutic management of non-muscle invasive (NMIBC) at intermediate and high risk of recurrence and progression (pTa - pT1 and high-grade carcinoma in situ, CIS). Despite its proven efficacy, this type of treatment can determine local and systemic side effects of moderate or severe gravity, with the histological diagnosis of epithelioid granulomas in different organs, even in the absence of microbiological positivity of BCG. The immunotherapy with BCG is usually well tolerated and the virulence of the attenuated BCG is very low in immuno-competent patients, although only 16% of patients are able to receive all the instillations of the maintenance period (3 years) of treatment provided by the protocols, precisely because of side effects. Minor side effects usually resolve within a few hours or days. They develop in 3-5% of patients and usually consist of local infectious complications. Manifestations of BCG dissemination, such as vascular and ocular complications, are much less common, while BCG-disseminated infections, with granulomatous pneumonia or hepatitis present, are quite rare, representing 0.5-2% of the complications recorded. We present the clinical case of granulomatous lung and possibly liver infection caused by BCG in a patient aged 56 years being treated for several weeks with intravesical BCG for NIMBC pT1 high grade associated with CIS.",
"affiliations": "Pneumology Unit, Macerata Hospital Area Vasta 3, ASUR MARCHE, Macerata - Italy.;Urology Unit, Macerata Hospital Area Vasta 3, ASUR MARCHE, Macerata - Italy.;Radiology Unit, Macerata Hospital, Area Vasta 3, ASUR MARCHE, Macerata - Italy.;Pathology Unit, Macerata Hospital, Area Vasta 3, ASUR MARCHE, Macerata - Italy.;Urology Unit, Macerata Hospital Area Vasta 3, ASUR MARCHE, Macerata - Italy.;Pneumology Unit, Macerata Hospital Area Vasta 3, ASUR MARCHE, Macerata - Italy.",
"authors": "Rosati|Yuri|Y|;Fabiani|Andrea|A|;Taccari|Tommaso|T|;Ranaldi|Renzo|R|;Mammana|Gabriele|G|;Tubaldi|Alberto|A|",
"chemical_list": "D000276:Adjuvants, Immunologic; D001500:BCG Vaccine",
"country": "United States",
"delete": false,
"doi": "10.5301/uro.5000130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-5603",
"issue": "83(1)",
"journal": "Urologia",
"keywords": null,
"medline_ta": "Urologia",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000283:Administration, Intravesical; D001500:BCG Vaccine; D002295:Carcinoma, Transitional Cell; D006801:Humans; D008875:Middle Aged; D014391:Tuberculosis, Miliary; D014397:Tuberculosis, Pulmonary; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0417372",
"other_id": null,
"pages": "49-53",
"pmc": null,
"pmid": "26616461",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravesical BCG therapy as cause of miliary pulmonary tuberculosis.",
"title_normalized": "intravesical bcg therapy as cause of miliary pulmonary tuberculosis"
} | [
{
"companynumb": "IT-SA-2017SA083378",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": null,
"drugadministrationroute": "043",
"drugauthorizationnumb": "103943",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "SIXTH DOSE (WEEKLY ADMINISTRATION OF INDUCTION CYCLES)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BLADDER CANCER STAGE I, WITH CANCER IN SITU",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BCG FOR IMMUNOTHERAPY"
}
],
"patientagegroup": "5",
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disseminated Bacillus Calmette-Guerin infection",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Disseminated tuberculosis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hepatic infection",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hyperpyrexia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pulmonary mass",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pulmonary granuloma",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cholestasis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ROSATI Y, FABIANI A, TACCARI T, RANALDI R, MAMMANA G, TUBALDI A. INTRAVESICAL BCG THERAPY AS CAUSE OF MILIARY PULMONARY TUBERCULOSIS. UROLOGIA 2016; 83 (1):49-53.",
"literaturereference_normalized": "intravesical bcg therapy as cause of miliary pulmonary tuberculosis",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20170519",
"receivedate": "20170516",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13549550,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "The off-label use of TNF antagonists in refractory sarcoidosis is increasingly reported but data on their efficacy and safety are still insufficient.\n\n\n\nTo report on efficacy and safety of TNF antagonists in severe and refractory sarcoidosis.\n\n\n\nExamination of retrospective demographic, clinical, therapeutic, and adverse event data on 132 sarcoidosis patients (58% women; mean (min-max) age = 45.5 (14-78) years) given TNF antagonists (mainly infliximab, 91%) and investigation of response-linked factors.\n\n\n\nThe overall clinical response (complete and partial) rate was 64%. TNF-antagonist efficacy (i.e., significant decrease of the ePOST score) was noted in cases with neurologic, heart, skin, and upper respiratory tract involvements. No significant difference in efficacy was found between anti-TNF used alone and TNF with immunosuppressant. The use of anti-TNF allowed reducing prednisone dosage at end of follow-up (p < 0.001). Adverse events were observed in 52% of the patients; they included infections (36%) and allergic reactions (8%) and required treatment interruption in 31 cases (23%). When TNF antagonists were interrupted, 13 patients experienced relapses within 14 months on average (median follow-up: 20.5 months).\n\n\n\nTNF antagonists were efficacious in about two-thirds of patients with severe/refractory sarcoidosis but their use led to a high rate of adverse events.",
"affiliations": "Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande rue de la Croix-Rousse F-69004, Lyon, France; Université Claude Bernard-Lyon 1, Villeurbanne, France.;Service de Médecine Interne 2, Institut E3M, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Paris VI, Paris, France.;Service de Médecine Interne et d׳Immunologie Clinique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.;Université Claude Bernard-Lyon 1, Villeurbanne, France; Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France; CNRS UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne, France.;Université Claude Bernard-Lyon 1, Villeurbanne, France; Service de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, F-Lyon, France.;Université Claude Bernard-Lyon 1, Villeurbanne, France; Service de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, F-Lyon, France.;Clinique de médecine interne, pôle pluridisciplinaire de médecine et de gérontologie clinique, Centre Hospitalier Universitaire Grenoble-Alpes, CS10217, Grenoble, France.;Clinique de médecine interne, pôle pluridisciplinaire de médecine et de gérontologie clinique, Centre Hospitalier Universitaire Grenoble-Alpes, CS10217, Grenoble, France.;Service de Médecine Interne, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France.;Service de Médecine Interne, Centre Hospitalier Universitaire Le Bocage, Dijon, France.;Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France.;Service de Médecine Interne, Centre Hospitalier Universitaire Gabriel Montpied, Clermont-Ferrand, France.;Service de Médecine Interne et d׳Immunologie Clinique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, UMR 1184, Le Kremlin Bicêtre, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Caen, Caen, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Rouen Rouen, France.;Université Claude Bernard-Lyon 1, Villeurbanne, France; Service de Neurologie, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.;Service d׳Ophtalmologie, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Paris VI, Paris, France.;Service de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, F-Lyon, France.;Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France; CNRS UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne, France.;Service de Médecine Interne 2, Institut E3M, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Paris VI, Paris, France.;Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande rue de la Croix-Rousse F-69004, Lyon, France; Université Claude Bernard-Lyon 1, Villeurbanne, France.;Service de Médecine Interne et d׳Immunologie Clinique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.;Service de Médecine Interne et d׳Immunologie Clinique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.;Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France.;Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 103 Grande rue de la Croix-Rousse F-69004, Lyon, France; Université Claude Bernard-Lyon 1, Villeurbanne, France. Electronic address: [email protected].",
"authors": "Jamilloux|Yvan|Y|;Cohen-Aubart|Fleur|F|;Chapelon-Abric|Catherine|C|;Maucort-Boulch|Delphine|D|;Marquet|Alicia|A|;Pérard|Laurent|L|;Bouillet|Laurence|L|;Deroux|Alban|A|;Abad|Sébastien|S|;Bielefeld|Philip|P|;Bouvry|Diane|D|;André|Marc|M|;Noel|Nicolas|N|;Bienvenu|Boris|B|;Proux|Alice|A|;Vukusic|Sandra|S|;Bodaghi|Bahram|B|;Sarrot-Reynauld|Françoise|F|;Iwaz|Jean|J|;Amoura|Zahir|Z|;Broussolle|Christiane|C|;Cacoub|Patrice|P|;Saadoun|David|D|;Valeyre|Dominique|D|;Sève|Pascal|P|;|||",
"chemical_list": "D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.semarthrit.2017.03.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "47(2)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Efficacy; Safety; Sarcoidosis; TNF antagonist",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012507:Sarcoidosis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "288-294",
"pmc": null,
"pmid": "28392046",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients.",
"title_normalized": "efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis a multicenter study of 132 patients"
} | [
{
"companynumb": "FR-JNJFOC-20171214773",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
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] |
{
"abstract": "Introduction,: Graft-versus-host disease (GVHD) is a recognized complication of allogeneic stem cell transplantation (allo-SCT) and may affect muscle. We investigated the incidence and subtypes of inflammatory myopathy (IM) in South Australian recipients of allo-SCT.\n\n\n\nRecipients of allo-SCT from 2004 to 2014 at the Royal Adelaide Hospital were identified. Records were reviewed to identify patients with weakness, creatine kinase (CK) elevation, and muscle biopsy confirming IM.\n\n\n\nWeakness was present in 32 of 224 patients who received allo-SCT patients reviewed, and CK was raised in 7 of 20 patients with weakness. Six patients developed biopsy-confirmed IM; 3 patients had chronic GVHD-related myopathy, 2 had necrotizing myopathy, and 1 had dermatomyositis (DM) associated with anti-melanoma differentiation associated protein 5 (MDA5) antibodies. The incidence of IM was calculated to be 2 cases per thousand annually.\n\n\n\nAmong recipients of allo-SCT, weakness is common, and the incidence of IM is increased. Histopathological diagnoses are varied, and we report findings of necrotizing myopathy and anti-MDA5-associated DM. Muscle Nerve 58:790-795, 2018.",
"affiliations": "University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia.;SA Pathology, Adelaide, South Australia, Australia.;SA Pathology, Adelaide, South Australia, Australia.;SA Pathology, Adelaide, South Australia, Australia.;Department of Rheumatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.;Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.;Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.;University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia.;University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia.;Department of Rheumatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"authors": "New-Tolley|Julia|J|;Smith|Caroline|C|;Koszyca|Barbara|B|;Otto|Sophia|S|;Maundrell|Adam|A|;Bardy|Peter|P|;Hiwase|Devendra|D|;Yong|Agnes S M|ASM|;Lewis|Ian|I|;Limaye|Vidya|V|",
"chemical_list": "D015703:Antigens, CD; D006649:Histocompatibility Antigens; D003402:Creatine Kinase",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.26341",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "58(6)",
"journal": "Muscle & nerve",
"keywords": "graft-versus-host disease; inflammatory myopathy; myositis; stem cell transplant; weakness",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D015703:Antigens, CD; D001315:Australia; D003402:Creatine Kinase; D004576:Electromyography; D005260:Female; D006086:Graft vs Host Disease; D006649:Histocompatibility Antigens; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness; D009220:Myositis; D011183:Postoperative Complications; D015995:Prevalence; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D055815:Young Adult",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "790-795",
"pmc": null,
"pmid": "30194844",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Inflammatory myopathies after allogeneic stem cell transplantation.",
"title_normalized": "inflammatory myopathies after allogeneic stem cell transplantation"
} | [
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{
"abstract": "A 21-year-old, gravida 1, para O, woman presented at approximately 25 weeks gestation with a large Ewing's sarcoma involving her iliac wing. She was treated with multiagent chemotherapy before a successful Cesarean delivery of a normal infant at approximately 34 weeks gestation. Four years later both the mother and child are doing well. The literature regarding sarcoma occurring during pregnancy and that regarding multiagent chemotherapy in pregnant patients is reviewed. Chemotherapy should be instituted early in the course of many malignant sarcomas, despite pregnancy, to prevent the occurrence of metastases.",
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"authors": "Haerr|R W|RW|;Pratt|A T|AT|",
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"issue": "56(5)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D005260:Female; D006801:Humans; D007085:Ilium; D007231:Infant, Newborn; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D012512:Sarcoma, Ewing; D014057:Tomography, X-Ray Computed",
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"pages": "1028-33",
"pmc": null,
"pmid": "4016693",
"pubdate": "1985-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Multiagent chemotherapy for sarcoma diagnosed during pregnancy.",
"title_normalized": "multiagent chemotherapy for sarcoma diagnosed during pregnancy"
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"abstract": "BACKGROUND\nCompliance with WHO guidelines on HBV screening and treatment in HIV-coinfected patients is often challenging in resource limited countries and has been poorly assessed in sub-Saharan Africa.\n\n\nMETHODS\nBetween 2015 and 2016, we assessed physician's compliance with WHO guidelines on HIV-HBV coinfection in the largest HIV clinic in The Gambia, and the hepatic outcomes in HIV-HBV coinfected patients as compared to randomly selected HIV-monoinfected controls.\n\n\nRESULTS\n870 HIV-infected patients regularly seen in this clinic agreed to participate in our study. Only 187 (21.5%, 95% CI 18.8-24.3) had previously been screened for HBsAg, 23 (12.3%, 95% CI 8.0-17.9) were positive of whom none had liver assessment and only 6 (26.1%) had received Tenofovir. Our HBV testing intervention was accepted by all participants and found 94/870 (10.8%, 95% CI 8.8-13.1) positive, 78 of whom underwent full liver assessment along with 40 HBsAg-negative controls. At the time of liver assessment, 61/78 (78.2%) HIV-HBV coinfected patients received ART with 7 (11.5%) on Tenofovir and 54 (88.5%) on Lamivudine alone. HIV-HBV coinfected patients had higher APRI score compared to controls (0.58 vs 0.42, p = 0.002). HBV DNA was detectable in 52/53 (98.1%) coinfected patients with 14/53 (26.4%) having HBV DNA >20,000 IU/L. 10/12 (83.3%) had at least one detectable 3TC-associated HBV resistance, which tended to be associated with increase in liver fibrosis after adjusting for age and sex (p = 0.05).\n\n\nCONCLUSIONS\nCompliance with HBV testing and treatment guidelines is poor in this Gambian HIV programme putting coinfected patients at risk of liver complications. However, the excellent uptake of HBV screening and linkage to care in our study suggests feasible improvements.",
"affiliations": "Division of Digestive Diseases, Department of Surgery & Cancer, St. Mary's Hospital Campus, Imperial College London, United Kingdom.;Section of Virology, Department of Medicine, Imperial College London, London, United Kingdom.;Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France.;Hepatitis Unit, Disease Control & Elimination, MRC Unit The Gambia, Fajara, The Gambia.;Hepatitis Unit, Disease Control & Elimination, MRC Unit The Gambia, Fajara, The Gambia.;Hepatitis Unit, Disease Control & Elimination, MRC Unit The Gambia, Fajara, The Gambia.;Laboratoire Bactériologie-Virologie, CHU Aristide Le Dantec, Université Cheikh Anta DIOP, Dakar, Senegal.;Laboratoire Bactériologie-Virologie, CHU Aristide Le Dantec, Université Cheikh Anta DIOP, Dakar, Senegal.;Division of Digestive Diseases, Department of Surgery & Cancer, St. Mary's Hospital Campus, Imperial College London, United Kingdom.;Hands on Care HIV Clinic, Brikama Health Centre, Brikama, The Gambia.;Hepatitis Unit, Disease Control & Elimination, MRC Unit The Gambia, Fajara, The Gambia.;Division of Digestive Diseases, Department of Surgery & Cancer, St. Mary's Hospital Campus, Imperial College London, United Kingdom.;Division of Digestive Diseases, Department of Surgery & Cancer, St. Mary's Hospital Campus, Imperial College London, United Kingdom.",
"authors": "Ndow|Gibril|G|http://orcid.org/0000-0001-5837-5110;Gore|Mindy L|ML|;Shimakawa|Yusuke|Y|;Suso|Penda|P|;Jatta|Abdoulie|A|;Tamba|Saydiba|S|;Sow|Amina|A|;Touré-Kane|Coumba|C|;Sadiq|Fouzia|F|;Sabally|Saihou|S|;Njie|Ramou|R|;Thursz|Mark R|MR|;Lemoine|Maud|M|",
"chemical_list": "D000998:Antiviral Agents; D019259:Lamivudine; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0179025",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0179025PONE-D-17-11255Research ArticleBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesLiver FibrosisBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis B virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis B virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis B virusMedicine and health sciencesInfectious diseasesViral diseasesHIV infectionsMedicine and health sciencesInfectious diseasesViral diseasesHepatitisHepatitis BMedicine and health sciencesGastroenterology and hepatologyLiver diseasesInfectious hepatitisHepatitis BMedicine and Health SciencesInfectious DiseasesCo-InfectionsPeople and PlacesGeographical LocationsAfricaGambiaMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementHepatitis B testing and treatment in HIV patients in The Gambia—Compliance with international guidelines and clinical outcomes HBV testing and treatment in HIV patientshttp://orcid.org/0000-0001-5837-5110Ndow Gibril 12*Gore Mindy L. 3Shimakawa Yusuke 4Suso Penda 2Jatta Abdoulie 2Tamba Saydiba 2Sow Amina 5Touré-Kane Coumba 5Sadiq Fouzia 1Sabally Saihou 6Njie Ramou 27Thursz Mark R. 1Lemoine Maud 11 Division of Digestive Diseases, Department of Surgery & Cancer, St. Mary’s Hospital Campus, Imperial College London, United Kingdom2 Hepatitis Unit, Disease Control & Elimination, MRC Unit The Gambia, Fajara, The Gambia3 Section of Virology, Department of Medicine, Imperial College London, London, United Kingdom4 Unité d’Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France5 Laboratoire Bactériologie-Virologie, CHU Aristide Le Dantec, Université Cheikh Anta DIOP, Dakar, Senegal6 Hands on Care HIV Clinic, Brikama Health Centre, Brikama, The Gambia7 International Agency for Research on Cancer (IARC), WHO, Lyon, FranceChemin Isabelle A EditorCentre de Recherche en Cancerologie de Lyon, FRANCECompeting Interests: The authors have declared that no competing interests exist.\n\nConceptualization: GN SS RN MRT ML.\n\nData curation: GN YS.\n\nFormal analysis: GN MLG YS MRT ML.\n\nFunding acquisition: GN RN MRT ML.\n\nInvestigation: GN MLG PS AJ ST AS CTK FS.\n\nMethodology: GN MLG YS SS RN MRT ML.\n\nProject administration: GN MRT ML.\n\nResources: GN MLG AS CTK SS RN MRT ML.\n\nSupervision: SS RN MRT ML.\n\nValidation: MLG AS CTK.\n\nVisualization: GN MLG YS MRT ML.\n\nWriting – original draft: GN MLG YS MRT ML.\n\nWriting – review & editing: GN MLG YS PS AJ ST AS CTK FS SS RN MRT ML.\n\n\n\n\n* E-mail: [email protected] 6 2017 2017 12 6 e017902522 3 2017 24 4 2017 © 2017 Ndow et al2017Ndow et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nCompliance with WHO guidelines on HBV screening and treatment in HIV-coinfected patients is often challenging in resource limited countries and has been poorly assessed in sub-Saharan Africa.\n\nMethods\nBetween 2015 and 2016, we assessed physician’s compliance with WHO guidelines on HIV-HBV coinfection in the largest HIV clinic in The Gambia, and the hepatic outcomes in HIV-HBV coinfected patients as compared to randomly selected HIV-monoinfected controls.\n\nResults\n870 HIV-infected patients regularly seen in this clinic agreed to participate in our study. Only 187 (21.5%, 95% CI 18.8–24.3) had previously been screened for HBsAg, 23 (12.3%, 95% CI 8.0–17.9) were positive of whom none had liver assessment and only 6 (26.1%) had received Tenofovir. Our HBV testing intervention was accepted by all participants and found 94/870 (10.8%, 95% CI 8.8–13.1) positive, 78 of whom underwent full liver assessment along with 40 HBsAg-negative controls. At the time of liver assessment, 61/78 (78.2%) HIV-HBV coinfected patients received ART with 7 (11.5%) on Tenofovir and 54 (88.5%) on Lamivudine alone. HIV-HBV coinfected patients had higher APRI score compared to controls (0.58 vs 0.42, p = 0.002). HBV DNA was detectable in 52/53 (98.1%) coinfected patients with 14/53 (26.4%) having HBV DNA >20,000 IU/L. 10/12 (83.3%) had at least one detectable 3TC-associated HBV resistance, which tended to be associated with increase in liver fibrosis after adjusting for age and sex (p = 0.05).\n\nConclusions\nCompliance with HBV testing and treatment guidelines is poor in this Gambian HIV programme putting coinfected patients at risk of liver complications. However, the excellent uptake of HBV screening and linkage to care in our study suggests feasible improvements.\n\nWellcome Trust-Imperial College Institutional Strategic Support Fund (ISSF) fellowshiphttp://orcid.org/0000-0001-5837-5110Ndow Gibril Wellcome Trust-Imperial College Centre for Global Health Researchhttp://orcid.org/0000-0001-5837-5110Ndow Gibril NIHR Imperial Biomedical Research CentreThursz Mark R. EU 7th Framework Programme (FP7-AFRICA-2010)Grant number 265994Thursz Mark R. http://dx.doi.org/10.13039/100004440Wellcome Trust104771/Z/14/ZThis work was supported by a Wellcome Trust-Imperial College Institutional Strategic Support Fund (ISSF) fellowship awarded to GN. Additional funding was provided by the Wellcome Trust-Imperial College Centre for Global Health Research (GN), the NIHR Imperial Biomedical Research Centre (MRT), and the EU 7th Framework Programme (FP7-AFRICA-2010, Collaborative Project PROLIFICA, Grant Nr. 265994). MLG is supported by a Wellcome Trust grant (award number 104771/Z/14/Z awarded to Dr Marcus Dorner). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of this manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nChronic hepatitis B virus (CHB) infection is a major public health problem and a leading cause of morbidity and mortality globally. It affects approximately 250 million persons worldwide [1] and accounts for 650,000 deaths annually [2]. Without effective interventions and treatment, CHB infection will lead to an estimated 11.8 million deaths by 2030, primarily as a result of cirrhosis and hepatocellular carcinoma (HCC) [3]. Most of these deaths will occur in low-income countries (LICs) in sub-Saharan Africa (sSA) and Asia where CHB infection is endemic.\n\nThe World Health Assembly (WHA), in response to the increasing CHB–related morbidity and mortality, adopted a resolution to improve viral hepatitis prevention, testing and treatment worldwide [4]. Subsequently, the United Nations General Assembly and the World Health Organisation (WHO) respectively incorporated viral hepatitis elimination in the 2030 Agenda for Sustainable Development [5,6] and the WHO global health sector strategy on viral hepatitis 2016–2021 [3,7]. The WHO further recommends hepatitis B surface antigen (HBsAg) testing for all HIV-infected patients, and highly active antiretroviral therapy (HAART) containing at least two drugs effective against hepatitis B virus (HBV) for all HIV-HBV coinfected patients irrespective of disease stage or CD4 count [8], or where not feasible to treat patients with severe liver disease [9].\n\nWhilst both HIV and HBV are endemic in sSA, the prevalence of HIV-HBV coinfection is highest in West Africa [10] where as many as 1 in 10 HIV-infected patients is coinfected with HBV. Uncontrolled HIV-HBV coinfection, due either to lack of or ineffective antiretroviral therapy (ART), increases the risk of death by more than twofold compared to HIV-monoinfected patients [11], irrespective of presence of liver disease [12]. Early and effective Tenofovir Disoproxil Fumarate (TDF) based ART, on the other hand, reduces risk of death among coinfected patients [10,11] underlying the need for implementing universal HBV testing and prompt ART treatment [8].\n\nThe Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) programme in 2016 found high HIV and HBV prevalence among Gambian communities (2% and 8.5% respectively), with poor knowledge of hepatitis B and limited access to screening and treatment for HBV infection [13]. One of Africa’s smallest and poorest nations, The Gambia has one of the highest prevalence of HCC in West Africa [14] with two-thirds of these cases attributable to HBV infection [15]. In order to comply with the recent WHO goal for HBV elimination, we assessed the coverage of hepatitis B testing and treatment, and its impact on clinical outcomes in the largest HIV treatment centre in The Gambia, West Africa.\n\nMaterials and methods\nPatients and study design\nThis cross-sectional study enrolled HIV infected patients aged ≥18years (range 22–63 years) registered at the Hands on Care HIV clinic in Brikama (The Gambia) who have had at least two successful clinic visits and baseline investigations. After written consent, we reviewed patient case notes to determine the coverage of hepatitis B surface antigen (HBsAg) testing for all HIV patients and use of TDF-based ART for known HIV-HBV coinfected patients. Thereafter, we screened the patients for HBsAg using the Determine® rapid point-of-care kit (Alere®, USA). All HBsAg positive patients (HIV-HBV coinfected) and randomly selected HBsAg negative controls (HIV-monoinfected) had confirmatory HBsAg serology test (Architect HBsAg, Abbott, USA) and were further invited for complete liver assessment. Demographic and clinical information such as age, gender, past medical history, duration of HIV infection and antiretroviral drug exposure were collected, and a clinical examination and bedside ultrasonography performed. Liver transaminases (Vitros 350 Analyzer, Ortho Clinical Diagnostics, USA), haemoglobin and platelet count (CELL-DYN 3700 sample loader, Abbott, USA), HIV RNA (Abbott Real Time HIV-1 assay, 40copies/mL limit of detection), CD4+ T-cell count (flow cytometry) and in-house HBV DNA viral load quantification [16] were measured for all patients.\n\nAssessment of liver fibrosis\nIn accordance with WHO guidelines for setting without access a transient elastography device (Fibroscan), we assessed liver fibrosis using biochemical markers—aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and FIB-4. APRI was calculated as [AST level (IU/L) / upper limit of normal for AST (IU/L) × 100/platelet count (109/L)], and FIB-4 as [age (years) x AST (IU/L) / (platelet count (109/L) x ALT (IU/L)1/2)]. Significant fibrosis defined was defined as APRI >1.5 [17] or FIB-4 >3.25 [18].\n\nHBV molecular analysis and polymerase gene sequencing\nDNA was extracted from 500μL plasma using the QIAamp DNA Blood MiniKit (QIAgen, Germany). HBV DNA was quantified was by TaqMan based quantitative PCR assay with lower limit of detection of 50IU/L [16], using probe (200nM) sequence HBVTAQPR:5'FAM-CCTCTKCATCCTGCTGCTATGCCTCATC-3’MGBNFQ with forward and reverse primer (400nM) sequences HBVTAQ1:5'-GTGTCTGCGGCGTTTTATCA-3' and HBVTAQ2:5'-GACAAACGGGCAACATACCTT-3’ respectively [19]. Hepatitis B polymerase gene sequence was assessed in all participants with HBV DNA viral load ≥20,000IU/L.\n\nThe region from nucleotide 101 to 1149 of the HBV polymerase (pol) gene containing the highly conserved tyrosine-methionine-aspartate-aspartate (YMDD) motif was amplified by standard PCR using high fidelity polymerases (Supermix High Fidelity polymerase from Invitrogen or Q5® High-Fidelity DNA Polymerase from New England BioLabs) and primers sense 5’-AYTGTCTCTTCCAYMTCRTC-3’ and antisense 5’-GGGGTAAAGGTTCAGRTAYTG-3’. Genotype of the amplified sequence was assessed using the NCBI genotyping tool [20].\n\nStatistical analyses\nDemographic, clinical and virological characteristics of the study participants were presented according to their HBsAg status, and comparison made between HIV-monoinfected and HIV-HBV coinfected patients using the chi-squared test, Fisher’s exact test, or Wilcoxon rank-sum test. Factors associated with significant fibrosis (APRI >1.5) were identified using univariable logistic regression. As the number of participants with APRI >1.5 was small, multivariable analysis was not performed.\n\nEthical approval\nThe MRC Scientific Coordinating committee and the joint Gambia Government/MRC Ethics committee approved this study (SCC1388). Consenting of participants followed group and individual sensitization, explanation of a study protocol and sufficient time for questions and discussion with spouse/family.\n\nResults\nStudy population and compliance with guidelines\nBetween September 2015 and February 2016, 870 HIV-infected patients regularly seen at the Hands on Care HIV clinic were invited to participate in our study and all agreed to take part. The review of patient case notes revealed that only 187 (21.5%, 95% CI 18.8–24.3) had previously been tested for HBsAg, with 23 (12.3%, 95% CI 8.0–17.9) found to be HIV-HBV coinfected. None had a liver assessment based on liver transaminases, ultrasound, measurement of liver fibrosis or liver biopsy. Whilst all 23 patients previously known to be coinfected had been receiving ART, only 6 (26.1%, 95 CI 10.2–48.4) had received a TDF-based regimen.\n\nOf 870 patients accepted for the HBsAg screening, 94 tested positive giving a seroprevalence of 10.8% (95% CI 8.8–13.1). Of these, 15 (16%) were lost to follow up, and 1 died before the liver assessment. The remaining 78 HIV-HBV coinfected patients underwent full liver assessment, along with 40 randomly selected HBsAg negative controls (Fig 1).\n\n10.1371/journal.pone.0179025.g001Fig 1 Flow diagram of the study population.\nOf the 78 coinfected patients who completed liver assessment as part of our study, 61 (78.2%, 95% CI 67.4–86.1) received ART, with 54/61 (88.5%, 95% CI 77.4–94.5) receiving Lamivudine (3TC) without TDF and only 7/61 (11.5%) receiving a TDF-based regimen. Median transaminase was within normal limits with only 5 patients (6.4%) having ALT above the upper limit of normal (ULN) and 1 (1.3%) with ALT >2xULN. Table 1 provides the characteristics of the study population by HBsAg status.\n\n10.1371/journal.pone.0179025.t001Table 1 Characteristics of the study population by HBV coinfection.\nParameters\tHIV-HBV (n = 78)\tHIV (n = 40)\tP value\t\nMedian age (years, IQR)\t38 (35–48)\t42 (35–46)\t0.5\t\nMale sex (n, %)\t8 (20)\t16 (21)\t0.9\t\nMedian BMI (Kg/m2, IQR)\t21 (19–24)\t22 (20–25)\t0.4\t\nHIV infection type (n, %)\nHIV1\nHIV2\nHIV1+2\t\n58 (78)\n3 (4)\n13 (18)\t\n34 (90)\n2 (5)\n2 (5)\t0.2\t\nMedian duration since HIV diagnosis (months, IQR)\t34 (14–68)\t66 (20–82)\t0.04\t\nCD4+ T-cell count (n, %)\n<200 cells/mm3\n≥200 cells/mm3\t\n24 (34)\n46 (66)\t\n13 (34)\n25 (66)\t1.0\t\nMedian CD4+ T-cell count (cells/mm3, IQR)\t293.5 (147–444)\t302 (170–411)\t0.7\t\nHIV RNA (n, %)\nUndetectable\nDetectable\t\n30 (53)\n27 (47)\t\n26 (70)\n11 (30)\t0.09\t\nMedian HIV RNA (log copies/mL, IQR)\t4.1 (3.2–5.0)\t4.2 (3.2–4.6)\t0.7\t\nHBV DNA (n, %)\nUndetectable\n50–2,000 IU/mL\n2,000–20,000 IU/mL\n≥2, 000 IU/mL\t\n1 (1)\n46 (60)\n12 (16)\n18 (23)\tNA\tNA\t\nMedian ALT (IU/L, IQR)\t15 (12–25)\t17 (11–26)\t0.9\t\nMedian AST (IU/L, IQR)\t28 (24–40)\t24 (19–30)\t0.004\t\nMedian platelet count (x109/L, IQR)\t186 (152–220)\t198 (163–238)\t0.1\t\nAPRI (n, %)\n<0.5\n0.5–1.5\n≥1.5\t\n29 (39)\n38 (51)\n7 (10)\t\n27 (69)\n12 (31)\n0\t0.005\t\nMedian APRI (IQR)\t0.58 (0.43–0.88)\t0.42 (0.35–0.53)\t0.002\t\nFIB-4 (n, %)\n<1.45\n1.45–3.25\n≥3.25\t\n30 (40)\n39 (53)\n5 (7)\t\n25 (64)\n14 (36)\n0\t0.03\t\nMedian FIB-4 (IQR)\t1.72 (1.22–2.34)\t1.35 (1.06–1.63)\t0.004\t\nART regimen (n, %)\nNever treated\n3TC without TDF\nTDF\t\n17 (22)\n54 (69)\n7 (9)\t\n5 (13)\n29 (74)\n5 (13)\t0.5\t\nDuration of 3TC exposure (n, %)*, **\n<12 months\n12–60 months\n≥60 months\t\n14 (23)\n32 (52)\n15 (25)\t\n7 (21)\n13 (38)\n14 (41)\t0.2\t\n*This analysis only includes those who have ever received ART;\n\n**3TC without a second HBV active anti-viral drug\n\nALT—alanine aminotransferase; APRI—AST to platelet ratio index; ART—antiretroviral therapy; AST—aspartate aminotransferase; BMI—body mass index; HIV—Human Immunodeficiency virus; RNA—ribonucleic acid; TDF—Tenofovir Disoproxil Fumarate; 3TC—Lamivudine\n\nAssessment of liver fibrosis\nCompared to HIV-monoinfected patients, HIV-HBV coinfected patients had significantly higher median APRI (0.42 vs 0.58, p = 0.002) and FIB-4 (1.72 vs 1.35, p = 0.004), suggesting higher rate of liver fibrosis in coinfected patients. Table 2 shows the factors associated with significant liver fibrosis.\n\n10.1371/journal.pone.0179025.t002Table 2 Factors associated with significant liver fibrosis (APRI ≥1.5) in HIV-infected participants (n = 113).\n\tPrevalence of significant fibrosis (%)\tCrude odds ratios\t\nOR, 95% CI\tP value\t\nAge group\n<40\n≥40\t\n5/58 (9)\n2/55 (4)\t\n1.0\n0.4 (0.1–2.2)\t0.3\t\nSex\nWomen\nMen\t\n6/90 (7)\n1/23 (4)\t\n1.0\n0.6 (0.1–5.6)\t0.7\t\nBMI\n<25\n≥25\t\n7/86 (8)\n0/27 (0)\t\n1.0\nNA\t0.1\t\nSteatosis\nNo\nYes\t\n6/105 (6)\n1/8 (13)\t\n1.0\n2.4 (0.2–22.4)\t0.5\t\nHIV infection type\nHIV1\nHIV2\nHIV1+2\t\n3/89 (3)\n0/4 (0)\n3/15 (20)\t\n1.0\nNA\n7.2 (1.3–39.6)\t0.02\t\nHIV RNA\nUndetectable\nDetectable\t\n0/53 (0)\n6/37 (16)\t\nNA\t0.002\t\nCD4+ T-cell count\n<200 cells/mm3\n≥200 cells/mm3\t\n1/36 (3)\n5/68 (7)\t\n1.0\n2.8 (0.3–24.7)\t0.4\t\nHBV co-infection\nNo\nYes\t\n0/39 (0)\n7/74 (10)\t\nNA\t0.04\t\nART\nNever\n3TC without TDF\nTDF\t\n2/19 (11)\n5/82 (6)\n0/11 (0)\t\n1.0\n0.6 (0.1–3.1)\nNA\t0.5\t\nHBV molecular virology in 3TC exposed patients\nOf 54 coinfected patients who were treated with 3TC without TDF, after a median duration of 28 months (IQR 12–60) on 3TC, HBV DNA and HIV RNA were detectable in 52/53 (98.1%, 95% CI 87.1–99.8) and 15/38 (39.5%, 95% CI 24.8–56.3) respectively. 14 of 53 (26.4%, 95% CI 16.0–40.3) had HBV DNA >20,000 IU/L. We successfully sequenced the region of the polymerase gene containing the YMDD motif in 12 of these 14 patients. 10 (83.3%) had M204V/I mutations present, with 8 (66.7%) having additional compensatory mutations at rtL180M and 3 (25.0%) at both rtL180M and rtV173L. Phylogenetic analysis of the polymerase gene sequence showed all but one patient (HBV genotype A) were infected with HBV genotype E.\n\nWe assessed the joint effect of HBV co-infection and 3TC resistance mutations on significant fibrosis (APRI >1.5) in HIV-infected patients. Compared to mono-infected, the prevalence of significant fibrosis was higher in those coinfected, and especially in those with 3TC resistance mutations. While no HIV-monoinfected patients (0/39) had significant fibrosis, 6/66 (9%) of patients coinfected with wild type HBV and 1/8 (13%) coinfected with resistant HBV strain had significant fibrosis (p for trend 0.05).\n\nDiscussion\nIn The Gambia, a West African country highly endemic for HBV infection [13], our study provides two key messages: 1) poor compliance with the WHO hepatitis B testing and treatment guidelines [9] is poor with only 21.5% of HIV patients systematically screened for HBV infection and less than 15% on TDF-based ART, which puts HIV patients at risk of liver complications; 2) testing and linkage to care for HBV infection in HIV patients is accepted and feasible in HIV care programme in The Gambia.\n\nTo date, the compliance with the WHO guidelines [8,9] on the management of HBV and HIV coinfection in sSA—a region with high HIV-HBV coinfection prevalence [10], has been poorly documented. We found that in 2016, despite strong international recommendations and increasing global commitment to HBV elimination, HBsAg testing and effective HBV treatment remains poor in the largest Gambian HIV facility predisposing coinfected patients to severe clinical and virological outcomes, increased risk of liver-related morbidity, and diminished benefits of ART.\n\nIn our study, none of the 870 HIV-infected patients refused to be screened for HBV and almost 85% of HBsAg positive participants accepted to undergo liver assessment. This result is important since it suggests that HBV screening and linkage to care for HBV infection may be widely accepted in HIV-infected patients and feasible in HIV care facilities in sSA. This needs to be confirmed on a larger scale.\n\nWhilst some countries in sSA successfully adopted a TDF-based first-line ART regimen in HIV reference centres [21], indication to treat and choice of ART regimen in Gambian HIV clinics was primarily determined by the type and stage of HIV infection. As a result, 3TC, a cheap and well-tolerated nucleoside analogue has been the backbone of first line ART in The Gambia since its introduction over a decade ago [22]. Although 3TC is an effective antiviral drug, it is associated with an increased risk of HBV resistance mutations following 12 to 24 months of monotherapy in patients with HBV infection [23]. Unsurprisingly, HBV DNA was detectable in almost all our study patients (98.1%) who received prolonged 3TC without TDF.\n\nWe found significantly higher prevalence (83.3%) of 3TC associated HBV resistance mutations compared to the 14.2% reported in a similar Gambian HIV-HBV cohort six year earlier who received 3TC without a second anti-HBV drug [24], as well as the 29.3% and 8.7% reported in a Ghanaian [25] and Ivorian [26] coinfected patients respectively. Our findings confirm that widespread prolonged usage of 3TC monotherapy in ART poses diagnostic and management problems to individual patients as well as a potential public health risk.\n\nThe high proportion of patients with detectable HIV viral load and low CD4 count after many months of ART, as well as the detectable HBV DNA among almost all coinfected patients receiving TDF in our study could be the result of unsatisfactory adherence to therapy, which might contribute to higher levels of HBV viremia and consequently to higher fibrosis and HBV resistance. Another explanation could be the deteriorating HIV services in The Gambia since 2007 when its former president claimed to have found herbal cure for HIV infection. This claim disrupted decades of HIV campaign and negatively impacted vital HIV services and research partnerships resulting in significant reduction in competent personnel and services in HIV facilities and suboptimal HIV care with frequent medication stock outs and several patients having their ARV regimens switched often. These underline the urgent need to improve HIV services and drug provision in Gambian HIV facilities.\n\nHBV co-infection increases liver fibrosis [25, 27–31] as well as both all cause and liver related mortality [11,32], often in the absence of any evidence of liver disease [12]. Although our study lacked statistical power to show definitively a positive relationship between 3TC resistance mutation and increase in liver fibrosis, we show a trend towards such relationship (p = 0.05). Prompt initiation of TDF-based ART has been shown to reduce HBV viral replication and mortality in European [33] and Africa HIV-HBV cohort [11,12], further strengthening the need for compliance with the WHO HBV testing and treatment guidelines in Africa. It is worth noting that the uptake of TDF in first-line ART regimens in sSA is poorly documented. Our study shows that until 2016, only a minority of HIV patients in The Gambia received HBV testing and an even lesser proportion (7/78) of HIV-HBV coinfected patients received TDF. None of the patients had benefitted from a liver assessment even on the basis of liver transaminases. Indeed the local laboratory at this HIV facility, and almost all other HIV facilities in The Gambia, do not have the capacity to assess liver biochemistry. The 2016 consolidated HIV guidelines [8] recommending TDF-based ART for all HIV patients irrespective of degree of liver disease are thus well adapted to resource limited African settings, and African HIV facilities need to be supported to implement these guidelines.\n\nOur study has a few limitations: first, we analysed a limited number of HIV-HBV coinfected patients; second, we assessed liver fibrosis using APRI score as recommended by the WHO for resource-limited settings without access to Fibroscan, which is the case for most HIV facilities in Africa where Fibroscan is rarely available outside research settings. The reliability and usefulness of platelet-based biomarkers like APRI for assessing liver fibrosis in HIV patients in Africa has been questioned [34] mainly because thrombocytopenia is commonly associated with advanced HIV infection. Third, our study did not assess for hepatitis C virus (HCV) and hepatitis D virus (HDV) coinfection. However, previous studies in The Gambia confirmed very low prevalence rates of both HCV and HDV infections [13]. Finally, our study suggests that adherence to ART was not satisfactory but we did not directly assess adherence to ART.\n\nConclusion\nCompliance with international HBV testing and treatment guidelines for HIV-infected patients is poor in this Gambian HIV programme, resulting in a low coverage of HBV testing, prolonged treatment with 3TC without TDF for coinfected patients, and poor HBV viral suppression with increased risk of HBV resistance and liver complication. However, interventions to improve HBV screening and linkage to care for HBV infection in HIV facilities are feasible.\n\nSupporting information\nS1 File Data underlying the findings described in the manuscript.\n(XLSX)\n\nClick here for additional data file.\n\n We thank the Medical Research Council Unit The Gambia, the Hands on Care HIV clinic and the Wellcome Trust-Imperial College Centre for Global Health Research for supporting this study. We are grateful to Professor Simon Taylor-Robinson for his continuous support all through the project, and Dr Marcus Dorner and his team for their advice and help with the molecular virology work. We thank all study participants, the PROLIFICA Gambia team, and the MRC data management unit. Lastly, we are grateful for the administrative and logistical support from Dr Peter Norsworthy, Dawn Campbell, Kimberley Trim, Susan Farrell, Mavis Foster-Nyarko and Amie Ceesay.\n==== Refs\nReferences\n1 Schweitzer A , Horn J , Mikolaiczyk RT , Krause G , Ott JJ . Estimations of worldwide prevalence of chronic hepatitis B infection: a systematic review of data published between 1965 and 2013 . Lancet . 2015 ; Vol 386 , Issue 10003 , 1546 –1555 \n2 Stanaway JD , Flaxman AD , Naghavi M , Fitzmaurice C , Vos T , Abubakar I \net al\nThe global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013 . Lancet . 2016 ; 388 : 1081 –88 \ndoi: 10.1016/S0140-6736(16)30579-7 \n27394647 \n3 World Health Organisation . Combatting Hepatitis B and C to reach elimination by 2030 . Geneva , WHO \n2016 \n4 World Health Organisation. WHA 67.6 Hepatitis. In: Sixty-Seventh World Health Assembly. 24th May 2014, Geneva, Switzerland.\n5 United Nations. Transforming our World: The 2030 Agenda for Sustainable Development. United Nations, 2015\n6 United Nations. Sustainable Development Goal 3 –Ensure healthy lives and promote well-being for all at all ages. https://sustainabledevelopment.un.org/sdg3\n7 World Health Organisation . Global Health Sector Strategy on Viral Hepatitis 2016–2021 . Geneva , WHO \n2015 \n8 World Health Organisation . Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations . 2016 update. Geneva , WHO 2016\n9 World Health Organisation . Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection . Geneva , WHO \n2013 \n10 Stabinski L , O’Connor S , Barnhart M , Kahn RJ , Hamm TE . Prevalence of HIV and Hepatitis B Virus Co-Infection in sub-Saharan Africa and the potential impact and program feasibility of Hepatitis B surface antigen screening in resource-limited settings . J Acquir Immune Defic Syndr . 2015 ; 68 :S274 –S285 \ndoi: 10.1097/QAI.0000000000000496 \n25768867 \n11 Kouamé MG, Moh R, Boyd A, Badjé A, Gabillard D, N’takpé JB, et al. Higher mortality in HIV-HBV co-infected persons with elevated HBV replication in the Temprano Trial. [WEAB0303]. Presented at: 21st International AIDS Conference, 18–22 July 2016; South Africa.\n12 Japhet MM, Ndhere A, Ndwiga S, Kirwa E, Yogev R, Murphy R, et al. Early mortality risk of HIV/Hepatitis B virus coinfected patients initiating ART [Abstract Number 562]. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI), 2016; Boston, Massachusetts.\n13 Lemoine M , Shimakawa Y , Njie R , Taal M , Ndow G , Chemin I , et al\nAcceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study . The Lancet Global Health . 2016 ; Vol 4 , Issue 8 , e559 –e567 \n14 Shimakawa Y , Bah E , Wild CP , Hall AJ . Evaluation of data quality at the Gambia National Cancer Registry . Int J Cancer . 2013 ; 132 : 658 –665 . doi: 10.1002/ijc.27646 \n22618962 \n15 Kirk GD , Lesi OA , Mendy M , Akano AO , Sam O , Goedert JJ , et al\nThe Gambia Liver Cancer Study: Infection with hepatitis B and C and the risk of hepatocellular carcinoma in West Africa . Hepatology . 2004 ; 39 (1 ):211 –9 \ndoi: 10.1002/hep.20027 \n14752840 \n16 Ghosh S , Sow A , Guillot C , Jeng A , Ndow G , Njie R , et al\nImplementation of an in-house quantitative real-time polymerase chain reaction method for hepatitis B virus quantification in West African countries . J Viral Hepat . 2016 ;23 (11 ):897 –904 \ndoi: 10.1111/jvh.12561 \n27353593 \n17 World Health Organisation . Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection . Geneva , WHO \n2015 .\n18 Bota S , Sirli R , Sporea I , Focsa M , Popescu A , Danila M , et al\nA new scoring system for prediction of fibrosis in chronic hepatitis C . Hepat Mon . 2011 ;11 :548 –555 . 22087193 \n19 Garson JA , Grant PR , Ayliffe U , Ferns RB , Tedder RS . Real-time PCR quantitation of hepatitis B virus DNA using automated sample preparation and murine cytomegalovirus internal control . J Virol Meth . 2005 ;126 (1–2 ):207 –13 \n20 Rozanov M , Plikat U , Chappey C , Kochergin A , Tatusova T . A web-based genotyping resource for viral sequences . Nucleic Acids Res . 2004 ;32 (suppl_2 ): W654 –659 15215470 \n21 Diop SA , Fortes-Déguénonvo L , Seydi M , Dieng AB , Basse CD , Manga NM , et al\nEfficacy and tolerance of tenofovir-lamivudine-efavirenz combination in HIV-1 patients in Fann Teaching Hospital in Dakar . Bull Soc Pathol Exot . 2013 \n2 ;106 (1 ):22 –6 . doi: 10.1007/s13149-012-0272-7. Epub 2012 Dec 17 23247755 \n22 Ministry of Health & Social Welfare , Republic of The Gambia . Guidelines for Antiretroviral Therapy for the Prevention and Treatment of HIV in The Gambia . Banjul, The Gambia , 2015 .\n23 Lok ASF , Lai CL , Leung N , Yao GB , Cui ZY , Schiff ER , et al\nLong-term safety of lamivudine treatment in patients with chronic hepatitis B . Gastroenterology , Volume 125 , Issue 6 , 1714 –1722 .\n24 Stewart B , Jobarteh ML , Sarge-Njie R , Alabi A , de Silva T , Peterson K , et al\nEmergence of HBV resistance to lamivudine (3TC) in HIV/HBV co-infected patients in The Gambia, West Africa . BMC Research Notes . 2011 ; 4 :561 \ndoi: 10.1186/1756-0500-4-561 \n22195774 \n25 Stockdale AJ , Phillips RO , Beloukas A , Appiah LT , Chadwick D , Bhagani S , et al\nLiver Fibrosis by Transient Elastography and Virologic Outcomes After Introduction of Tenofovir in Lamivudine-Experienced Adults With HIV and Hepatitis B Virus Coinfection in Ghana . Clin Infect Dis . 2015 \n9 \n15 :61 (6 ):883 –91 . doi: 10.1093/cid/civ421. Epub 2015 May 28. 26021992 \n26 Boyd A , Moh R , Gabillard D , le Carrou J , Danel C , Anglaret X , et al\nLow risk of lamivudine-resistant HBV and hepatic flares in treated HIV-HBV-coinfected patients from Côte d'Ivoire . Antivir Ther . 2015 ;20 (6 ):643 –54 . doi: 10.3851/IMP2959. Epub 2015 Apr 8. 25852125 \n27 Stabinski L , Reynolds SJ , Ocama P , Laeyendecker O , Ndyanabo A , Kiggundu V , et al\nHigh prevalence of liver fibrosis associated with HIV infection: a study in rural Rakai, Uganda . Antivir Ther . 2011 ; 16 (3 ):405 –11 . doi: 10.3851/IMP1783 \n21555823 \n28 Hawkins C , Agbaji O , Ugoagwu P , Thio CL , Auwal MM , Ani C , et al\nAssessment of liver fibrosis by transient elastography in patients with HIV and hepatitis B virus coinfection in Nigeria . Clin Infect Dis . 2013 ;57 (12 ):e189 –92 \ndoi: 10.1093/cid/cit564 \n24014732 \n29 Vinikoor MJ , Mulenga L , Siyunda A , Musukuma K , Chilengi R , Moore CB , et al\nAssociation between hepatitis B co-infection and elevated liver stiffness among HIV-infected adults in Lusaka, Zambia . Trop Med Int Health . 2016 ; 21 : 1435 –1441 . doi: 10.1111/tmi.12764 \n27499385 \n30 Ramírez-Mena A , Glass TR , Winter A , Kimera N , Ntamatungiro A , Hatz C , et al\nPrevalence and Outcomes of Hepatitis B Coinfection and Associated Liver Disease Among Antiretroviral Therapy-Naive Individuals in a Rural Tanzanian Human Immunodeficiency Virus Cohort . Open Forum Infect Dis . 2016 \n7 \n29 :3 (3 ):ofw162 eCollection 2016 doi: 10.1093/ofid/ofw162 \n27704017 \n31 Gitau SN , Vinayak S , Silaba M , Adam R , Shah R . High Prevalence of Liver Fibrosis in Patients with Human Immunodeficiency Virus Monoinfection and Human Immunodeficiency Virus Hepatitis-B Co-infection as Assessed by Shear Wave Elastography: Study at a Teaching Hospital in Kenya . J Clin Imaging Sci . 2016 ;6 :22 \ndoi: 10.4103/2156-7514.183582 \n27403400 \n32 Vinikoor MJ , Sinkala E , Mweemba A , Zanolini A , Mulenga L , Sikazwe I , et al\nElevated AST-to-platelet ratio index is associated with increased all-cause mortality among HIV-infected adults in Zambia . Liver Int . 2015 ; 35 : 1886 –1892 \ndoi: 10.1111/liv.12780 \n25581487 \n33 Boyd A , Bottero J , Miailhes P , Lascoux-Combe C , Rougier H , Girard PM , et al\nLiver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with Tenofovir Disoproxil Fumarate in France: a prospective cohort study . Journal of International AIDS Society . 2017 ; 20 :21426 \n34 Johannessen A , Lemoine M . Is aspartate aminotransferase-to-platelet ratio index a reliable tool in human immunodeficiency virus patients in Africa? \nLiver Int . 2015 ; 35 : 2059 \ndoi: 10.1111/liv.12793 \n25646656\n\n",
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{
"abstract": "BACKGROUND\nPosterior reversible encephalopathy syndrome (PRES) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Among others, calcineurin inhibitors (CNI) for prophylaxis of graft-versus-host disease (GvHD) may promote the development of PRES, but the pathomechanism is still controversial. Discontinuation of CNI facilitates remission of symptoms but might contribute to the unfavorable prognosis of PRES due to an elevated incidence of GvHD.\n\n\nMETHODS\nThis is a case series of 7 patients with PRES from a retrospective analysis of 146 consecutive patients who received alloHSCT for hematologic malignancies.\n\n\nRESULTS\nAt the onset of PRES, all patients presented a systemic infection, while no influence was seen for underlying disease, conditioning regimen, donor type, or GvHD. Discontinuation of CNI and control of the blood pressure reversed neurological symptoms in 6 patients, while 1 patient died from septic multiorgan failure. After bridging with prednisolone and/or mycophenolic acid, replacement of CNI by the mammalian target of rapamycin (mTOR) inhibitor everolimus effectively prevented severe GvHD without recurrence of PRES.\n\n\nCONCLUSIONS\nA systemic infection/inflammation may be an important cause of PRES. Prophylaxis of GvHD by the mTOR inhibitor everolimus in case of PRES after alloHSCT demonstrated promising results but needs to be validated in larger cohorts.",
"affiliations": "Abteilung Hx00E4;matologie und Internistische Onkologie, Klinik fx00FC;r Innere Medizin II, Universitx00E4;tsklinikum Jena, Jena, Germany.",
"authors": "Schmidt|Volker|V|;Prell|Tino|T|;Treschl|Anne|A|;Klink|Anne|A|;Hochhaus|Andreas|A|;Sayer|Herbert G|HG|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000430489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "135(1)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D001927:Brain Diseases; D065095:Calcineurin Inhibitors; D000068338:Everolimus; D005260:Female; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007239:Infections; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "1-10",
"pmc": null,
"pmid": "26159650",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Clinical Management of Posterior Reversible Encephalopathy Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Series and Review of the Literature.",
"title_normalized": "clinical management of posterior reversible encephalopathy syndrome after allogeneic hematopoietic stem cell transplantation a case series and review of the literature"
} | [
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"abstract": "To assess the potential impact of Pharmacogenomic (PGx) variation in cytochrome P450 2D6 (CYP2D6) enzyme function, using loss in quality-adjusted life years (QALYs) associated with treatment problems, and the willingness to pay to avoid treatment problems from patients' and payers' perspectives.\nThe study included patients prescribed tramadol or codeine, or both, between January 1, 2005, and December 31, 2017. Demographic information and adverse drug events, including adverse drug events and poor pain control, were collected from the electronic health records using natural language processing techniques and review by trained abstractors. Patients' willingness to pay and QALY estimates were based on comprehensive literature review. The CYP2D6 phenotypes were divided into 4 groups: ultra-rapid metabolizers, normal metabolizers, intermediate metabolizers, and poor metabolizers.\nAmong the 2860 identified patients, 63 (2%) were ultrarapid metabolizers, 1449 (50%) were normal metabolizers, 1155 (40%) were intermediate metabolizers, and 193 (7%) were poor metabolizers. The patients' average estimated willingness-to-pay value to avoid treatment problems was $23 per month; poor metabolizers developed problems with the highest estimated willingness-to-pay value ($32 per month). The mean QALY loss among all patients was 0.024 QALYs (8.8 healthy days); poor metabolizers had the highest loss (0.027 QALYs, 9.9 healthy days).\nPatients with various phenotypes developed different treatment problem profiles. Poor CYP2D6 metabolizers developed problems with highest willingness to pay, and they might potentially benefit most from PGx-guided treatment and problem prevention.",
"affiliations": "Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.;Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.;Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.;Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.;Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.;Division of Clinical Biochemistry & Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.;Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.;Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.;Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.",
"authors": "Zhu|Ye|Y|;Lopes|Guilherme S|GS|;Bielinski|Suzette J|SJ|;Borah|Bijan J|BJ|;Larson|Nicholas B|NB|;Moyer|Ann M|AM|;Olson|Janet E|JE|;Wang|Liewei|L|;Weinshilboum|Richard|R|;St Sauver|Jennifer L|JL|",
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"doi": "10.1016/j.mayocpiqo.2020.08.009",
"fulltext": "\n==== Front\nMayo Clin Proc Innov Qual Outcomes\nMayo Clin Proc Innov Qual Outcomes\nMayo Clinic Proceedings: Innovations, Quality & Outcomes\n2542-4548\nElsevier\n\nS2542-4548(20)30162-4\n10.1016/j.mayocpiqo.2020.08.009\nOriginal Article\nImpact of Pharmacogenomic Information on Values of Care and Quality of Life Associated with Codeine and Tramadol-Related Adverse Drug Events\nZhu Ye MD, PhD ab\nLopes Guilherme S. PhD cd\nBielinski Suzette J. PhD, MEd c\nBorah Bijan J. PhD ab\nLarson Nicholas B. PhD, MS d\nMoyer Ann M. MD, PhD e\nOlson Janet E. PhD c\nWang Liewei MD, PhD f\nWeinshilboum Richard MD f\nSt. Sauver Jennifer L. PhD [email protected]\nc∗\na Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN\nb Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, MN\nc Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN\nd Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN\ne Division of Clinical Biochemistry & Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN\nf Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN\n∗ Correspondence: Address to Jennifer L. St. Sauver, PhD, Mayo Clinic, 200 First St SW, Rochester, MN 55905 [email protected]\n13 1 2021\n2 2021\n13 1 2021\n5 1 3545\n© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.\n2020\nMayo Foundation for Medical Education and Research\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nTo assess the potential impact of Pharmacogenomic (PGx) variation in cytochrome P450 2D6 (CYP2D6) enzyme function, using loss in quality-adjusted life years (QALYs) associated with treatment problems, and the willingness to pay to avoid treatment problems from patients’ and payers’ perspectives.\n\nPatients and Methods\n\nThe study included patients prescribed tramadol or codeine, or both, between January 1, 2005, and December 31, 2017. Demographic information and adverse drug events, including adverse drug events and poor pain control, were collected from the electronic health records using natural language processing techniques and review by trained abstractors. Patients’ willingness to pay and QALY estimates were based on comprehensive literature review. The CYP2D6 phenotypes were divided into 4 groups: ultra-rapid metabolizers, normal metabolizers, intermediate metabolizers, and poor metabolizers.\n\nResults\n\nAmong the 2860 identified patients, 63 (2%) were ultrarapid metabolizers, 1449 (50%) were normal metabolizers, 1155 (40%) were intermediate metabolizers, and 193 (7%) were poor metabolizers. The patients’ average estimated willingness-to-pay value to avoid treatment problems was $23 per month; poor metabolizers developed problems with the highest estimated willingness-to-pay value ($32 per month). The mean QALY loss among all patients was 0.024 QALYs (8.8 healthy days); poor metabolizers had the highest loss (0.027 QALYs, 9.9 healthy days).\n\nConclusion\n\nPatients with various phenotypes developed different treatment problem profiles. Poor CYP2D6 metabolizers developed problems with highest willingness to pay, and they might potentially benefit most from PGx-guided treatment and problem prevention.\n\nAbbreviations and Acronyms\n\nADE, adverse drug event\nCYP2D6, Cytochrome P450 2D6\nPGx, pharmacogenomics\nQALY, quality-adjusted life year\nRIGHT, Right Drug\nRight Dose, Right Time-Using Genomic Data to Individualize Treatment\nREP, Rochester Epidemiology Project\n==== Body\nOpioid analgesics are frequently used for management of both acute and chronic pain.1,2 Opioid prescriptions in the United States are common, with a rate of 59 per 100 persons in 2017.3 Codeine and tramadol are two of the most commonly used opioids. Codeine yields adverse effects of gastrointestinal discomfort, vertigo, sleepiness, and rash4; tramadol has been reported to cause nausea, vomiting, fatigue, sedation, sweating, and serotonin toxicity.5,6 Many of these treatment problems, including adverse drug events (ADEs) and poor pain control, are not life-threatening, and they can require limited management by health care providers. Therefore, the direct financial effects of these problems may be limited; however, these problems also affect quality of life, and information quantifying the effects of such outcomes on patient quality of life is lacking.\n\nCytochrome P450 2D6 (CYP2D6) is the primary enzyme that bioactivates codeine, and variation in CYP2D6 function has been associated with treatment problems related to use of tramadol and codeine.7 At the genetic level, persons exposed to codeine and tramadol with the CYP2D6 poor metabolizer phenotype have lower levels of the active opioid metabolites, while patients with ultrarapid CYP2D6 phenotypes experience higher systemic levels of the metabolites.8 Therefore, poor CYP2D6 metabolizers might have less pain control compared with normal metabolizers.9 In contrast, ultrarapid CYP2D6 metabolizers require less pain medication to achieve pain control, but they may be at greater risk of other ADEs compared with normal metabolizers.10, 11, 12\n\nConsideration of patient pharmacogenomics (PGx) information at the time of drug prescriptions holds the potential to avoid ADEs and to maximize drug effectiveness.13, 14, 15 Ideally, access to CYP2D6 phenotype information at the time of drug prescription would enable genotype-guided drug and dose selection.13, 14, 15 Such information could improve the patient experience and reduce health care costs. However, clinical guidelines regarding the implementation of PGx information into clinical practice were mainly established using data from pharmacokinetic studies. Data regarding value of care or improvements in quality of life owing to the implementation of PGx information for opioid prescriptions is currently limited.16,17\n\nTherefore, the goal of our study was to understand to what extent PGx-guided treatment might decrease potential costs associated with treatment problems or improve the quality of life for patients who receive codeine and tramadol prescriptions. To accomplish this goal, we described the types of treatment problems experienced by patients who received codeine or tramadol prescriptions. Second, using existing literature, we assigned monetary values to the problems based on what patients have reported that they are willing to pay to avoid these events; we also assigned quality-adjusted life years (QALYs) to each ADE or case of poor pain control. QALY is a generic measure of disease burden that aggregates both health-related quality of life and length of life into a single measure.18 QALYs are frequently used in cost-effectiveness analyses to measure health outcomes related to treatment effectiveness. One QALY reflects the treatment benefit of gaining the patient 1 full year of life with good health, and it was designed for interpersonal comparison.19 Finally, we estimated health insurance’s (payer’s) willingness to pay to treat the problems. Together, our study provides an innovative approach to examine the monetary effects that PGx information could provide on treatment problems and loss in QALYs that patients might experience with codeine or tramadol prescriptions.\n\nPatients and Methods\n\nStudy Population\n\nThis study included patients who participated in the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment (RIGHT Study), and who were prescribed tramadol and codeine between January 1, 2005, and December 31, 2017.20 In brief, the RIGHT study enrolled 10,074 participants with self-reported demographic information and blood samples sequenced for CYP2D6.20 The initiation of tramadol and codeine treatment was captured using the Rochester Epidemiology Project (REP) research infrastructure, with the details reported previously.21 Normalized names for clinical drugs provided by RxNorm were used to identify the ingredients that included tramadol or codeine.22 We excluded persons who were found to have prior tramadol or codeine use between January 1, 2004, and December 31, 2004, and those who used codeine as a cough suppressant. We also excluded persons who were prescribed strong or moderately strong CYP2D6 inhibitors (Supplemental Table 1, available online at http://mcpiqojournal.org) during this period23 to minimize the effect of phenoconversion, which is a change in apparent drug metabolism phenotype owing to drug–drug interaction rather than to genetic variation.24 The study was approved by the Mayo Clinic Institutional Review Board (IRB# 16-000189), and all the study subjects gave informed consent.\n\nPharmacogenomic Phenotyping\n\nThe CYP2D6 phenotypes were divided into 4 groups according to the drug metabolism rates estimated from patients’ genotypes: (1) ultra-rapid metabolizers, including ultra-rapid and rapid metabolizers; (2) normal metabolizers, including normal and intermediate to normal metabolizers; (3) intermediate metabolizers, including intermediate and poor to intermediate metabolizers; and (4) poor metabolizers. The processes of genotyping and phenotype prediction have been reported previously.25\n\nIdentifying Treatment Problems and Their Values\n\nTreatment Problems\n\nTreatment problems included ADEs and poor pain control. These data were captured from reviewing the electronic health records. The reviewing process included two steps. First, a natural language processing technique was applied in the initial screening for opioid-related adverse outcomes. This process captured all electronic health record sentences with normalized opioid names and key words related to treatment problems (eg, nausea, vomiting, constipation and poor-pain-control). Second, two abstractors (J.L.S. and a trained nurse abstractor) reviewed the screened sentences and recorded any adverse symptom or poor pain control event attributed to codeine or tramadol within 6 weeks after the first codeine or tramadol prescription. Adverse symptoms were further grouped in 6 system categories (eg, nausea and vomiting were classified as “gastrointestinal symptoms”). Our final definition of treatment problems included the presence of either an adverse symptom attributed to codeine or tramadol or documentation of poor pain control (eg, “patient has been taking Ultram but continues to complain of severe neck pain”) after prescription of these medications. If there was no mention of adverse symptoms or poor pain control in the medical record notes, the patient was classified as not having treatment problems. Figure 1 lists all treatment problem types and their system categories.Figure 1 Patients’ willingness-to-pay values, loss of QALYs for each type of adverse drug outcome. Bubble size represents the proportion of the study population that experienced the specific treatment problem. QALY, quality-adjusted life year.\n\nPatients’ Willingness to Pay to Avoid Treatment Problems\n\nWe estimated patients’ willingness to pay to avoid treatment problems resulting from a codeine or tramadol prescription. Willingness to pay provides a useful estimate of a patient’s perceived value of care, because monetary value is a proxy for the trade-off and priority a person places on receiving a particular outcome.26 To obtain willingness-to-pay monetary values for each problem, we conducted a comprehensive literature review across multiple databases from inception through October 11, 2019, and the inception varies by database. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO, and Scopus. Controlled vocabulary supplemented with keywords was used to search for patients’ willingness to pay in monetary values of opioid-induced symptoms from the patient’s perspective, in the United States and Canada. We found 21 relevant studies (of 1294 possible studies) reporting the monetary values patients that were willing to pay to treat the problem types identified in our study. The literature review process and the search strategies are shown in the Supplemental Table 2 and Supplemental Figure 1 (available online at http://mcpiqojournal.org). All the monetary values were converted from the study year to 2018 US dollars using the gross domestic product price deflator from the Bureau of Economic Analysis.27\n\nHealth-Related Quality of Life Loss Owing to Treatment Problems\n\nWe also used loss in QALYs to quantitatively measure the effect of individual treatment problems on both length of life and health-related quality of life. The decrease in QALYs for each of the problem types was estimated using the available literature from the best possible similar patient populations within the most recent 20 years (1998-2018). If we were unable to find estimated QALYs for ADEs using studies from US or Canadian populations, we used results from European countries as close estimations.\n\nPayer’s Willingness to Pay for the Improvement of Health-Related Quality of Life\n\nThe widely accepted threshold for payers’ willingness to cover the costs associated with decreases in quality of life is $50,000-10,000/QALY.28 We estimated the payer’s monthly willingness to pay by multiplying the QALYs by $50,000/QALY (Equation 1).29,30 This threshold has been adopted by most of the recent cost-effectiveness studies for most countries.31 Payers’ willingness to pay was calculated using the following function:Willingness_to_Payi/month=Uiyears×$50000/year12 months(Equation1)\n\nwhere Ui is the number of QALY lost for each adverse outcome.\n\nPatients’ and payers’ willingness to pay estimates and decreases in QALYs associated with each of the ADEs are listed in Supplemental Table 3 (available online at http://mcpiqojournal.org).\n\nAnalysis\n\nThis study examined the baseline patient characteristics for the overall sample and by the 4 CYP2D6 phenotypes. Average values of patients’ willingness to pay, QALYs, and payers’ willingness to pay were calculated for the overall sample and by phenotypes. The timeframe for QALYs and willingness to pay was calculated by month, because the opioid can be used as postoperational pain control, which is relatively short period. P for trend values were calculated from ordered logistic regression, and P < .05 were considered statistically significant. The study results were achieved under multiple assumptions (Supplemental Table 4, available online at http://mcpiqojournal.org).\n\nResults\n\nThis study included 2877 patients with new tramadol and codeine prescriptions from January 1, 2005, to December 31, 2017. Characteristics of the study population are shown in Table. Overall, 792 patients (28%) were prescribed codeine, 2396 patients (83%) were prescribed tramadol, and 311 patients (11%) were prescribed both of the medications. Overall, 61 patients (2%) were CYP2D6 ultrarapid metabolizers, 1448 patients (50%) were normal metabolizers, 1175 patients (41%) were intermediate metabolizers, and 193 patients (7%) were poor metabolizers.Table Patient Characteristics for Full Study Sample and by CYP2D6 Phenotypea\n\nVariable\tFull sample\tUltra-rapid metabolizer\tNormal metabolizer\tIntermediate metabolizer\tPoor metabolizer\t\nNumber of patients\t2860\t63 (2%)\t1449 (51%)\t1155 (40%)\t193 (7%)\t\nMean BMI, kg/m2 (SD)\t29.74 (7.36)\t29.27 (5.66)\t29.53 (6.53)\t30.02 (8.58)\t29.68 (5.47)\t\nMean age, years (SD)\t61.27 (13.58)\t63.84 (11.33)\t60.83 (13.94)\t61.39 (13.22)\t62.99 (13.49)\t\nSex, n (%)\t\t\t\t\t\t\n Female\t1680 (59%)\t37 (59%)\t869 (60%)\t666 (58%)\t108 (56%)\t\n Male\t1180 (41%)\t26 (41%)\t580 (40%)\t489 (42%)\t85 (44%)\t\nRace, n (%)\t\t\t\t\t\t\n White\t2690 (94%)\t56 (89%)\t1354 (93%)\t1101 (95%)\t179 (93%)\t\n African American\t11 (0%)\t0 (0%)\t7 (0%)\t4 (0%)\t0 (0%)\t\n Asian/Native\t22 (1%)\t0 (0%)\t18 (1%)\t4 (0%)\t0 (0%)\t\n Othersb\t137 (5%)\t7 (11%)\t70 (5%)\t46 (4%)\t14 (7%)\t\nEthnicity, n (%)\t\t\t\t\t\t\n Non-Hispanic\t2823 (99%)\t62 (98%)\t1428 (99%)\t1140 (99%)\t193 (100%)\t\n Hispanic\t33 (1%)\t1 (2%)\t18 (1%)\t14 (1%)\t0 (0%)\t\n Unknown\t4 (0%)\t0 (0%)\t3 (0%)\t1 (0%)\t0 (0%)\t\nMarital status, n (%)\t\t\t\t\t\t\n Married\t2259 (79%)\t55 (87%)\t1131 (78%)\t917 (79%)\t156 (81%)\t\n Previously marriedc\t409 (14%)\t6 (10%)\t209 (14%)\t172 (15%)\t22 (11%)\t\n Never married\t191 (7%)\t2 (3%)\t108 (7%)\t66 (6%)\t15 (8%)\t\n Unknown\t1 (0%)\t0 (0%)\t1 (0%)\t0 (0%)\t0 (0%)\t\nEducation, n (%)\t\t\t\t\t\t\n ≤High school\t423 (15%)\t7 (11%)\t227 (16%)\t154 (13%)\t35 (18%)\t\n College\t1363 (48%)\t28 (44%)\t678 (47%)\t570 (49%)\t87 (45%)\t\n Postgraduate\t1070 (37%)\t28 (44%)\t542 (37%)\t429 (37%)\t71 (37%)\t\n Unknown\t4 (0%)\t0 (0%)\t2 (0%)\t2 (0%)\t0 (0%)\t\nPrescription, n (%)d\t\t\t\t\t\t\n Codeine\t785 (27.4%)\t14 (22.2%)\t394 (27.2%)\t314 (27.2%)\t63 (32.6%)\t\n Tramadol\t2384 (83.4%)\t55 (87.3%)\t1206 (83.2%)\t969 (83.9%)\t154 (79.8%)\t\nNumber of ADEs\t\t\t\t\t\t\n 1 ADE type\t241 (8.4%)\t3 (4.8%)\t118 (8.1%)\t103 (8.9%)\t17 (8.8%)\t\n 2 ADE types\t44 (1.5%)\t3 (4.8%)\t27 (1.9%)\t11 (1.0%)\t3 (1.6%)\t\n ≥3 ADE types\t8 (0.3%)\t0 (0.0%)\t5 (0.3%)\t3 (0.3%)\t0 (0.0%)\t\n Any ADE\t301 (10.5%)\t6 (9.5%)\t155 (10.7%)\t120 (10.4%)\t20 (10.4%)\t\n No ADE\t2567 (89.8%)\t57 (90.5%)\t1299 (89.6%)\t1038 (89.9%)\t173 (89.6%)\t\na ADE, adverse drug event; BMI, body mass index.\n\nb Others including race reported by patients as “other,” mixed, or unknown.\n\nc Includes widowed or divorced but currently not married.\n\nd A total of 311 (10.8%) patients were prescribed of both codeine and tramadol.\n\nTwo hundred forty-three patients (8.4%) had 1 type of ADE, 44 patients (1.5%) had 2 types, and 8 patients (0.3%) experienced 3 or more types of ADEs recorded in their medical records (Table). Type of ADE did not differ significantly by CYP2D6 phenotype, with the exception of neurologic reactions (Figure 2). Neurologic reactions were most frequent among ultra-rapid metabolizers and least frequent among poor metabolizers (P = .006). However, when ADEs were combined, the proportion of persons experiencing at least one ADE did not differ significantly by phenotype. Poor pain control was highest in poor metabolizers and lowest among ultrarapid metabolizers.Figure 2 Differences in types of treatment problems (including drug adverse effects and poor pain control) due to codeine and tramadol prescriptions by CYP2D6 phenotype. P values were from logistic regressions of genetic groups on adverse events.\n\nFigure 1 illustrates the patients’ estimated willingness to pay to avoid individual treatment problems and the estimated QALYs for each problem. Bubble size represents the proportion of the study population that experienced the problem. For example, tinnitus was rare in our study population (n = 2; small bubble), but it had the highest estimated patient willingness-to-pay value ($1084 per month; Figure 1). Pain, nausea, and vomiting were more common problems (n = 117 and 79, respectively), but the corresponding estimated willingness to pay was lower ($333 and $138 per month, respectively). Pain had the highest QALY value, with an estimated loss of 0.33 QALYs owing to pain (Figure 1, right panel).\n\nOn average, patients’ average willingness to pay for avoiding a problem associated with codeine or tramadol treatment was estimated at $23.16 per month (Figure 3A). The mean QALY loss owing to the treatment problems among all the patients was 0.024 QALYs (8.8 quality-adjusted days; Figure 3B). Finally, the overall estimated payers’ willingness to pay was $100 per month (Figure 3C). Patients with a poor metabolizer phenotype had the highest estimated willingness to pay to avoid their treatment problems ($32 per month), worst QALYs (10 quality-adjusted days), and the highest estimated payer willingness to pay ($113 per month). These results were not statistically significant (all P values >.05). We used the threshold of $100,000 per QALY to examine the cost-effectiveness of genetic testing. The results suggested that if the testing costs were less than $88.86 for each patient, it would be cost-effective for all the genetic groups. The testing value changed among genetic variant groups (Figure 4). We found that health care payers’ willingness to pay was $75-$87 per month higher than patients’ willingness to pay for each phenotype group. Figure 4 illustrates the differences in patients’ willingness to pay versus payers’ willingness to pay for treatment problems owing to codeine and tramadol prescriptions.Figure 3 Estimated patient willingness to pay, QALYs, and payer willingness to pay overall and by CYP2D6 phenotype. (A) Estimated amount patients would be willing to pay to avoid treatment problems. (B) Estimated loss of QALYS owing to treatment problems. (C) Estimated willingness to pay from payer’s perspective. P values are from logistic regressions of genetic groups on adverse events. ADE, adverse drug events; QALY, quality-adjusted life-years.\n\nFigure 4 Estimated patient willingness to pay and payer willingness to pay overall and by CYP2D6 phenotype with patients’ total values for opioid treatments, including all adverse symptoms and poor pain control. Payers’ willingness to pay was calculated from $50,000 per QALY multiplied by the QALYs lost owing to treatment problems. All the values were converted to 2018 US dollars using the gross domestic product price deflator.\n\nDiscussion\n\nThis study provided important information that the number of problems from treatment does not provide enough information in evaluating the adverse effects. When weighted by patients’ values in either monetary values or QALYs, differences appeared among groups of patients with different PGx backgrounds.\n\nOverall, estimated amounts that patients would be willing to pay to avoid treatment problems, and the estimated QALYs lost owing to these problems, were modest. However, estimated payer willingness to pay to improve QALYs was nearly 5 times greater than patient willingness to pay, suggesting the substantially large benefit that PGx information could bring to both stakeholders. Finally, patients with poor CYP2D6 metabolizer phenotypes had the highest willingness to pay and the worst QALY estimates, suggesting that this population is the most likely to benefit from PGx-directed prescribing.\n\nThe significance of this study is that we estimated the amount patients would be willing to pay to avoid specific problems, which was captured from previous studies in similar populations. This study provided information that could facilitate clinical communication on treatment outcomes, based on the theory that people use the subjective value of the treatment outcome to generate expectations for the treatment.32 Overall, we found that patients would be willing to pay modest amounts ($23 per month) to avoid treatment problems and that the number of QALYs lost owing to codeine and tramadol were also modest (9 quality-adjusted days). These figures reflect the relatively limited proportion of persons who had treatment problem information documented in their medical records, and the fact that most effects of codeine and tramadol are relatively short term. One important reason is that only 10% of the patients in our study had documentation in their medical record indicating a treatment problem resulting from codeine or tramadol, which is consistent with other studies on tramadol and codeine.4,6 Similar to other studies, the ADEs observed in our study could reflect the real-world nature of our study, as patients are not routinely asked about medication responses. We expect that some patients who were prescribed these medications experienced treatment problems, coped with the problems at home, and did not report problems to their health care providers. Therefore, our estimates are likely to be an underestimate of both the true proportion of persons who experienced treatment problems following codeine and tramadol use, and an underestimate of the costs of these problem. Another important phenomenon discovered by this study was that tramadol was predominantly used in clinical practice than codeine (80% vs. 20%), and the problem profiles were similar to what developed from tramadol use (Supplemental Figure 2, available online at http://mcpiqojournal.org).\n\nWe also found that persons with poor metabolizer CYP2D6 phenotypes had the highest estimated values of willingness to pay owing to codeine and tramadol. For example, the average estimated willingness to pay for a poor metabolizer to avoid a treatment problem was $32 per month compared with an estimated $19 per month for an ultrarapid metabolizer. We also found that treatment problems can decrease patients’ health-related quality of life by approximately 8-10 days during 1 healthy year. If these could be avoided, poor metabolizers would receive the biggest benefit (gaining 9.9 healthy days) compared with normal metabolizer patients (gaining 8.6 healthy days). We also compared this benefit to health care payers’ willingness to pay and found that the threshold was $113 per month for poor metabolizer patients and $98 per month for normal metabolizer patients, which suggests that the costs below this threshold would be cost-effective from the health care payers’ perspective. In summary, although cost differences among metabolizer phenotypes were not statistically significant, our results suggest that poor metabolizer patients could benefit more from PGx-guided prescribing compared with normal metabolizers.\n\nStrengths of our study include our adoption of innovative methods of conducting cost-effectiveness analysis by assigning each problem value captured from a literature review. This method is advantageous because it can increase study generalizability to inform decision making in a wide range of the population.33 The values assigned to treatment problems were previously reported by patient populations who actually developed the symptoms, and were from the US patients’ perspective. Therefore, these values theoretically provide a practical and accurate view of the treatment experience and treatment burden following opioid prescriptions in the United States.\n\nAn additional strength of our study included our examination of willingness to pay from both patients’ and payers’ perspectives. We followed the recommendation from the Second Panel on Cost-effectiveness in Health and Medicine that more studies are needed to investigate the health care costs from societal, patient’s and payer’s perspectives.34 In comparing both perspectives, we are able to identify potential benefits that PGx information would bring to both of the stakeholders. In particular, the health care payers had 5-fold higher willingness to pay than patients did; therefore, avoiding ADEs could potentially bring a much greater benefit from health care payers’ perspective than from patients’ perspective. However, we suggest that PGx implementation needs to be evaluated at both levels separately. In addition, we note that the health care payers’ willingness-to-pay threshold used in this study ($50,000 per QALY) was relatively low compared with the threshold of $100,000 per QALY that has been used recently in other cost-effectiveness analyses in developed countries.31 Therefore, the differences between patients perceived value of care and payers’ willingness to pay may be underestimated.\n\nOur study results were limited by the scarce results from the current literature. We adopted the best possible evidence from the available literature, but some values could still be an underestimation or overestimation of true costs. For example, the value we assigned to tinnitus was $1085 per month. This value was adopted from a survey study in which the patient population was self-registered for a “Tinnitus Update” email listserv. Therefore, the responders could be patients with relatively severe tinnitus that impaired their social functions, who tend to look for more treatment information.35 Although we adopted the values reported from patients with the mildest tinnitus level, and only 2 of the patients in our population reported tinnitus in our study, this value of tinnitus could overestimate the average patient’s experience of tinnitus, and it might overestimate the average treatment value for tinnitus.\n\nThis study is also limited by the treatment problems captured through medical record review. As such, the problem needed to be shared with the health care provider and documented in the medical record. We therefore expect that our capture of treatment problems is likely an underestimate of the true number of problems that occur in patients after using tramadol or codeine. Fewer outcomes results in more limited power and a reduced ability to detect associations should they actually exist. Our results are therefore conservative, and we might have missed weaker associations. We also note that the patient is the best source of information for treatment problems, and future studies that collect treatment problem information at the time of treatment are needed to obtain complete information. Despite these limitations, we note that when compared with other studies of tramadol and codeine, our ADE rates are comparable. For example, the study by Nossol et al6 found that patients received tramadol developed nausea (3.4%), dizziness (1.5%), and vomiting (1.1%).\n\nFinally, we conducted multiple tests of association, and considering associations as significant at P < .05 may be too permissive; however, P values are completely dependent on sample size, and they should be used only as a guide to highlight potentially interesting patterns.\n\nConclusion\n\nWe estimated willingness to pay related to treatment problems resulting from treatment with codeine and tramadol from both the patient and the payer perspective. Although overall costs were modest, we found that patients with a poor metabolizer CYP2D6 phenotype are likely to benefit most from PGx-guided prescribing designed to reduce treatment problems resulting from these prescription medications.\n\nSupplemental Online Material\n\nSupplemental Material\n\nAcknowledgments\n\nThis research was partially supported by a research grant from 10.13039/100000871 Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery and the Mayo Clinic Center for Individualized Medicine. The views expressed in the article are those of the authors and do not necessarily reflect the views of Mayo Clinic.\n\nPotential Competing Interests: Drs. Wang and Weinshilboum are cofounders and stockholders of OneOme, LLC, a pharmacogenomic decision support company.\n\nAll authors made substantial contributions to this study. Y.Z. and J.L.S. conceptualized and designed the study; Y.Z. performed the analysis, and drafted the manuscript; Y.Z., G.S.L., and J.L.S. finalized the results, interpretation of the data and the first draft of the manuscript; S.J.B., B.J.B., N.B.L., A.M.M., J.E.O., L.W., and R.W. provided critical comments for significant intellectual content; J.L.S. provided acquisition, supervision and funding support for this study, and acts as the study guarantor. All authors read and approved the manuscript for publication.\n\nSupplemental material can be found online at http://mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.\n==== Refs\nReferences\n\n1 Dowell D. Haegerich T.M. Chou R. CDC guideline for prescribing opioids for chronic pain--United States, 2016 JAMA 315 15 2016 1624 1645 26977696\n2 Thorson D. Biewen P. Bonte B. Acute Pain Assessment and Opioid Prescribing Protocol 2014 Health Care Protocol Bloomington, MN\n3 Guy G.P. Jr. Zhang K. Schieber L.Z. Young R. Dowell D. County-level opioid prescribing in the United States, 2015 and 2017 JAMA Intern Med 179 4 2019 574 576 30742206\n4 Gruber C.M. Codeine phosphate, propoxyphene hydrochloride, and placebo JAMA 164 9 1957 966 969\n5 Beakley B.D. Kaye A.M. Kaye A.D. Tramadol, pharmacology, side effects, and serotonin syndrome: A review Pain Physician 18 4 2015 395 400 26218943\n6 Nossol S. Schwarzbold M. Stadler T. Treatment of pain with sustained-release tramadol 100, 150, 200 mg: Results of a post-marketing surveillance study Int J Clin Pract 52 2 1998 115 121 9624795\n7 Vuilleumier P.H. Stamer U.M. Landau R. Pharmacogenomic considerations in opioid analgesia Pharmgenomics Pers Med 5 2012 73 87 23226064\n8 Lotsch J. Skarke C. Liefhold J. Geisslinger G. Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives Clin Pharmacokinet 43 14 2004 983 1013 15530129\n9 Zahari Z. Ismail R. Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics Drug Metab Pharmacokinet 29 1 2014 29 43 23759977\n10 Candiotti K.A. Yang Z. Rodriguez Y. The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption Pain Med 10 5 2009 799 805 19523031\n11 Yiannakopoulou E. Pharmacogenomics and opioid analgesics: Clinical implications Int J Genomics 2015 2015 368979 26075211\n12 Ting S. Schug S. The pharmacogenomics of pain management: Prospects for personalized medicine J Pain Res 9 2016 49 56 26929662\n13 Wang L. McLeod H.L. Weinshilboum R.M. Genomics and drug response N Engl J Med 364 12 2011 1144 1153 21428770\n14 Weinshilboum R. Wang L. Pharmacogenomics: Bench to bedside Nat Rev Drug Discov 3 9 2004 739 748 15340384\n15 Weinshilboum R.M. Wang L. Pharmacogenetics and pharmacogenomics: Development, science, and translation Annu Rev Genomics Hum Genet 7 2006 223 245 16948615\n16 Kaye A.D. Garcia A.J. Hall O.M. Update on the pharmacogenomics of pain management Pharmacogenomics Pers Med 12 2019 125 143\n17 Crews K. Gaedigk A. Dunnenberger H. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype Clin Pharmacol Ther 91 2 2012 321 326 22205192\n18 Drummond M.F. Sculpher M.J. Claxton K. Stoddart G.L. Torrance G.W. Methods for the economic evaluation of health care programmes 2015 Oxford University Press Oxford\n19 Drummond M.F. Drummond M.F. McGuire A. Economic Evaluation in Health Care: Merging Theory with Practice 2001 Oxford University Press Oxford\n20 Bielinski S.J. Olson J.E. Pathak J. Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol Mayo Clin Proc 89 1 2014 25 33 24388019\n21 St Sauver J.L. Grossardt B.R. Yawn B.P. Data resource profile: The Rochester Epidemiology Project (REP) medical records-linkage system Int J Epidemiol 41 6 2012 1614 1624 23159830\n22 Liu S. Ma W. Moore R. Ganesan V. Nelson S. RxNorm: Prescription for electronic drug information exchange IT Professional 7 5 2005 17 23\n23 US Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2 Accessed January 7, 2020\n24 Preskorn S.H. Reproducibility of the in vivo effect of the selective serotonin reuptake inhibitors on the in vivo function of cytochrome P450 2D6: An update (part II) J Psychiatr Pract 9 3 2003 228 236 15985935\n25 Black J.L. 3rd Walker D.L. O’Kane D.J. Harmandayan M. Frequency of undetected CYP2D6 hybrid genes in clinical samples: Impact on phenotype prediction Drug Metab Dispos 40 1 2012 111 119 22004686\n26 Olson S. Berger A.C. The Economics of Genomic Medicine: Workshop Summary 2013 National Academies Press Washington, DC\n27 Bureau of Economic Analysis GDP Price Deflator Available at: https://www.bea.gov/data/prices-inflation/gdp-price-deflator\n28 Grosse S.D. Assessing cost-effectiveness in healthcare: History of the $50,000 per QALY threshold Expert Rev Pharmacoecon Outcomes Res 8 2 2008 165 178 20528406\n29 Ryen L. Svensson M. The willingness to pay for a quality adjusted life year: A review of the empirical literature Health Econ 24 10 2015 1289 1301 25070495\n30 Gyrd-Hansen D. Willingness to pay for a QALY: Theoretical and methodological issues Pharmacoeconomics 23 5 2005 423 432 15896094\n31 Neumann P.J. Cohen J.T. Weinstein M.C. Updating cost-effectiveness—the curious resilience of the $50,000-per-QALY threshold N Engl J Med 371 9 2014 796 797 25162885\n32 Kahneman D. Tversky A. Choices, values, and frames Handbook of the fundamentals of financial decision making: Part I 2013 World Scientific Singapore 269 278\n33 Briggs A. Sculpher M. Claxton K. Decision Modelling for Health Economic Evaluation 2006 Oxford University Press Oxford\n34 Sanders G.D. Neumann P.J. Basu A. Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: Second panel on cost-effectiveness in health and medicine JAMA 316 10 2016 1093 1103 27623463\n35 Engineer N.D. Rosellini W.M. Tyler R.S. Willingness to accept and pay for implantable tinnitus treatments: A survey Neuromodulation 16 2 2013 154 162 22849609\n\n",
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"journal": "Mayo Clinic proceedings. Innovations, quality & outcomes",
"keywords": "ADE, adverse drug event; CYP2D6, Cytochrome P450 2D6; PGx, pharmacogenomics; QALY, quality-adjusted life year; REP, Rochester Epidemiology Project; RIGHT, Right Drug; Right Dose, Right Time-Using Genomic Data to Individualize Treatment",
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"title": "Impact of Pharmacogenomic Information on Values of Care and Quality of Life Associated with Codeine and Tramadol-Related Adverse Drug Events.",
"title_normalized": "impact of pharmacogenomic information on values of care and quality of life associated with codeine and tramadol related adverse drug events"
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{
"abstract": "Aripiprazole is a new drug for the treatment of adults with schizophrenia. Ocular side effects of aripiprazole are very rare. Review of literature revealed few cases of aripiprazole-induced myopia. We report a rare case of aripiprazole-induced transient myopia. A 22-year-old female patient presented to the department of psychiatry with worsening of symptoms of schizophrenia and was started on aripiprazole. She presented with complaints of blurring of vision in both eyes for 1 week which started on the 3rd day following the use of aripiprazole. Anterior segment examination revealed a shallow anterior chamber and narrow angles. Intraocular pressure was normal. A diagnosis of aripiprazole-induced acute myopia was made and the treating psychiatrist was advised to stop the medication. At 2-week follow-up, the unaided visual acuity improved to 20/20 in both the eyes. Ophthalmologists should be aware of the myopic shift that may occur as an ocular side effect with aripiprazole.",
"affiliations": "Department of Ophthalmology, Narayana Medical College, Nellore, Andhra Pradesh, India.;Department of Ophthalmology, Narayana Medical College, Nellore, Andhra Pradesh, India.;Department of Oculoplasty, Sankara Nethralaya, Chennai, Tamil Nadu, India.",
"authors": "Praveen Kumar|K V|KV|;Chiranjeevi|P|P|;Alam|Md Shahid|MS|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "India",
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"doi": "10.4103/ijo.IJO_907_16",
"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 29283140IJO-66-13010.4103/ijo.IJO_907_16Case ReportsAripiprazole-induced transient myopia: A rare entity Praveen Kumar K V Chiranjeevi P Alam Md Shahid 1Department of Ophthalmology, Narayana Medical College, Nellore, Andhra Pradesh, India1 Department of Oculoplasty, Sankara Nethralaya, Chennai, Tamil Nadu, IndiaCorrespondence to: Dr. K V Praveen Kumar, Department of Ophthalmology, Narayana Medical College, Nellore - 524 002, Andhra Pradesh, India. E-mail: [email protected] 2018 66 1 130 131 22 11 2016 26 9 2017 Copyright: © 2017 Indian Journal of Ophthalmology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Aripiprazole is a new drug for the treatment of adults with schizophrenia. Ocular side effects of aripiprazole are very rare. Review of literature revealed few cases of aripiprazole-induced myopia. We report a rare case of aripiprazole-induced transient myopia. A 22-year-old female patient presented to the department of psychiatry with worsening of symptoms of schizophrenia and was started on aripiprazole. She presented with complaints of blurring of vision in both eyes for 1 week which started on the 3rd day following the use of aripiprazole. Anterior segment examination revealed a shallow anterior chamber and narrow angles. Intraocular pressure was normal. A diagnosis of aripiprazole-induced acute myopia was made and the treating psychiatrist was advised to stop the medication. At 2-week follow-up, the unaided visual acuity improved to 20/20 in both the eyes. Ophthalmologists should be aware of the myopic shift that may occur as an ocular side effect with aripiprazole.\n\nAripiprazoleciliochoroidal effusionmyopia\n==== Body\nAripiprazole, a quinolinone derivative recently has become a new valuable therapeutic option for the treatment of adults with schizophrenia.[1] The drug is also used in the treatment of depression, bipolar disorder, and obsessive-compulsive disorder. Common adverse effects reported to the use of aripiprazole are insomnia, anxiety, headache, nausea, vomiting, weight gain, and somnolence.[2] Acute transient myopia as an adverse effect has been reported following the use of certain drugs such as topiramate and zonisamide.[34] Ocular side effects of aripiprazole are very rare. Thorough review of literature revealed only four cases of aripiprazole-induced myopia and one case of diplopia following the use of the drug.[5678] We report the fifth case of aripiprazole-induced transient myopia in a 22-year-old female.\n\nCase Report\nA 22-year-old female patient presented to the department of psychiatry with worsening of symptoms of schizophrenia. She was diagnosed to have schizophrenia elsewhere and was on treatment under a psychiatrist. She was referred to the department of ophthalmology with complaints of blurring of vision in both eyes for 1 week. Previous treatment details were not available with the patient. The patient was started on aripiprazole 10 days back by the treating psychiatrist in doses of 20 mg daily for worsening of symptoms. She complained of blurring of vision on the 3rd day following the use of aripiprazole. There was no history of pain and redness in both the eyes. On examination, the uncorrected visual acuity was 20/200 in both eyes and her best-corrected visual acuity improved to 20/20 in both eyes with −3.5 diopters sphere. Anterior segment examination revealed a shallow anterior chamber with a van hericks grading of II in both the eyes [Figs. 1 and 2]. On gonioscopy, the iridocorneal angles were found to be Grade 1 by Shaffers grading. Intraocular pressure measured on Goldmann applanation tonometry was 14 mmHg in the right eye and 16 mmHg in the left eye. Rest of the anterior segment and dilated fundus examination was unremarkable. However, ultrasound biomicroscopy to look for ciliochoroidal effusion could not be done in this patient as the facility was not available in the department. A diagnosis of aripiprazole-induced acute myopia was entertained, and the treating psychiatrist was advised to stop the medication. At 2-week follow-up after discontinuation of the drug, the unaided visual acuity improved to 20/20 in both the eyes. Anterior chamber depth and gonioscopy were normal. Fundus examination was normal.\n\nFigure 1 Slit lamp photograph of right eye showing shallow anterior chamber with Van Hericks grading of 1\n\nFigure 2 Slit lamp photograph of the left eye showing shallow anterior chamber with Van Hericks grading of 1\n\nDiscussion\nAripiprazole is pharmacologically distinct from other antipsychotics and acts as a potent partial agonist at dopamine D2, D3, and serotonin (5-HT/5-hydroxytryptamine) 5-HT1A receptors and as an antagonist at 5-HT2A receptors. This accounts for the functionally selective action of the drug in humans.[2]\n\nVarious mechanisms have been attributed to the development of transient myopia following the use of systemic medications. Ciliochoroidal effusion and swelling of the ciliary body resulting due to an idiosyncratic reaction from the use of the drug can result in anterior rotation of the ciliary processes, causing narrowing of the ciliary sulcus and forward displacement of the iris and lens which can result in myopia.[9] Another mechanism is that the entry of drug itself into the crystalline lens alters the osmotic status, causing the lens to swell and consequently, resulting in myopia and angle closure.[10]\n\nAs the anterior chamber depth was shallow and the iridocorneal angles were also narrow in this patient, we attribute the myopic shift in our patient to these changes. We suspect an idiosyncratic reaction resulting in ciliochoroidal effusion to have caused myopia in this patient. However, an ultrasound biomciroscopy would have confirmed the hypothesis.\n\nConclusion\nIn view of the existing case reports in the literature and the present case, patients should be informed of the possibility of acute visual loss as an adverse effect of aripiprazole. Ophthalmologists should be aware of the myopic shift that may occur as an ocular side effect with the use of this drug. Ophthalmologists should consult with the prescribing psychiatrist and stop the drug immediately to reverse the condition.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Swainston Harrison T Perry CM Aripiprazole: A review of its use in schizophrenia and schizoaffective disorder Drugs 2004 64 1715 36 15257633 \n2 Shapiro DA Renock S Arrington E Chiodo LA Liu LX Sibley DR Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology Neuropsychopharmacology 2003 28 1400 11 12784105 \n3 Gazieva L Thomassen VH Kaas-Hansen M Baggesen K Topiramate-induced acute bilateral myopia Acta Ophthalmol 2013 91 e332 3 23452405 \n4 Weiler DL Zonisamide-induced angle closure and myopic shift Optom Vis Sci 2015 92 e46 51 25525893 \n5 Kaya H Yılbas B Dilbaz N Yazar Z Aripiprazole induced acute myopia: A case report Bull Clin Psychopharmacol 2009 19 147 8 \n6 Selvi Y Atli A Aydin A Yener HI Aripiprazole-related acute transient myopia and diplopia: A case report J Clin Psychopharmacol 2011 31 249 50 21364340 \n7 Nair AG Nair AG George RJ Biswas J Gandhi RA Aripiprazole induced transient myopia: A case report and review of literature Cutan Ocul Toxicol 2012 31 74 6 21830909 \n8 Karadaǧ H Acar M Özdel K Aripiprazole induced acute transient bilateral myopia: A Case report Balkan Med J 2015 32 230 2 26167352 \n9 Ikeda N Ikeda T Nagata M Mimura O Ciliochoroidal effusion syndrome induced by sulfa derivatives Arch Ophthalmol 2002 120 1775 12470170 \n10 Sen HA O’Halloran HS Lee WB Case reports and small case series: Topiramate-induced acute myopia and retinal striae Arch Ophthalmol 2001 119 775 7 11346412\n\n",
"fulltext_license": "CC BY-NC-SA",
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"journal": "Indian journal of ophthalmology",
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"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D005260:Female; D006801:Humans; D033401:Microscopy, Acoustic; D009216:Myopia; D012029:Refraction, Ocular; D012559:Schizophrenia; D000072776:Slit Lamp Microscopy; D055815:Young Adult",
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"pages": "130-131",
"pmc": null,
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"title": "Aripiprazole-induced transient myopia: A rare entity.",
"title_normalized": "aripiprazole induced transient myopia a rare entity"
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"abstract": "We encountered a case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by duloxetine, serotonin and norepinephrine reuptake inhibitor (SNRI). A 74-year-old woman complaining of severe lethargy was transferred to our emergency department. Her serum sodium level was 109 mEq/L. Plasma hypo-osmolality with urine normo-osmolality was observed, indicating SIADH. Her essential hypertension had long been treated with telmisartan, and she had just started duloxetine 20 mg/day for chronic musculoskeletal pain 4 days prior to admission. On prescribing duloxetine in the primary care setting, clinicians should be aware of the possibility of duloxetine-induced hyponatremia, particularly in combination with telmisartan.",
"affiliations": "Department of Family Medicine, Iwakuni Municipal Miwa Hospital, Japan.;Sunlight Brain Research Center, Japan.;Department of Emergency Medicine, Matsumoto Surgical Hospital, Japan.;Department of Psychiatric Internal Medicine, Kosekai-Kusatsu Hospital, Japan.",
"authors": "Takayama|Atsushi|A|;Nagamine|Takahiko|T|;Matsumoto|Yoshinobu|Y|;Nakamura|Masaru|M|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D000068736:Duloxetine Hydrochloride",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2059-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3079934910.2169/internalmedicine.2059-18Case ReportDuloxetine and Angiotensin II Receptor Blocker Combination Potentially Induce Severe Hyponatremia in an Elderly Woman Takayama Atsushi 12Nagamine Takahiko 34Matsumoto Yoshinobu 4Nakamura Masaru 5\n1 Department of Family Medicine, Iwakuni Municipal Miwa Hospital, Japan\n2 Jichi Medical University Center for Community Medicine, Division of Community and Family Medicine, Japan\n3 Sunlight Brain Research Center, Japan\n4 Department of Emergency Medicine, Matsumoto Surgical Hospital, Japan\n5 Department of Psychiatric Internal Medicine, Kosekai-Kusatsu Hospital, JapanCorrespondence to Dr. Atsushi Takayama, [email protected]\n\n25 2 2019 15 6 2019 58 12 1791 1794 31 8 2018 11 12 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We encountered a case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by duloxetine, serotonin and norepinephrine reuptake inhibitor (SNRI). A 74-year-old woman complaining of severe lethargy was transferred to our emergency department. Her serum sodium level was 109 mEq/L. Plasma hypo-osmolality with urine normo-osmolality was observed, indicating SIADH. Her essential hypertension had long been treated with telmisartan, and she had just started duloxetine 20 mg/day for chronic musculoskeletal pain 4 days prior to admission. On prescribing duloxetine in the primary care setting, clinicians should be aware of the possibility of duloxetine-induced hyponatremia, particularly in combination with telmisartan. \n\nhyponatremiaSIADHduloxetinechronic musculoskeletal painprimary care setting\n==== Body\nIntroduction\nDuloxetine is the first dual serotonin and noradrenaline re-uptake inhibitor (SNRI) indicated for chronic musculoskeletal pain (1). Recently, more and more physicians have been prescribing this medicine to elderly patients (2). However, many doctors are unaware that duloxetine can cause life-threating hyponatremia as a side-effect (3). This also, means that many medications potentially inducing hyponatremia may be prescribed along with duloxetine. Evidence surrounding the combination of this new analgesic agent with other drug is insufficient at present.\n\nWe herein report the first case of the combination of duloxetine and telmisartan causing severe and rapid-onset hyponatremia for a 74 year-old woman, 4 days after starting her prescription.\n\nCase Report \nA 74-year-old woman (154 centimeters in height, weighing 63 kg) with a history of hypertension was transferred to the emergency department of our hospital by emergency services because of severe lethargy at home. She had taken telmisartan 40 mg/day and benidipine hydrochloride 8 mg/day for hypertension for several years and had just started duloxetine 20 mg/day for chronic musculoskeletal pain 4 days prior to the emergency admission, as prescribed by her regular attending physician. She was not taking any diuretic. She did not have any other medical or particular family history that might imply a hereditary disease.\n\nOn arrival, she was complaining of headache and nausea but had not vomited. Her vital signs were in the normal range (blood pressure, 143/79 mmHg; heart rate, 66 bpm; respiratory rate, 18/min; oxygen saturation on ambient air, 99%, and body temperature, 36.5℃). A physical examination revealed no conjunctival pallor, indicating no anemia. Her thyroid was not palpable; neither crackles in the lungs nor heart murmurs were audible. There were no physical signs of systemic edema or dehydration. A neurological examination revealed no obvious muscle weakness, or any sensory abnormalities or abnormalities of deep tendon reflex. However, her chief complaint was severe lethargy, which made her unable to walk by herself. An emergent laboratory evaluation indicated the following serum sodium of 110 mEq/L, potassium 3.8 mEq/L, chloride 73 mEq/L, BUN 11.4 mg/dL, and creatinine 0.6 mg/dL. Her plasma osmolality was 230 mOsm/kg・H20, whereas urine osmolality was 493 mOsm/kg・H20. Urine sodium was found to be 59 mEq/L, and the plasma antidiuretic hormone (ADH) concentration was 2.1 pg/mL severe hyponatremia. Thyroid-stimulating hormone (TSH), free T3, and free T4 levels were found to be normal at 2.3 μIU/mL, 2.7 pg/mL, and 1.7 ng/dL, respectively. Computed tomography (CT) of her brain and chest revealed no abnormalities. Her level of serum sodium continued to drop, reaching 109 mEq/L after the infusion of 500 mL intravenous saline.\n\nThe patient was restricted to 1 L of water per day for 7 days and administered 2.0 g/day sodium chloride for 5 days. The duloxetine was discontinued immediately, and we stopped telmisartan on the third day of admission. Her serum sodium slowly increased from 109 mEq/L to 130 mEq/L over 10 days. She attained a full recovery without any complications and was discharged 14 days after admission (Figure).\n\nFigure. The patient’s clinical course. The change in the patient’s serum sodium levels in relation to duloxetine administration. Severe hyponatremia occurred 4 days after the initiation of duloxetine, and resolved 10 days after its discontinuation.\n\nDiscussion \nWe encountered an elderly patient who developed hyponatremia most likely related to SIADH caused by duloxetine. SIADH is defined by hyponatremia and hypo-osmolality resulting from the inappropriate continued secretion or action of ADH despite a normal or increased plasma volume, which results in impaired water excretion (4). In our patient, severe hyponatremia, plasma hypo-osmolality, urine normo-osmolality, and measurable levels of plasma ADH indicated SIADH.\n\nThere are four main categories of differential diagnoses for euvolemic hyponatremia (5). First, complication due to diuretics other medications should be considered. However, our patient had never been on other medications that result in SIADH aside from the duloxetine and telmisartan. Second, thyroid dysfunction and adrenal insufficiency should be considered, but this possibility was also dismissed because of her present illness and laboratory findings. Third, traumatic brain injury and brain tumor were should be considered, but we were able to rule them out based on her history and brain CT findings. Fourth, lung cancer and certain other types of cancer should also be considered. However, these were unlikely because of her normal chest CT findings. Her symptoms associated with hyponatremia emerged just 4 days after the initiation of duloxetine treatment and resolved with its discontinuation subsequent conservative care. Therefore, we concluded that she was suffering from the duloxetine and telmisartan-induced SIADH.\n\nSIADH accounts for nearly 60% of cases of hyponatremia among geriatric ambulatory outpatients (6). One of the most common causes of SIADH is medications such as diuretics, antiepileptics, antipsychotics, and antidepressants. A case control study found that serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and SNRIs increase the risk of hyponatremia 5.6-fold in elderly patients (7). According to the data of the French National Pharmacovigilance Database, a comparison of the incidence rates from spontaneous reports indicated a greater risk of hyponatremia with duloxetine than with other serotonergic antidepressants (8). Animal experiments showed that both serotonin and norepinephrine stimulate ADH secretion (9). Thus, duloxetine causes SIADH by increasing ADH secretion via the stimulation of serotonergic and norepinephrinergic receptors in the hypothalamus.\n\nThe following three characteristic features constitute the learning points of our case. First, female sex seems to be a particular risk factor for duloxetine-induced SIADH (10). Previous case reports have noted that most cases of duloxetine-induced SIADH occur in women (11-13). The effectiveness of duloxetine for chronic musculoskeletal pain is known to differ between men and women (14), and women are more likely than men to achieve pain reduction with the same dose of duloxetine. Furthermore, in an animal study, a sex-specific difference in the diuretic response to a water load caused by collecting duct nitrous oxide was noted (15). Second, this was the first report to declare the possibility of a bad combination between telmisartan and duloxetine. Angiotensin II type 2 receptor blockers inhibit aldosterone from causing renal tubules to increase the reabsorption of sodium. There is a high probability that this mechanism causes hyponatremia as a side effect. One previous study reported that angiotensin II type 2 receptor blockers increase the risk of hyponatremia 4.097-fold (16). Angiotensin II type 2 receptors also show sex-related differences in their expression, likely due to sexual dimorphism in the physiological mechanisms that regulate the renin-angiotensin system and sodium level (17). Previous studies have warned that duloxetin should not be used in combination with CYP1A2 and CYP2D6 (18, 19) However, telmisartan is not related to CYP metabolism, and benidipine hydrochloride is metabolized with CYP3A4. This result may suggest that no angiotensin-converting enzyme inhibitors or angiotensin II type 2 receptor blockers should be prescribed alongside duloxetine. Third, old age is a risk factor for hyponatremia induced by duloxetine (20), as elderly patients tend to develop hyponatremia due to a reduced renal function, increased level of antidiuretic hormone, and polypharmacy (21).\n\nTreatment of symptomatic hyponatremia is guided by the level of clinical severity. The rapid onset of marked hyponatremia with unconsciousness may induce life-threatening encephalopathy, which requires an emergent infusion of intravenous hypertonic (3%) saline to reverse acute cerebral edema (22). However, sub-acute or chronic hyponatremia presenting with headache, nausea, and lethargy requires gradual correction (10, 11). Current guidelines call for a rate of correction with a maximal increase in sodium of 8-10 mEq/L in the first 24 hours to avoid complications of osmotic demyelination syndrome or central pontine myelinolysis (23). Conservative treatment of drug-induced SIADH includes removing the inciting agent and restricting fluids.\n\nOur patient was successfully treated by the discontinuation of duloxetine and fluid restriction with salt intake. In addition, we stopped telmisartan because it affects the renin-angiotensin system, resulting in sodium depletion. Fluid restriction is considered the first-line therapy according to the recent published guidelines (23). However, it is ineffective or unfeasible in some patients with SIADH. Our patient showed a gradual improvement on her serum sodium level with fluid restriction, but did not recover to the normal level.\n\nTolvaptan therapy was recently reported able to improve and maintain the sodium level in an elderly SIADH patient (24). This drug can efficiently reverse the antidiuretic effect of ADH by competitively binding to vasopressin V2 receptors, thereby increasing the free water clearance and elevating the plasma sodium level. Vasopressin V2 receptor antagonists might therefore be useful as a therapeutic agent for the treatment of chronic dilutional hyponatremia caused by SIADH in the future (25).\n\nDuloxetine is an SNRI, used mainly to treat major depressive disorder. However, duloxetine has recently been indicated for not only neuropathic pain disorders, such as diabetic neuropathy or fibromyalgia, but also the management of chronic musculoskeletal pain, as it helps inhibit pain signals by activating the descending pain inhibitory pathways (26). Duloxetine is increasingly being prescribed by doctors who are not familiar with psychopharmacology in the primary care setting (3). As elderly patients are easily predisposed to hyponatremia due to multiple factors, the use of SNRI may be more likely to aggravate hyponatremia in these patients than in younger ones. Doctors who prescribe duloxetine for chronic musculoskeletal pain should weigh the benefits against the side effects. Clinicians should be encouraged to monitor the serum sodium level, especially a few days after the prescription of duloxetine.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nHoward SS , Eric JS , Benjamin RS \nDuloxetine in the management of chronic musculoskeletal pain Smith . Ther Clin Risk Manag \n8 : 267 -277 , 2012 .22767991 \n2. \nGahimer J , Wernicke J , Yalcin I , Ossanna MJ , Wulster-Radcliffe M , Viktrup L \nA retrospective pooled analysis of duloxetine safety in 23,983 subjects . Curr Med Res Opin \n23 : 175 -184 , 2007 .17257478 \n3. \nNagamine T \nResponsibility of the doctor who prescribes serotonin and noradrenaline reuptake inhibitors for patients with chronic musculoskeletal pain . Psychiatry Clin Neurosci \n72 : 45 -46 , 2018 .\n4. \nEsposito P , Piotti G , Bianzina S , Malul Y , Dal Canton A \nThe syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options . Nephron Clin Pract \n119 : c62 -c73 , 2011 .21677440 \n5. \nAdrogué HJ , Madias NE \nHyponatremia . N Engl J Med \n343 : 886 -887 , 2000 .\n6. \nMiller M , Hecker MS , Friedlander DA , Carter JM \nApparent idiopathic hyponatremia in an ambulatory geriatric population . J Am Geriatr Soc \n44 : 404 -408 , 1996 .8636585 \n7. \nKirby D , Harrigan S , Ames D \nHyponatraemia in elderly psychiatric patients treated with Selective Serotonin Reuptake Inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit . Int J Geriatr Psychiatry \n17 : 231 -237 , 2002 .11921151 \n8. \nRevol R , Rault C , Polard E , Bellet F , Guy C \nHyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance . Encephale \n44 : 291 -296 , 2018 .29248119 \n9. \nIovino M , Steardo L \nEffect of substances influencing brain serotonergic transmission on plasma vasopressin levels in the rat . Eur J Pharmacol \n113 : 99 -103 , 1985 .2931284 \n10. \nKulkarni M \nDuloxetine induced hyponatremia . Indian J Nephrol \n25 : 259 , 2015 .26199483 \n11. \nNakamura M , Satoh Y , Hiraoka A , Fujita Y , Nagamine T \nDuloxetine-induced hyponatremia in the elderly . Clin Neuropsychopharmacol Ther \n3 : 33 -36 , 2012 .\n12. \nAmoako AO , Brown C , Riley T \nSyndrome of inappropriate antidiuretic hormone secretion: a story of duloxetine-induced hyponatraemia . BMJ Case Rep \n2015 : 208037 , 2015 .\n13. \nSiegel AJ , Forte SS , Bhatti NA , Gelda SE \nDrug-related hyponatremic encephalopathy: rapid clinical response averts life-threatening acute cerebral edema . Am J Case Rep \n17 : 150 -153 , 2016 .26956638 \n14. \nAlev L , Fujikoshi S , Yoshikawa A , et al \nDuloxetine 60 mg for chronic low back pain: post hoc responder analysis of double-blind, placebo-controlled trials . J Pain Res \n10 : 1723 -1731 , 2017 .28769588 \n15. \nGao Y , Stuart D , Pollock JS , Takahishi T , Kohan DE \nCollecting duct-specific knockout of nitric oxide synthase 3 impairs water excretion in a sex-dependent manner . Am J Physiol Renal Physiol \n311 : F1074 -F1083 , 2016 .27707708 \n16. \nCorreia L , Ferreira R , Correia I , et al \nSevere hyponatremia in older patients at admission in an internal medicine department . Arch Gerontol Geriatr \n59 : 642 -647 , 2014 .25217102 \n17. \nHilliard LM , Mirabito KM , Denton KM \nUnmasking the potential of the angiotensin AT2 receptor as a therapeutic target in hypertension in men and women: what we know and what we still need to find out . Clin Exp Pharmacol Physiol \n40 : 542 -550 , 2013 .23406015 \n18. \nKnadler MP , Lobo E , Chappell J , Bergstrom R \nDuloxetine: clinical pharmacokinetics and drug interactions . Clin Pharmacokinet \n50 : 281 -294 , 2011 .21366359 \n19. \nWernicke JF , Gahimer J , Yalcin I , Wulster-Radcliffe M , Viktrup L \nSafety and adverse event profile of duloxetine . Expert Opin Drug Saf \n4 : 987 -993 , 2005 .16255658 \n20. \nKirby D , Ames D \nHyponatraemia and selective serotonin re-uptake inhibitors in elderly patients . Int J Geriatr Psychiatry \n16 : 484 -493 , 2001 .11376464 \n21. \nGanguli A , Mascarenhas RC , Jamshed N , Tefera E , Veis JH \nHyponatremia: incidence, risk factors, and consequences in the elderly in a home-based primary care program . Clin Nephrol \n84 : 75 -85 , 2015 .26042411 \n22. \nCuesta M , Garrahy A , Thompson CJ \nSIAD: practical recommendations for diagnosis and management . J Endocrinol Invest \n39 : 991 -1001 , 2016 .27094044 \n23. \nSiegel AJ \nHyponatremia in psychiatric patients: update on evaluation and management . Harv Rev Psychiatry \n16 : 13 -24 , 2008 .18306096 \n24. \nFoppiani L \nSIADH with severe hyponatremia in an elderly man with herpes zoster infection: a causal or casual association? \nIntern Med \n57 : 3393 -3398 , 2018 .29984775 \n25. \nPalmer BF \nThe role of V2 receptor antagonists in the treatment of hyponatremia . Electrolyte Blood Press \n11 : 1 -8 , 2013 .23946759 \n26. \nPergolizzi JV Jr, Raffa RB , Taylor R Jr, Rodriguez G , Nalamachu S , Langley P \nA. Review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain . Pain Pract \n13 : 239 -252 , 2013 .22716295\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "SIADH; chronic musculoskeletal pain; duloxetine; hyponatremia; primary care setting",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1791-1794",
"pmc": null,
"pmid": "30799349",
"pubdate": "2019-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11376464;11921151;16255658;17257478;18306096;21366359;21677440;22716295;22767991;23406015;23946759;25217102;25911354;26042411;26199483;26956638;27094044;27707708;28769588;29064131;29248119;2931284;29984775;8636585",
"title": "Duloxetine and Angiotensin II Receptor Blocker Combination Potentially Induce Severe Hyponatremia in an Elderly Woman.",
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{
"abstract": "Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Without an effective therapy, patients may progress quickly to functional disability. Recently, depletion of B cells emerged as a new approach for the treatment of autoimmune diseases, including JIA. We describe six cases of JIA patients followed at a referral center for Rheumatology and Pediatric Rheumatology, submitted to treatment with rituximab (RTX) after refractoriness to three anti-TNF agents. Patients received RTX cycles with two infusions every six months. Response to treatment was assessed by DAS28, HAQ/CHAQ, and an overall assessment by the doctor and the patient. Of our six patients, four were girls (mean age at onset of disease: 6.1 years; mean disease evolution time: 15.1 years; mean age upon receiving RTX: 21.6 years). Four patients belonged to polyarticular subtype (1 rheumatoid factor [RF]-negative, 3 FR-positive), a patient with systemic JIA subtype with a polyarticular course and arthritis related to enthesitis. Of our six patients, five responded to treatment; and during the course of 12 months, the clinical response was maintained, although not sustained. However, discontinuation by infusion reactions caused the withdrawal of RTX in two patients. The use of RTX in JIA is restricted to cases refractory to other biological agents and, even considering that this study was held in a small number of advanced patients, RTX proved to be an effective therapeutic option.",
"affiliations": "Universidade Federal de São Paulo, São Paulo, SP, Brasil.;Universidade Federal de São Paulo, São Paulo, SP, Brasil.;Hospital Infantil Darcy Vargas, São Paulo, SP, Brasil.;Universidade Federal de São Paulo, São Paulo, SP, Brasil.;Universidade Federal de São Paulo, São Paulo, SP, Brasil.;Universidade Federal de São Paulo, São Paulo, SP, Brasil. Electronic address: [email protected].",
"authors": "Sakamoto|Ana Paula|AP|;Pinheiro|Marcelo M|MM|;Barbosa|Cássia Maria Passarelli Lupoli|CM|;Fraga|Melissa Mariti|MM|;Len|Claudio Arnaldo|CA|;Terreri|Maria Teresa|MT|",
"chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0482-5004",
"issue": "55(6)",
"journal": "Revista brasileira de reumatologia",
"keywords": "Artrite idiopática juvenil; Children; Crianças; Juvenile idiopathic arthritis; Refractoriness; Refratariedade; Rituximab; Rituximabe",
"medline_ta": "Rev Bras Reumatol",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D005260:Female; D006801:Humans; D008297:Male; D000069283:Rituximab; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "0404256",
"other_id": null,
"pages": "536-41",
"pmc": null,
"pmid": "26066294",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab use in young adults diagnosed with juvenile idiopathic arthritis unresponsive to conventional treatment: report of 6 cases.",
"title_normalized": "rituximab use in young adults diagnosed with juvenile idiopathic arthritis unresponsive to conventional treatment report of 6 cases"
} | [
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{
"abstract": "Multiple strategies have been implemented to increase the donor pool to avoid transplant wait-list mortality. The approval of highly effective direct-acting antiviral regimens for the treatment of hepatitis C virus (HCV) has enabled expansion of the donor pool by allowing the transplantation of organs from HCV-viremic donors to HCV-negative recipients. Multiple centers have recently published data on outcomes of heart transplantation from HCV-viremic heart donors to HCV-negative recipients, with acceptable posttransplant outcomes. However, areas of uncertainty remain, particularly in the long-term risks of intentional HCV transmission, as well as the possibility that sustained virologic response may not be achieved. In this article, we review the literature illustrating both the risks and benefits of transplantation of organs from HCV-viremic donors to HCV-negative recipients. We also present the data collected at our institution regarding this special patient population.",
"affiliations": "From the Department of Medicine, Division of Gastroenterology and Hepatobiliary Disease.;Department of Medicine, Division of Infectious Diseases.;Department of Medicine, Division of Cardiology.;Department of Medicine, Division of Cardiology.;Department of Surgery, Cardiothoracic Surgery.;Department of Medicine, Division of Infectious Diseases.;Department of Surgery, Division of Transplant Hepatology, New York Medical College, Westchester Medical Center, Valhalla, NY.;Department of Surgery, Division of Transplant Hepatology, New York Medical College, Westchester Medical Center, Valhalla, NY.",
"authors": "Frager|Shalom Z|SZ|;Dhand|Abhay|A|;Gass|Alan|A|;Levine|Avi|A|;Spielvogel|David|D|;Nog|Rajat|R|;Wolf|David C|DC|;Bodin|Roxana I|RI|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/CRD.0000000000000255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1061-5377",
"issue": "27(4)",
"journal": "Cardiology in review",
"keywords": null,
"medline_ta": "Cardiol Rev",
"mesh_terms": "D016027:Heart Transplantation; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D011379:Prognosis; D014019:Tissue Donors; D066027:Transplant Recipients; D014766:Viremia",
"nlm_unique_id": "9304686",
"other_id": null,
"pages": "179-181",
"pmc": null,
"pmid": "31180937",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Heart Transplantation for Hepatitis C Virus Non-Viremic Recipients From Hepatitis C Virus Viremic Donors.",
"title_normalized": "heart transplantation for hepatitis c virus non viremic recipients from hepatitis c virus viremic donors"
} | [
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{
"abstract": "Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis, characterized by progressive remodelling of the small pulmonary arteries that precede the clinical and haemodynamic manifestations of the disease. Thus, a prompt diagnosis and early intervention are crucial.\nA 39-year-old pregnant women presented with persistent severe hypoxaemia after the diagnosis of influenza B and an elective caesarean delivery at 33 weeks. Ten months after, an extensive and inconclusive investigation that included a lung biopsy, despite of a spontaneous improvement in oxygen saturation, clinical deterioration led to further testing, namely genetic screening. It revealed a fast-progressing case of hereditary PAH caused by BMRP2 mutation.\nThis case highlights the challenges of a timely diagnosis of PAH and the importance of close clinical monitoring of patients at high risk of PAH. In addition, it emphasizes the fast development of severe haemodynamic changes associated with a BMPR2 mutation. The availability of a lung biopsy without signs of pulmonary vascular disease (PVD) and a right heart catheterization with mild pulmonary hypertension at the baseline assessment demonstrates that PVD can progress in a neoplastic-like manner in a matter of months.",
"affiliations": "Cardiology Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal.;Pneumology Unit, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal.;Pneumology Unit, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal.;Cardiology Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal.",
"authors": "Santos-Ferreira|Cátia|C|https://orcid.org/0000-0001-8312-5199;Cardoso|Daniela|D|https://orcid.org/0000-0002-5898-8803;Paiva|Benedita|B|https://orcid.org/0000-0003-3113-7109;Baptista|Rui|R|https://orcid.org/0000-0002-7411-7039",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab149",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab149\nytab149\nCase Report\nAcademicSubjects/MED00200\nPulmonary arterial hypertension unveils itself: a cancer-like progression — a case report\nhttps://orcid.org/0000-0001-8312-5199\nSantos-Ferreira Cátia 1\nhttps://orcid.org/0000-0002-5898-8803\nCardoso Daniela 2\nhttps://orcid.org/0000-0003-3113-7109\nPaiva Benedita 2\nhttps://orcid.org/0000-0002-7411-7039\nBaptista Rui 134\n1 Cardiology Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal\n2 Pneumology Unit, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal\n3 Cardiology Department, Centro Hospitalar Entre Douro e Vouga, R. Dr. Cândido Pinho 5, 4520-211 Santa Maria da Feira, Portugal\n4 Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal\nTan Timothy C Handling Editor\nAbumuaileq Rami Riziq Yousef Editor\nLorusso Roberto Editor\nKurdi Hibba Editor\nAhmed Nida Editor\nCátia Santos-Ferreira, Daniela Cardoso contributed equally to this manuscript.\n\nCorresponding author. Tel: +351 912 406 484, Email: [email protected]\n5 2021\n22 5 2021\n22 5 2021\n5 5 ytab14926 8 2020\n13 1 2021\n09 4 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]\n\nAbstract\n\nBackground\n\nPulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis, characterized by progressive remodelling of the small pulmonary arteries that precede the clinical and haemodynamic manifestations of the disease. Thus, a prompt diagnosis and early intervention are crucial.\n\nCase summary\n\nA 39-year-old pregnant women presented with persistent severe hypoxaemia after the diagnosis of influenza B and an elective caesarean delivery at 33 weeks. Ten months after, an extensive and inconclusive investigation that included a lung biopsy, despite of a spontaneous improvement in oxygen saturation, clinical deterioration led to further testing, namely genetic screening. It revealed a fast-progressing case of hereditary PAH caused by BMRP2 mutation.\n\nDiscussion\n\nThis case highlights the challenges of a timely diagnosis of PAH and the importance of close clinical monitoring of patients at high risk of PAH. In addition, it emphasizes the fast development of severe haemodynamic changes associated with a BMPR2 mutation. The availability of a lung biopsy without signs of pulmonary vascular disease (PVD) and a right heart catheterization with mild pulmonary hypertension at the baseline assessment demonstrates that PVD can progress in a neoplastic-like manner in a matter of months.\n\nHypoxaemia\nPulmonary arterial hypertension\nPulmonary hypertension\nInterstitial lung disease\nBMRP2\nCase report\n==== Body\nLearning points\n\nPulmonary vascular disease can progress in a matter of months from mild to severe haemodynamics.\n\nCardiopulmonary exercise testing is an invaluable tool to assess dyspnoea symptoms.\n\nIntroduction\n\nPulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive remodelling of the small pulmonary arteries that precede the clinical and haemodynamic manifestations of the disease.1 A prompt diagnosis and early intervention are crucial in improving survival, given the poor prognosis.2,3 Here, we report a fast-progressing case of hereditary pulmonary arterial hypertension (HPAH).\n\nTimeline\n\nDay 0 (February 2018)\t30-week pregnant patient develops dyspnoea, cough, and fever; diagnosed with influenza B infection and treated as an outpatient with oseltamivir.\t\nDay 2\tClinical deterioration with severe hypoxaemia, admitted to the Infectious Diseases Department and treated with oseltamivir and amoxicillin-clavulanate.\t\nDay 9\tTransferred to the Prenatal Ward after clinical improvement; but severe hypoxaemia persisted.\t\nDay 14\tWorsening fatigue and persistent hypoxaemia; ventilation/perfusion lung scan negative for pulmonary embolism.\t\nDay 20\tWorsening fatigue and persistent hypoxaemia; computed tomography pulmonary angiogram negative for pulmonary embolism.\t\nDay 21 (March 2018)\tElective caesarean delivery at 33 weeks.\t\nDay 24\tPersistent severe hypoxaemia after caesarean; transferred to the Pneumology Department for further explorations.\t\nDay 52\tAfter an extensive and inconclusive investigation, including a right heart catheterization (RHC) and a lung biopsy, the patient was discharged under continuous supplementary oxygen therapy (SaO2 92% with FiO2 21%).\t\nJune and August 2018\tRe-evaluation as an outpatient: hypoxaemia requiring supplementary oxygen therapy with relatively stable levels of fatigue (SaO2 94% with FiO2 21%).\t\nDecember 2018\tWorsening fatigue with spontaneous resolution of hypoxaemia (SaO2 98% with FiO2 21%); cardiopulmonary exercise test suggestive of significant tissue hypoxia and transthoracic echocardiogram showed de novo mild dilatation of the right ventricle and a tricuspid regurgitation velocity of 3.5 m/s.\t\nJanuary 2019\tA diagnosis of heritable pulmonary arterial hypertension was made based on the RHC that revealed severe haemodynamics, with markers of high risk, and identification of a pathogenic heterozygous variant in BMRP2 gene. Upfront double combination pulmonary vasodilator therapy with sildenafil 20 mg t.i.d. and bosentan 125 mg b.i.d. was initiated.\t\nApril 2019\tMarked clinical improvement, as well as improvement of the 6-min walking test and normalization of the cardiac biomarkers.\t\nOctober 2020\tDespite clinical stability [New York Heart Association (NYHA) functional class II] and normal cardiac biomarkers, a low cardiac index (1.95 L/min/m2) led to the addition of selexipag 200 mg b.i.d.\t\nFebruary 2021\tClinical improvement (NYHA functional class I) and normal cardiac biomarkers. Selexipag was slowly titrated to 1000 mg b.i.d. based on clinical tolerance.\t\n\nCase presentation\n\nA Caucasian 39-year-old 30-week pregnant woman presented with dyspnoea, cough, and fever. She was severely hypoxaemic, and a diagnosis of influenza B infection by real-time polymerase chain reaction was made. After a course of oseltamivir and amoxicillin-clavulanate, no improvement was found in the pattern of hypoxaemia and hypocapnia. A pulmonary embolism workup, including a computed tomography (CT) pulmonary angiogram and a ventilation/perfusion lung scan, was carried out and was negative. Following an elective caesarean delivery at 33 weeks, hypoxaemia requiring supplemental oxygen persisted.\n\nHer past medical history was significant for arterial hypertension and hypothyroidism during the current pregnancy. Her family history was remarkable by the death of a sister at a young age.\n\nOn admission, she denied chest pain, syncope, haemoptysis, and prior smoking. On physical examination, she was slightly dyspnoeic and hypoxaemic [oxygen saturation (SaO2) with supplemental oxygen at 4 L/min 99%]. There were bibasilar lung crackles but no peripheral oedema, and no skin, finger, or nail changes.\n\nThe initial investigation showed severe hypoxaemia [PaO2 59 mmHg with fraction of inspired oxygen (FiO2) 21%] with hypocapnia, but with a good response to oxygen therapy (Table 1). The biochemical and autoimmunity studies were unremarkable (Table 1). The chest radiography did not reveal pleural or pulmonary changes (Figure 1). Pulmonary function testing revealed normal spirometry volumes, but a low diffusing capacity for carbon monoxide (DLCO)—56.9%. High-resolution CT excluded lung parenchymal involvement (Figure 1).\n\nFigure 1 Chest imaging. (A) Normal chest radiograph. (B and C) Normal high-resolution computed tomography.\n\nTable 1 Basic laboratory studies: comprehensive metabolic panel\n\n\tValue\tReference range\t\nArterial blood gas\t\t\t\n PaO2 (FiO2 21%)\t59\t80–100 mmHg\t\n PaCO2 (FiO2 21%)\t21\t35–45 mmHg\t\n PaO2 (FiO1 40%)\t132\t80–100 mmHg\t\n PaCO2 (FiO2 40%)\t24\t35–45 mmHg\t\nBiochemical profile\t\t\t\n Sodium\t139\t136–146 mmol⋅L−1\t\n Potassium\t3.8\t3.5–5.1 mmol⋅L−1\t\n Chloride\t105\t101–109 mmol⋅L−1\t\n Blood urea nitrogen\t17.4\t7.94–20.9 mg⋅dL−1\t\n Creatinine\t0.62\t0.55–1.02 mg⋅dL−1\t\n Estimated glomerular filtration rate\t114\t>59 mL⋅min−1⋅1.73 m−2\t\n Calcium\t8.6\t8.8–10.6 mg⋅dL−1\t\n AST\t26\t<31 U⋅L−1\t\n ALT\t53\t<34 U⋅L−1\t\n Alkaline phosphatase\t126\t30–120 U⋅L−1\t\n Total bilirubin\t0.3\t0.2–1.2 mg⋅dL−1\t\n Albumin\t3.0\t3.5–5.2 g⋅dL−1\t\n LDL\t106\t<130 mg⋅dL−1\t\nComplete blood count\t\t\t\n Haemoglobin\t11.1\t12.0–16.0 g⋅dL−1\t\n Platelets\t271\t150–400 ×109⋅L−1\t\n White blood cells\t10.9\t4.0–10.0 ×109⋅L−1\t\n Mean corpuscular value\t78.2\t\t\nCardiac enzymes\t\t\t\n Troponin I\t23\t<27 ng⋅L−1\t\n BNP\t<10\t<100 pg⋅mL−1\t\nInflammatory markers\t\t\t\n C-reactive protein\t0.57\t0–0.5 mg⋅dL−1\t\nIron studies\t\t\t\n Ferritin\t13\t4.6–204 ng⋅mL−1\t\n Iron\t31\t60–180 µg⋅dL−1\t\n Total iron binding capacity\t378\t250–400 µg⋅dL−1\t\n Percent saturation\t8\t20–40%\t\nALT, alanine aminotransferase; AST, aspartate transaminase; BNP, brain natriuretic peptide; FiO2, fraction of inspired oxygen; LDL, low-density lipoprotein.\n\nA transthoracic echocardiogram (TTE) demonstrated a non-dilated right ventricle (RV) and a tricuspid regurgitation velocity gradient of 3.0 m/s (Figure 2A). A bubble study excluded an intracardiac or intrapulmonary shunt. Finally, a right heart catheterization (RHC) was performed and revealed severe resting hypoxaemia (SaO2 86%) and mild, pre-capillary pulmonary hypertension (PH), partially reversible with 100% O2 (Table 2).\n\nFigure 2 Serial transthoracic echocardiogram. (A) Normal-sized chambers. (B) Mildly dilated right ventricle.\n\nTable 2 Hemodynamic parameters measured using RHC\n\nBaselin\tBaselin RHC\tFollow-up RHC\n(10 months later)\tFollow-up RHC\n(18 months after PAH therapy)\t\n\tFiO2 21%\tAfter FiO2 100%\tFiO2 21%\tFiO2 21%\t\nRight atrial pressure -mmHg\t7\t7\t4\t8\t\nMean pulmonary artery pressure -mmHg\t29\t26\t48\t28\t\nPulmonary capillary wedge pressure -mmHg\t8\t13\t4\t15\t\nTranspulmonary pressure gradient -mmHg\t21\t13\t44\t13\t\nPulmonary vascular resistance—Wood units\t7.7\t3.9\t16\t3.7\t\nCardiac index –L/min/m2\t2.2\t2.0\t1.6\t1.95\t\nMixed venous oxygen saturation -%\t57\t69\t53\t-\t\nAortic oxygen saturation -%\t86\t100\t98\t-\t\nFiO2: fraction of inspired oxygen; PAH: pulmonary artery hypertension; RHC: right heart catheterization.\n\nTaking into consideration the relative disproportion between the severity of the hypoxia and the mild PH, a surgical lung biopsy was performed. The main finding was a non-specific pattern of chronic bronchiolitis (Figure 3). As the findings did not support the diagnosis of pulmonary vascular disease (PVD), the patient was discharged under oxygen therapy without specific medication.\n\nFigure 3 Lung biopsy. (A and B) Peri-arteriolar and peri-bronchiolar lymphocytes and macrophages with epithelioid granuloma immune response running with arteriolar wall hyperplasia and constrictive bronchiolitis (H&E ×100/CD68 ×100). (C and D) Revision of the biopsy highlighted previous non-characterized capillary vessel walls changes overdue to lymphocytes infiltration and epithelioid granulomas exuberance. The presence of singular millimetric fibrovascular remodelling, mostly found in BMPR2-related pulmonary arterial hypertension, was underestimated and prevented pulmonary arterial hypertension diagnosis (Elastin–van Gieson ×100/Actin ×100).\n\nDuring the next 10 months, a progressive and spontaneous improvement in SaO2 was seen, leading to oxygen supplementation withdrawal. Conversely, fatigue worsened, prompting the performance of a cardiopulmonary exercise test. Although no desaturation at rest or peak exertion was noted, it revealed a decreased peak oxygen consumption (VO2 16.4 mL/min/kg; predicted value >25 mL/min/kg), a VE/VCO2 slope of 32.9 (predicted value 22–28), and a marked increase of arterial lactate level upon exertion. Additionally, as the breathing reserve was not exhausted, pulmonary limitation to exertion was not an issue. TTE repetition showed de novo mild dilatation of the RV and an increasing tricuspid regurgitation velocity of 3.5 m/s (Figure 2B). These findings led to a new RHC that confirmed PAH (Table 2). Later on, the patient recalled that the death of her 17-year-old sister, 20 years ago, was due to an unspecified pulmonary disease, leading to the performance of genetic testing of PVD-related genes and the identification of a pathogenic heterozygous variant in BMRP2 gene [c.647dup p.(Val217Serfs*3)]. A diagnosis of HPAH was then made, based on haemodynamic and genetic grounds. Sildenafil 20 mg t.i.d. and bosentan 125 mg b.i.d. was initiated, leading to a marked clinical and functional improvement. Eighteen months later, despite clinical stability and normal cardiac biomarkers, the follow-up RHC revealed a low cardiac index (Table 2), and selexipag 200 mg b.i.d. was promptly added to the initial therapy.\n\nDiscussion\n\nPH is a clinical syndrome, and the guidelines recommend a comprehensive set of investigations after an echocardiogram with a moderate-to-high probability of PH, in order to establish an aetiology.1 However, the interpretation of such investigations is challenging, as our case showed. Initially, the first set of inconclusive exams lead to the performance of a lung biopsy, which actually is no longer recommended in PAH patients due to a substantial risk of morbimortality.1 However, the combination of mild PH in the context of severe, unexplained hypoxaemia after a viral pneumonia and a non-suggestive lung biopsy shifted away the suspicion of PVD. Additionally, the degree of hypoxaemia in PAH is generally mild to moderate, with a mean PaO2 (FiO2 21%) of 70 ± 13 mmHg in males and 72 ± 16 mmHg in females.4,5 More severe hypoxaemia should prompt the consideration of alternative causes of PH, namely pulmonary veno-occlusive disease (excluded by the chest CT and biopsy), thromboembolic disease (excluded by a pulmonary ventilation/perfusion lung scan), and intracardiac or intrapulmonary shunts.6 Besides PVD, an isolated decrease in the DLCO with normal spirometry raises the suspicion for early interstitial lung disease (ILD), anaemia, hepatopulmonary syndrome, and carboxyhaemoglobinemia due to cigarette smoking.7 These last three causes were promptly excluded. Finally, ILD was the strongest diagnostic hypothesis after the initial investigation. The presumed low risk of complications led to the performance of a lung biopsy, a valuable diagnostic tool in ILD8; however, its findings were unspecific.\n\nTen months later, after significant clinical deterioration despite the SaO2 normalization, genetic testing confirmed the HPAH diagnosis. Although BMPR2 genetic testing should be offered to patients with idiopathic PAH (IPAH), drug-induced PAH, or with a family history of PAH,1 the timing of the screening is not clear. We acknowledge that if it was performed sooner, it could have obviated the need for a lung biopsy; however, neither the clinical presentation nor the diagnostic testing strongly supported PAH at first. Nonetheless, there was a game-changing clue that was initially missed and might have prevented an earlier diagnosis, the family history of the death of her adolescent sister due to lung disease, which was only recalled by the patient later on. Heterozygous BMPR2 mutations account for approximately 75% of HPAH and up to 25% of sporadic PAH cases1 and may be associated with PAH development at younger ages and a more severe clinical and haemodynamic phenotype.9 Importantly, the availability of a lung biopsy without signs of PVD and an RHC with mild PH on baseline demonstrates that PVD can progress in a neoplastic-like manner in a matter of months, in the presence of a BMPR2 mutation.\n\nThe mechanism of the hypoxaemia that persisted for months after influenza B infection and spontaneously ameliorated is debatable, particularly in the setting of a PAH-causing mutation. Pregnant women are a high-risk group for influenza complications,10 and it is known that the physiological changes seem to be poorly tolerated by PAH patients.11\n\nThe treatment strategy for PAH includes general, supportive, and PAH-specific therapy. Regarding PAH-specific therapy, the first step is to identify who is suitable for high-dose calcium channel blockers among patients with IPAH, HPAH, or drug-induced PAH.1 Our patient did not undergo pulmonary vasoreactivity testing during the second RHC due to symptomatic hypotension secondary to a vagal response. The patient was treated with upfront combination therapy, as it has proven to be superior to monotherapy.12 Lastly, when treatment goals are not met, sequential combination therapy is recommended.1\n\nConclusions\n\nWe present a case of HPAH caused by a BMRP2 mutation in a patient with symptom onset during pregnancy, progressing in a neoplastic-like manner, from an unremarkable biopsy to overt disease in a matter of months. Close monitoring is paramount in patients at high risk.\n\nLead author biography\n\nCátia Santos-Ferreira graduated from Faculty of Medicine, University of Coimbra in 2015. She is following a residency in Cardiology at Centro Hospitalar e Universitário de Coimbra. Moreover, she is completing a PhD degree on Health Sciences at University of Coimbra. Her academic interests include pulmonary hypertension and heart failure.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\n\nytab149_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nThe authors would like to acknowledge Prof. Lina Carvalho for the revision of the lung biopsy, and Prof. Lino Gonçalves and Dr Graça Castro for their revision of the manuscript.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.\n\nConflict of interest: None declared.\n\nFunding: This work was supported by the Fundação para Ciência e Tecnologia (FCT) [POCI-01-0145-FEDER-032414 to R.B.].\n==== Refs\nReferences\n\n1 Galié N , HumbertM, VachieryJL, GibbsS, LangI, TorbickiA et al 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016;37 :67–119.26320113\n2 Brown LM , ChenH, HalpernS, TaichmanD, McGoonMD, FarberHW et al Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry. Chest 2011;140 :19–26.21393391\n3 Swinnen K , QuarckR, GodinasL, BelgeC, DelcroixM. Learning from registries in pulmonary arterial hypertension: pitfalls and recommendations. Eur Respir Rev 2019;28 :190050.31852746\n4 Rich S , DantzkerDR, AyresSM, BergofskyEH, BrundageBH, DetreKM et al Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107 :216–223.3605900\n5 Khirfan G , NaalT, AbuhalimehB, NewmanJ, HeresiGA, DweikRA et al Hypoxemia in patients with idiopathic or heritable pulmonary arterial hypertension. PLoS One 2018;13 :e0191869.29377954\n6 Porteous MK , FritzJS. Hypoxemia in a patient with pulmonary arterial hypertension: getting to the heart of the matter. Ann Am Thorac Soc 2014;11 :836–840.24936696\n7 McCormack M . Diffusing capacity for carbon monoxide. Up-to-date. https://www.uptodate.com/contents/diffusing-capacity-for-carbon-monoxide?search=Diffusing%20capacity%20for%20carbon%20monoxide.&source=search_result&selectedTitle=1∼150&usage_type=default&display_rank=1 (6 May 2020).\n8 Raj R , RapariaK, LynchDA, BrownKK. Surgical lung biopsy for interstitial lung diseases. Chest 2017;151 :1131–1140.27471113\n9 Soubrier F , ChungWK, MachadoR, GrünigE, AldredM, GeraciM et al Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62 (25 Suppl ):D13–D21.24355637\n10 Louie JK , AcostaM, JamiesonDJ, HoneinMA. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 2010;362 :27–35.20032319\n11 Warnes CA. Pregnancy and pulmonary hypertension. Int J Cardiol 2004;97 :11–13.15590074\n12 Galiè N , BarberàJA, FrostAE, GhofraniHA, HoeperMM, McLaughlinVv et al Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373 :834–844.26308684\n\n",
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"keywords": "BMRP2; Case report; Hypoxaemia; Interstitial lung disease; Pulmonary arterial hypertension; Pulmonary hypertension",
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{
"abstract": "Osmotic demyelination syndrome commonly affects the pons and infrequently involves the extrapontine region. We report a patient with severe hyponatraemia who developed osmotic demyelination syndrome as a consequence of rapid sodium correction. The condition manifested as acute severe parkinsonism, bilateral ptosis and gaze impairment. MRI revealed typical features of central pontine and extrapontine myelinolysis. The patient improved gradually after treatment with a combination of levodopa, intravenous immunoglobulin and dexamethasone. However, it is important to emphasise that the improvement of neurological symptoms is not necessarily causal with these experimental therapies.",
"affiliations": "Department of Medicine (Neurology), School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.;Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.",
"authors": "Abdul Halim|Sanihah|S|http://orcid.org/0000-0001-8100-3251;Mohd Amin|Nur Aida|NA|",
"chemical_list": "D007980:Levodopa",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225751",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "brain stem / Cerebellum; fluid electrolyte and acid-base disturbances; parkinson’s disease; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001763:Blepharoptosis; D003937:Diagnosis, Differential; D006801:Humans; D007010:Hyponatremia; D007980:Levodopa; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017590:Myelinolysis, Central Pontine; D020734:Parkinsonian Disorders; D013577:Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30344146",
"pubdate": "2018-10-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12002984;23660544;18235152;26106753;15975595;21918655;21885671;17981159;20539224;16218318;15316041;10209986;23346434;14970019;9667573;28321080;20453633;22036854;27091143;26240598;20826870;1910933;10460448;17903865;11723299;10803802;13616772;10404700",
"title": "Treatment response in osmotic demyelination syndrome presenting as severe parkinsonism, ptosis and gaze palsy.",
"title_normalized": "treatment response in osmotic demyelination syndrome presenting as severe parkinsonism ptosis and gaze palsy"
} | [
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"abstract": "Epinephrine, in all modes of use, may pose a wide range of cardiotoxic events, ranging from sinus tachycardia to heart failure, life threatening arrhythmias, and even death. Because of daily and extensive use of epinephrine, these unusual and rare events tend to be forgotten by physicians. We present a case of dilated cardiomyopathy that developed following routine use of epinephrine-impregnated tampons during function endoscopic sinus (FESS) surgery.\n\n\n\nA healthy, 24-year-old man with no family history of heart disease has undergone elective surgery under general anesthesia to repair the paranasal sinuses using endoscopic approach. During surgery, soon after being treated with 1: 1000 diluted epinephrine-soaked tampons, an hypertensive crisis was noticed followed by pulseless electrical activity. An extensive examination led to the diagnosis of non-ischemic dilated cardiomyopathy. After several days of heart failure medical therapy, complete resolution of all structural and functional changes was achieved.\n\n\n\nIn our case, we present an unusual and rare event of acute dilated cardiomyopathy following the use of epinephrine-soaked tampons during elective FESS surgery. A prompt response was observed after several days of heart failure treatment. Awareness of the epinephrine cardiotoxic potential even in the form of soaked tampons is essential for proper diagnosis and prompt treatment.",
"affiliations": "Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.;Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.;Department of Anaesthesia, Emek Medical Center, Afula, Israel.;Heart Institute, Emek Medical Center, Afula, Israel.;Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.;Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. [email protected].",
"authors": "Naddaf|Sari|S|;Ehrenberg|Scott|S|;Hakim|Rony|R|;Mahamid|Muhamad|M|;Turgeman|Yoav|Y|;Koren|Ofir|O|0000-0002-8666-8276",
"chemical_list": "D000322:Adrenergic Agonists; D004837:Epinephrine",
"country": "England",
"delete": false,
"doi": "10.1186/s12872-020-01706-8",
"fulltext": "\n==== Front\nBMC Cardiovasc Disord\nBMC Cardiovasc Disord\nBMC Cardiovascular Disorders\n1471-2261 BioMed Central London \n\n1706\n10.1186/s12872-020-01706-8\nCase Report\nEpinephrine soaked tampons induced transient acute dilated cardiomyopathy during FESS procedure\nNaddaf Sari 1 Ehrenberg Scott 1 Hakim Rony 2 Mahamid Muhamad 3 Turgeman Yoav 13 http://orcid.org/0000-0002-8666-8276Koren Ofir [email protected] 13 1 grid.6451.60000000121102151Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel \n2 grid.469889.20000 0004 0497 6510Department of Anaesthesia, Emek Medical Center, Afula, Israel \n3 grid.469889.20000 0004 0497 6510Heart Institute, Emek Medical Center, Afula, Israel \n16 10 2020 \n16 10 2020 \n2020 \n20 4525 6 2020 16 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nEpinephrine, in all modes of use, may pose a wide range of cardiotoxic events, ranging from sinus tachycardia to heart failure, life threatening arrhythmias, and even death. Because of daily and extensive use of epinephrine, these unusual and rare events tend to be forgotten by physicians. We present a case of dilated cardiomyopathy that developed following routine use of epinephrine-impregnated tampons during function endoscopic sinus (FESS) surgery.\n\nCase presentation\nA healthy, 24-year-old man with no family history of heart disease has undergone elective surgery under general anesthesia to repair the paranasal sinuses using endoscopic approach. During surgery, soon after being treated with 1: 1000 diluted epinephrine-soaked tampons, an hypertensive crisis was noticed followed by pulseless electrical activity. An extensive examination led to the diagnosis of non-ischemic dilated cardiomyopathy. After several days of heart failure medical therapy, complete resolution of all structural and functional changes was achieved.\n\nConclusion\nIn our case, we present an unusual and rare event of acute dilated cardiomyopathy following the use of epinephrine-soaked tampons during elective FESS surgery. A prompt response was observed after several days of heart failure treatment. Awareness of the epinephrine cardiotoxic potential even in the form of soaked tampons is essential for proper diagnosis and prompt treatment.\n\nKeywords\nEpinephrineDilated cardiomyopathyHeart failureFESSSurgeryissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDilated cardiomyopathy (DCM) is recognized by the dilation of the right, left, or both ventricles in the absence of abnormal loading conditions as hypertension and valve disease, or significant coronary artery disease [1–5].\n\nThe etiology of DCM is extremely heterogeneous sometimes classified based on known genetic mutation. Among the non-genetics cause are different etiologies, including myocarditis, exposure to drugs as cocaine, certain toxins as alcohol or allergens; complication of pregnancy, systemic endocrine or autoimmune diseases, and infection as HIV [6].\n\nOne of the rarest etiologies regarding toxin and metabolic-related cause of DCM is catecholamines, and its various derivates, which has been reported mainly in case reports or short series review [7–13].\n\nPheochromocytoma, as a rare neuroendocrine catecholamine-producing tumor, has also been described as an etiology of reversible DCM and was found in ~ 39% of pheochromocytoma-related cardiomyopathies [14]. Paul et al. proposed that catecholamine-induced vasoconstriction, a direct toxic effect of the by-products of catecholamine degradation and direct receptor-mediated mechanisms, contribute to cardiomyopathy in subjects with pheochromocytoma [15].\n\nCase description\nA 24-year old male with chronic rhinosinusitis was admitted for an elective Functional endoscopic sinus surgery (FESS) procedure under general anesthesia. During the operation, the surgeon applied several tampons soaked in 1:1000 dilution epinephrine to the nasal mucosa. Ninety minutes into the surgery, unexpectedly, blood pressure rose to 210/130 mmHg followed by pulseless electrical activity. CPR was initiated, with the administration of 2 mg of IV epinephrine in consecutive doses, leading to the return of spontaneous circulation. ECG showed sinus tachycardia and a prolonged QTc interval of 486 ms, Inverted T waves in leads I and aVL, and no signs of acute ischemic changes (Fig. 1). A chest x-ray demonstrated pulmonary edema and a borderline enlarged cardiac silhouette (Fig. 2).\nFig. 1 ECG at admission indicate sinus tachycardia, prolonged QTc (QTc = 486 ms), Inverted T waves in leads I and aVL, and no signs of acute Ischemic changes\n\nFig. 2 Chest X-ray at admission indicate bilateral pulmonary edema and normal heart silhouette\n\n\n\nThe patient was placed on mechanical ventilation. Transthoracic echocardiogram showed a dilated left ventricle with an increased end-diastolic dimension (124% of normal value) with a mild reduction in LV mass, a severe reduction in systolic function, apical akinesis, and hyperdynamic base. The estimated systolic left ventricular ejection fraction was 30% (Fig. 3). Cardiac troponin and CPK were elevated. NT or NT pro-BNP were not taken. A head CT was performed and demonstrated mild global cerebral edema, with multiple maxillary sinus fractures (Fig. 4).\nFig. 3 Transthoracic Echocardiography at admission demonstrates a dilated left ventricle dimension. Apical 4 Chambers view at the end of the diastole\n\nFig. 4 Head CT at admission shown Global Edema (Left-sided) and multiple Maxillary Sinuses fractures (Right-sided red arrow)\n\n\n\nMedical information gathered from family members indicated no family history of heart diseases. The patient did not smoke, use illegal drugs nor consumed alcohol on daily basis. The patient was diagnosed with dilated cardiomyopathy and admitted to the intensive cardiac care unit. Upon arrival, upload titration of ACE inhibitors, β-blockers, and diuretics initiated. The following ECG strips indicate normal sinus rhythm, QTc interval of 420 ms, and normal T wave in lateral leads. We decided not to perform a diagnostic coronary catheterization since the patient's risk profile for ischemic cardiomyopathy was low. Objectively, there were no ischemic changes on ECGs strips and no regional wall motional abnormalities were seen on TTE upon arrival.\n\nThree days later, a second echocardiogram was performed which showed a normal-sized left ventricle, with preserved systolic function (Fig. 5).\nFig. 5 Transthoracic Echocardiography at discharge demonstrates a normal-sized left ventricle dimension with normal LV mass. Apical 4 Chambers view at the end of the diastole\n\n\n\nThe patient was discharged in full functional capacity. An ambulatory cardiac MRI performed two weeks after discharge revealed mildly dilated LV cavity, good global systolic function, and no signs of late gadolinium enhancement or edema.\n\nDiscussion\nThe relationship between exogenous catecholamines and dilated cardiomyopathy is not fully understood. Some propose that elevated catecholamine levels decrease myocardial viability via cyclic -AMP mediated Ca + overload [16, 17].\n\nWhile reductions in ejection fraction and left ventricular dysfunction was found to be reversible, mild histologic changes were found in dog studies indicate chronic perivascular fibrosis which seems to be irreversible [18].\n\nSince activation of alpha or adrenergic receptors has been shown to induce stress-induced cardiomyopathy, it has been shown in studies that these cardiac effects can be attenuated by pretreatment with the use of alpha and beta blockers [19–23]. In addition, increasing levels of estrogen have shown partial attenuation of these cardiac changes [24, 25].\n\nDilated cardiomyopathy is usually characterized by long-standing processes or conditions, its appearance in the acute setting is not common and a detailed evaluation of acute onset dilated cardiomyopathy (ADCM) typically does not elucidate a specific etiology in most cases [26].\n\nConclusion\nWe report a rare case of a transient acute non-ischemic transient dilated cardiomyopathy following exposure to sstandard diluted dose epinephrine soaked-tampons during ENT procedure. Prompt heart failure treatment resulted in complete resolution. Our report provides supporting evidence of the cardiotoxic devastating potential effect of epinephrine and its role in acute dilated cardiomyopathy. We hope that this paper will raise awareness among physicians and surgeons to the relevance of cardiotoxic effect of epinephrine, especially in the form of soaked tampons.\n\nAbbreviations\nFESSFunctional endoscopic sinus surgery\n\nENTEar, nose and throat\n\nDCMDilated cardiomyopathy\n\nECGElectrocardiography\n\nTTETransthoracic echocardiography\n\nCTComputerized tomography\n\nMRIMagnetic resonance imaging\n\nPEAPulseless electrical activity\n\nCPRCardiopulmonary resuscitation\n\nACEIAngiotensin-converting enzyme inhibitor\n\nBBBeta-blocker\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nn/a\n\nAuthors’ contributions\nSN, SE, RH, MM, and OK contributed to the writing, editing, formatting of the main manuscript, and production of the Figs. MM, OK and YT provided care to the patient and revised the manuscript. All authors have read and approved the manuscript.\n\nFunding\nThe authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nInformed consent was waived due to the use of anonymous patient’s data as well as due to the retrospective nature of the case study.\n\nConsent for publication\nWritten consent to publish the information presented in the clinical case was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Dec GW Fuster V Idiopathic dilated cardiomyopathy N Engl J Med 1994 331 23 1564 1575 10.1056/NEJM199412083312307 7969328 \n2. Elliott P Diagnosis and management of dilated cardiomyopathy Heart 2000 84 1 106 112 10.1136/heart.84.1.106 10862601 \n3. Towbin JA Bowles NE Dilated cardiomyopathy: a tale of cytoskeletal proteins and beyond J Cardiovasc Electrophysiol 2006 17 8 919 926 10.1111/j.1540-8167.2006.00530.x 16764708 \n4. Lakdawala NK Winterfield JR Funke BH Dilated cardiomyopathy Circulation 2013 6 228 237 23022708 \n5. Oakley CM Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies Br Heart J 1980 44 6 672 673 10.1136/hrt.44.6.672 7459150 \n6. Schultheiss H Fairweather D Caforio ALP Dilated cardiomyopathy Nat Rev Dis Primers 2019 5 32 10.1038/s41572-019-0084-1 31073128 \n7. Paur H Wright PT Sikkel MB High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy Circulation. 2012 126 6 697 706 10.1161/CIRCULATIONAHA.112.111591 22732314 \n8. Rona G Catecholamine cardiotoxicity J Mol Cell Cardiol 1985 17 4 291 306 10.1016/S0022-2828(85)80130-9 3894676 \n9. Litvinov IV Kotowycz MA Wassmann S Iatrogenic epinephrine-induced reverse Takotsubo cardiomyopathy: direct evidence supporting the role of catecholamines in the pathophysiology of the “broken heart syndrome” Clin Res Cardiol 2009 98 457 462 10.1007/s00392-009-0028-y 19513776 \n10. Lyon AR Rees PS Prasad S Poole-Wilson PA Harding SE Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning Nat Clin Pract Cardiovasc Med 2008 5 1 22 29 10.1038/ncpcardio1066 18094670 \n11. Stewart MJ Fraser DM Boon N Dilated cardiomyopathy associated with chronic overuse of an adrenaline inhaler Heart. 1992 68 8 221 222 10.1136/hrt.68.8.221 \n12. Szakacs JE Cannon A L-norepinephrine myocarditis Am J Clin Pathol 1958 30 5 425 434 10.1093/ajcp/30.5.425 13594914 \n13. Zhang R Gupta D Albert SG Pheochromocytoma as a reversible cause of cardiomyopathy: analysis and review of the literature Int J Cardiol 2017 249 319 323 10.1016/j.ijcard.2017.07.014 29121733 \n14. Paul T Varghese R John A Catecholamine induced cardiomyopathy in pheochromocytoma Indian J Endocrinol Metab 2013 17 4 733 10.4103/2230-8210.113771 23961496 \n15. Wittstein IS Thiemann DR Lima JA Neurohumoral features of myocardial stunning due to sudden emotional stress N Engl J Med 2005 352 6 539 548 10.1056/NEJMoa043046 15703419 \n16. Spina R Song N Kathir K Muller DWM Baron D Takotsubo cardiomyopathy following unintentionally large subcutaneous adrenaline injection: a case report Eur Heart J Case Rep 2018 2 2 yty043 10.1093/ehjcr/yty043 31020123 \n17. Hens L Dambrink JH Alcohol and drugs: twins or evil in a young heart Acta Cardiol 2012 67 469 471 10.1080/AC.67.4.2170691 22998004 \n18. Movahed A Reeves WC Mehta PM Gilliland MGF Mozingo SL Jolly SR Norepinephrine-induced left ventricular dysfunction in anesthetized and conscious, sedated dogs Int J Cardiol 1994 45 1 23 33 10.1016/0167-5273(94)90051-5 7995660 \n19. Mizia-Stec K Gasior Z Wojnicz R Severe dilated cardiomyopathy as a consequence of ecstasy intake Cardiovasc Pathol 2008 17 4 250 253 10.1016/j.carpath.2007.07.006 18402796 \n20. Dorn GW II Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodeling Cardiovasc Res 2009 81 3 465 473 10.1093/cvr/cvn243 18779231 \n21. Barison A Masci PG Emdin M Fibrosis and mortality in patients with dilated cardiomyopathy J Am Med Assoc 2013 309 24 2547 2549 10.1001/jama.2013.6453 \n22. Zhong L Ghista DN Tan RS Left ventricular wall stress compendium Comput Methods Biomechanics Biomed Eng 2012 15 10 1015 1041 10.1080/10255842.2011.569885 \n23. Goldstein S Ali AS Sabbah H Ventricular remodeling: mechanisms and prevention Cardiol Clin 1998 16 4 623 632 10.1016/S0733-8651(05)70039-4 9891592 \n24. Pahl E Sleeper LA Canter CE Incidence of and risk factors for sudden cardiac death in children with dilated cardiomyopathy: a report from the pediatric cardiomyopathy registry J Am Coll Cardiol 2012 59 6 607 615 10.1016/j.jacc.2011.10.878 22300696 \n25. Okutucu S Oto A Risk stratification in nonischemic dilated cardiomyopathy: current perspectives Cardiol J 2010 17 3 219 229 20535711 \n26. Felker M Thompson RE Hare JM Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy N Engl J Med 2000 342 1077 1084 10.1056/NEJM200004133421502 10760308\n\n",
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"mesh_terms": "D000208:Acute Disease; D000322:Adrenergic Agonists; D002311:Cardiomyopathy, Dilated; D066126:Cardiotoxicity; D004724:Endoscopy; D004837:Epinephrine; D006801:Humans; D008297:Male; D059747:Nasal Surgical Procedures; D010256:Paranasal Sinuses; D013630:Tampons, Surgical; D016896:Treatment Outcome; D055815:Young Adult",
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"abstract": "BACKGROUND\nSerotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far.\n\n\nMETHODS\nA 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful.\n\n\nCONCLUSIONS\nDiscontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.",
"affiliations": "Tertiary Emergency Medical Center, Tokyo Metropolitan Bokutoh Hospital.;Department of Neuropsychiatry, Keio University School of Medicine, Tokyo.;Tertiary Emergency Medical Center, Tokyo Metropolitan Bokutoh Hospital.;Tertiary Emergency Medical Center, Tokyo Metropolitan Bokutoh Hospital.;Tertiary Emergency Medical Center, Tokyo Metropolitan Bokutoh Hospital.;Department of Neuropsychiatry, Keio University School of Medicine, Tokyo.;Department of Neuropsychiatry, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.",
"authors": "Ishida|Takuto|T|;Uchida|Hiroyuki|H|;Kaneko|Satoru|S|;Sugiyama|Kazuhiro|K|;Hamabe|Yuichi|Y|;Mimura|Masaru|M|;Suzuki|Takefumi|T|",
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"title_normalized": "life threatening serotonin syndrome precipitated by discontinuation of serotonin dopamine antagonist in the presence of serotonergic agents a case report"
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},
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}
],
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},
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"literaturereference": "ISHIDA T, UCHIDA H, KANEKO S, SUGIYAMA K ET AL. LIFE-THREATENING SEROTONIN SYNDROME PRECIPITATED BY DISCONTINUATION OF SEROTONIN-DOPAMINE ANTAGONIST IN THE PRESENCE OF SEROTONERGIC AGENTS: A CASE REPORT. CLIN NEUROPHARM. 2020?00:UNK",
"literaturereference_normalized": "life threatening serotonin syndrome precipitated by discontinuation of serotonin dopamine antagonist in the presence of serotonergic agents a case report",
"qualification": "1",
"reportercountry": "JP"
},
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"receiptdate": "20200417",
"receivedate": "20200417",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17678721,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
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"transmissiondate": "20200714"
}
] |
{
"abstract": "An increasing number of drugs of abuse are sold word wide over the internet. Names like \"legal highs\", \"herbal highs\" etc. give the impression that these are safe products, although the risk of fatal reactions might be substantial. Leaves from the plant Mitragyna speciosa, contain active compounds like mitragynine and 7-hydroxymitragynine. It has been reported that the potency of 7-hydroxymitragynine at the μ-opioid receptor is 30 times higher than that of mitragynine and 17 times higher than that of morphine. Case reports regarding poisoning with Kratom are reported, but the toxic or lethal ranges for the concentrations of the active substances have not been established, and concentrations of 7-hydroxymitragynine have not been reported previously. We present a case report where a middle aged man was found dead at home. The deceased had a history of drug abuse and mental illness for several years. At autopsy, there were no significant pathological findings. Post-mortem analysis of peripheral blood revealed: zopiclone 0.043mg/L, citalopram 0.36mg/L and lamotrigine 5.4mg/L, i.e. concentrations regularly seen after therapeutic ingestion of these drugs. Additionally mitragynine 1.06mg/L and 7-hydroxymitragynine 0.15mg/L were detected in blood and both also in urine. The high concentrations of mitragynine and 7-hydroxymitragynine indicate that the cause of death is intoxication by these substances; and the circumstances point toward the manner of death being accidental. We recommend that both mitragynine and 7-hydroxymitragynine are analyzed for in cases with suspected Kratom intoxication.",
"affiliations": "Norwegian Institute of Public Health, Division of Forensic Sciences, Box 4404, Nydalen, 0403 Oslo, Norway. Electronic address: [email protected].;Norwegian Institute of Public Health, Division of Forensic Sciences, Box 4404, Nydalen, 0403 Oslo, Norway.;Norwegian Institute of Public Health, Division of Forensic Sciences, Box 4404, Nydalen, 0403 Oslo, Norway; Faculty of Medicine, University of Oslo, Norway.;Norwegian Institute of Public Health, Division of Forensic Sciences, Box 4404, Nydalen, 0403 Oslo, Norway.",
"authors": "Karinen|Ritva|R|;Fosen|Jan Toralf|JT|;Rogde|Sidsel|S|;Vindenes|Vigdis|V|",
"chemical_list": "D010936:Plant Extracts; D046948:Secologanin Tryptamine Alkaloids; C482678:7-hydroxymitragynine; C001801:mitragynine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "245()",
"journal": "Forensic science international",
"keywords": "7-Hydroxymitragynine; Blood drug concentration; Drug fatality; Forensic toxicology; Mitragynine; UPLC–MS/MS",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000059:Accidents; D062787:Drug Overdose; D006801:Humans; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts; D018515:Plant Leaves; D046948:Secologanin Tryptamine Alkaloids; D019966:Substance-Related Disorders",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e29-32",
"pmc": null,
"pmid": "25453780",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An accidental poisoning with mitragynine.",
"title_normalized": "an accidental poisoning with mitragynine"
} | [
{
"companynumb": "NO-GLAXOSMITHKLINE-NO2016100965",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
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"medicinalproduct": "LAMOTRIGINE."
},
{
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"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
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"medicinalproduct": "CITALOPRAM HYDROBROMIDE."
},
{
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"activesubstance": {
"activesubstancename": "ZOPICLONE"
},
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}
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"reaction": [
{
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"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cardiomegaly",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pulmonary oedema",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug therapy enhancement",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pulmonary congestion",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
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"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Scar",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
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},
"primarysource": {
"literaturereference": "KARINEN, R. AN ACCIDENTAL POISONING WITH MITRAGYNINE.. FORENSIC SCIENCE INTERNATIONAL. 2014;245:E29-E32",
"literaturereference_normalized": "an accidental poisoning with mitragynine",
"qualification": "3",
"reportercountry": "NO"
},
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"receiptdate": "20160719",
"receivedate": "20160719",
"receiver": {
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},
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}
] |
{
"abstract": "Zoledronic acid (zoledronate) is a bisphosphonate used predominantly as a second-line treatment for post-menopausal osteoporosis. Its administration is associated with an acute phase reaction. Here, we present two cases of anterior uveitis following initial administration of zoledronate. In the first case, an 80-year-old lady presented with right eye pain and decreased visual acuity 24-hours post-infusion. Uveitis was diagnosed and sub-conjunctival injection of corticosteroids was required. In the second case, a 78-year-old lady presented with right eye pain, vomiting and decreased acuity 24-hours after infusion. She was treated with topical steroids and required cataract surgery to normalise visual acuity. Patients prescribed zoledronate should be warned of the risk of ocular side effects and asked to report promptly for treatment if they develop a red, painful eye or blurred vision.",
"affiliations": "Newcastle University.;West Cumberland Hospital.;James Cook University Hospital.;James Cook University Hospital.",
"authors": "Kennedy|T|T|;Sellar|P W|PW|;Vaideanu-Collins|D|D|;Ng|J|J|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D050071:Bone Density Conservation Agents; D000077211:Zoledronic Acid",
"country": "England",
"delete": false,
"doi": "10.1093/ageing/afy070",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-0729",
"issue": "47(5)",
"journal": "Age and ageing",
"keywords": null,
"medline_ta": "Age Ageing",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D002386:Cataract; D002387:Cataract Extraction; D058447:Eye Pain; D005260:Female; D006801:Humans; D016896:Treatment Outcome; D014606:Uveitis, Anterior; D014792:Visual Acuity; D000077211:Zoledronic Acid",
"nlm_unique_id": "0375655",
"other_id": null,
"pages": "754-755",
"pmc": null,
"pmid": "29718071",
"pubdate": "2018-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two case reports of zoledronic acid-induced uveitis.",
"title_normalized": "two case reports of zoledronic acid induced uveitis"
} | [
{
"companynumb": "PHHY2018GB005529",
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"occurcountry": "GB",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
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"medicinalproduct": "ZOLEDRONATE"
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Ocular hyperaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vision blurred",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Iritis",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Iridocyclitis",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Vomiting",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Conjunctival haemorrhage",
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"reactionoutcome": "6"
}
],
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},
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},
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},
{
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},
{
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},
{
"reactionmeddrapt": "Iridocyclitis",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hypopyon",
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"reactionoutcome": "1"
}
],
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},
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"reportercountry": "NZ"
},
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"receivedate": "20190515",
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},
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},
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"transmissiondate": "20200122"
},
{
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},
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{
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},
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},
{
"reactionmeddrapt": "Iritis",
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},
{
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},
{
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},
{
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}
],
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},
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},
{
"reactionmeddrapt": "Cataract",
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},
{
"reactionmeddrapt": "Vomiting",
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},
{
"reactionmeddrapt": "Iridocyclitis",
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}
],
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},
"primarysource": {
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"literaturereference_normalized": "two case reports of zoledronic acid induced uveitis",
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"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "GB",
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},
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},
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},
{
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
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"drugdosageform": "INJECTION",
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"medicinalproduct": "ZOLEDRONIC ACID"
}
],
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"reaction": [
{
"reactionmeddrapt": "Uveitis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cataract",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vomiting",
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"reactionoutcome": "2"
}
],
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},
"primarysource": {
"literaturereference": "KENNEDY T, SELLAR PW, VAIDEANU-COLLINS D, NG J. TWO CASE REPORTS OF ZOLEDRONIC ACID-INDUCED UVEITIS. AGE AND AGEING. 2018?47(5):754-755",
"literaturereference_normalized": "two case reports of zoledronic acid induced uveitis",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20191116",
"receivedate": "20191116",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17039823,
"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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{
"abstract": "OBJECTIVE\nThe gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial-mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered.\n\n\nMETHODS\nHybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements.\n\n\nCONCLUSIONS\nThis is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC.",
"affiliations": "Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA.;Divsion of Hematology-Oncology, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92307, USA.;Comprehensive Cancer Centers of Nevada, Las Vegas, NV 89169, USA.;University Cancer and Blood Center, Athens, GA 30607, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA.;Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA; Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA.;Foundation Medicine Inc., Cambridge, MA 02141, USA.;Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA. Electronic address: [email protected].",
"authors": "Klempner|Samuel J|SJ|;Bazhenova|Lyudmila A|LA|;Braiteh|Fadi S|FS|;Nikolinakos|Petros G|PG|;Gowen|Kyle|K|;Cervantes|Claudia M|CM|;Chmielecki|Juliann|J|;Greenbowe|Joel R|JR|;Ross|Jeffrey S|JS|;Stephens|Philip J|PJ|;Miller|Vincent A|VA|;Ali|Siraj M|SM|;Ou|Sai-Hong Ignatius|SH|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret",
"country": "Ireland",
"delete": false,
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"issn_linking": "0169-5002",
"issue": "89(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Acquired resistance; EGFR mutations; Non-small cell lung cancer; Post-progression; RET rearrangement",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D015321:Gene Rearrangement; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "357-9",
"pmc": null,
"pmid": "26187428",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI.",
"title_normalized": "emergence of ret rearrangement co existing with activated egfr mutation in egfr mutated nsclc patients who had progressed on first or second generation egfr tki"
} | [
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-48826GD",
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"activesubstancename": "AFATINIB"
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"drugindication": "NON-SMALL CELL LUNG CANCER",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KLEMPNER S,BAZHENOVA L,BRAITEH F,NIKOLINAKOS P,GOWEN K,CERVANTS C,ET AL. EMERGENCE OF RET REARRANGEMENT CO-EXISTING WITH ACTIVATED EGFR MUTATION IN EGFR-MUTATED NSCLC PATIENTS WHO HAD PROGRESSED ON FIRST- OR SECOND-GENERATION EGFR TKI. LUNG CANCER (NETH) 2015;89:3:357-359.",
"literaturereference_normalized": "emergence of ret rearrangement co existing with activated egfr mutation in egfr mutated nsclc patients who had progressed on first or second generation egfr tki",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20150908",
"receivedate": "20150908",
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"serious": 1,
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{
"abstract": "The objective of the current study was to provide more appropriate therapeutic strategies for reducing severe hemorrhaging by assessing the recovery of abnormal coagulation indexes in patients with acute promyelocytic leukemia (APL) during induction therapy. Retrospective analyses of 112 patients newly diagnosed with APL were performed during initial treatment. In our study, the early death rate was 5.36%. Hemorrhage was the leading cause of death during the induction period (4/6). The values of white blood cell count, lactate dehydrogenase, prothrombin time (PT), fibrinogen (Fbg), hemoglobin, and bone marrow leukemic promyelocytes were significantly different in the high-risk group compared to the low/intermediate-risk groups. There were significant differences in the white blood cell count, bone marrow leukemic promyelocytes, platelet (PLT) count, and the levels of lactate dehydrogenase, d-dimer, PT, and Fbg, as well as in FLT3-ITD mutations between patients with major bleeding and those with minor bleeding. Hemostatic variables significantly improved over time during induction therapy. The recovery times of the PLT, PT, and Fbg values were significantly slower in patients with major bleeding than in those with minor bleeding. Specifically, the PLT level in patients with major bleeding was not similar to that in the minor bleeding group until after 4 weeks of treatment. Hemorrhages were the most common cause of induction death in this study. High-risk patients were more prone to serious clinical bleeding symptoms. Patients with major bleeding had more rapid proliferation characteristics and an increased incidence of FLT3-ITD mutations compared to patients with minor bleeding. Hemostatic variables recovered significantly more slowly in patients with major bleeding than in those with minor bleeding. Active induction therapy and blood product infusion are effective in preventing severe bleeding. Our results suggested that low PLT count might be the leading cause of fatal bleeding in patients newly diagnosed with APL.",
"affiliations": "Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital.;Department of Oncology, The Second Hospital of Nanjing, Nanjing, People's Republic of China.;Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital.;Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital.;Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital.;Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital.",
"authors": "Song|Yu-Hua|YH|;Peng|Peng|P|;Qiao|Chun|C|;Zhang|Run|R|;Li|Jian-Yong|JY|;Lu|Hua|H|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S144438",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S144438ott-10-4917Original ResearchLow platelet count is potentially the most important contributor to severe bleeding in patients newly diagnosed with acute promyelocytic leukemia Song Yu-hua 12Peng Peng 3Qiao Chun 1Zhang Run 1Li Jian-yong 1Lu Hua 1\n1 Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital\n2 Department of Hematology, The Second Hospital of Nanjing, Nanjing, People’s Republic of China\n3 Department of Oncology, The Second Hospital of Nanjing, Nanjing, People’s Republic of ChinaCorrespondence: Hua Lu, Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, No 300 Guangzhou Road, Gulou District, Nanjing 210029, Jiangsu Province, People’s Republic of China, Email [email protected] 09 10 2017 10 4917 4924 © 2017 Song et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.The objective of the current study was to provide more appropriate therapeutic strategies for reducing severe hemorrhaging by assessing the recovery of abnormal coagulation indexes in patients with acute promyelocytic leukemia (APL) during induction therapy. Retrospective analyses of 112 patients newly diagnosed with APL were performed during initial treatment. In our study, the early death rate was 5.36%. Hemorrhage was the leading cause of death during the induction period (4/6). The values of white blood cell count, lactate dehydrogenase, prothrombin time (PT), fibrinogen (Fbg), hemoglobin, and bone marrow leukemic promyelocytes were significantly different in the high-risk group compared to the low/intermediate-risk groups. There were significant differences in the white blood cell count, bone marrow leukemic promyelocytes, platelet (PLT) count, and the levels of lactate dehydrogenase, d-dimer, PT, and Fbg, as well as in FLT3-ITD mutations between patients with major bleeding and those with minor bleeding. Hemostatic variables significantly improved over time during induction therapy. The recovery times of the PLT, PT, and Fbg values were significantly slower in patients with major bleeding than in those with minor bleeding. Specifically, the PLT level in patients with major bleeding was not similar to that in the minor bleeding group until after 4 weeks of treatment. Hemorrhages were the most common cause of induction death in this study. High-risk patients were more prone to serious clinical bleeding symptoms. Patients with major bleeding had more rapid proliferation characteristics and an increased incidence of FLT3-ITD mutations compared to patients with minor bleeding. Hemostatic variables recovered significantly more slowly in patients with major bleeding than in those with minor bleeding. Active induction therapy and blood product infusion are effective in preventing severe bleeding. Our results suggested that low PLT count might be the leading cause of fatal bleeding in patients newly diagnosed with APL.\n\nKeywords\nacute promyelocytic leukemiaall-trans retinoic acidarsenic trioxidecoagulationhemorrhage\n==== Body\nIntroduction\nAcute promyelocytic leukemia (APL) is identified by the predominance of abnormal promyelocytes in the bone marrow (BM) and a specific chromosomal translocation – t(15;17) – resulting in a fusion transcript between the promyelocytic (PML) gene on chromosome 15 and the retinoic acid receptor alpha (RARα) gene on chromosome 17; this transcript is known as PML–RARα.1 The t(15;17) chromosomal translocation can induce hyperexpression of tissue factor (TF) in cells of patients with APL and render the patient hypercoagulable.2 All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are the current cornerstones of APL therapy, and these treatments have dramatically improved patient outcomes. ATRA improves the terminal differentiation of leukemic promyelocytes in patients with APL, and ATRA-induced remission is associated with an improvement in the coagulopathy of these patients.3 ATO also promotes the molecular remission of APL and addresses the associated coagulopathy by reducing membrane procoagulant activity (PCA) and TF expression.4,5 Despite this tremendous progress, APL still remains associated with a high incidence of premature death due to the frequent occurrence of abrupt bleeding diathesis. The presence of coagulopathy is an important risk factor for early hemorrhagic death in APL patients.6 Changes in clinical and laboratory parameters before and during induction therapy were examined in this study to identify more appropriate therapeutic strategies in order to reduce hemorrhage-mediated mortality.\n\nPatients and ethics statement\nA total of 112 patients newly diagnosed with APL were treated at Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University (Nanjing, People’s Republic of China), between May 2009 and April 2016. This cohort included 66 males and 46 females with a median age of 41 years (range: 12–75). The APL diagnostic criteria were based on the World Health Organization Classification of Tumors–Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues (2008) and French–American–British classification systems (1976) criteria.7 A molecular diagnosis was confirmed by identification of t(15;17) in a cytogenetic analysis and/or positive detection of PML–RARα using either fluorescence in situ hybridization or reverse transcription-polymerase chain reaction. The immune phenotype diagnosis of APL was established by positivity for CD33, CD9, CD13, and CD117, and low expression of HLA-DR and CD34. Early death (ED) was defined as death due to any cause within 30 days of diagnosis. Other inclusion criteria were as follows: no severe liver disease (abnormal liver function, alanine aminotransferase/aspartate aminotransferase greater than 2.5 times the normal value, or total bilirubin greater than 1.5 times the normal value), no cardiovascular disorders or other hemorrhagic diseases, and no usage of anticoagulants during induction therapy. We collected data from May 2009 to April 2016 and identified the diagnostic information during and after data collection. The study was approved by the ethics committee at Jiangsu Province Hospital, affiliated with Nanjing Medical University. Written informed consent was obtained from all the enrolled subjects, including legal guardians on behalf of the minors recruited in our study.\n\nTreatment strategies\nThe treatment followed the Shanghai APL protocol with some minor adjustments during the introduction period.8 Daily administration of intravenous ATO (10 mg/day) was started immediately when APL was suspected, and oral ATRA (25 mg/m2/d) was then prescribed upon genetic confirmation until the patient achieved complete remission (CR) after induction therapy. Additional chemotherapy (idarubicin 8 mg/m2/d for 3–4 days or daunorubicin 45 mg/m2/d for 3–4 days) was administered to control hyperleukocytosis if the peripheral white blood cell (WBC) count was greater than 10×109/L or on the second day in high-risk patients (pretreatment WBC count >10×109/L).\n\nIn addition to systemic treatment, patients were given central nervous system prophylaxis via six intrathecal injections of 10 mg of methotrexate, 50 mg of cytosine arabinoside, and 5 mg of dexamethasone. Therapeutic platelets (PLTs), fresh frozen plasma (FFP), or cryoprecipitate was transfused when clinically relevant bleeding occurred. A prophylactic PLT transfusion strategy (when available) was administered when the PLT count was lower than 50×109/L. Patients received only random ABO identical (non-HLA-typed) apheresis PLTs for PLT transfusions. In China, one apheresis unit is standardized to contain at least 2.5×1011 PLTs with less than 5×108 leukocytes. Prophylactic transfusion of either FFP or cryoprecipitate was mainly based on fibrinogen (Fbg) levels lower than 1.5 g/L. One unit of cryoprecipitate was converted into 200 mL of plasma for the subsequent statistical analysis.\n\nLaboratory studies and clinical outcomes\nThe obtained information included demographic (age, gender), clinical (initial bleeding events and early hemorrhagic death events), and laboratory variables (WBC count, hemoglobin [HB] levels, PLT count, prothrombin time [PT], activated partial thromboplastin time [APTT], Fbg, d-dimer, lactate dehydrogenase [LDH], FLT3-ITD transcript type, and bone marrow leukemic promyelocyte [BMP] percentage). Routine blood tests were performed using a Sysmex XT-4000i Hematology Analyzer (Sysmex, Kobe, Japan) on EDTA-anticoagulated blood samples. The Sysmex CS-2000i Automated Hemostasis Analyzer (Sysmex) was used to detect coagulation and fibrinolysis parameters such as the PT, APTT, and Fbg levels (Clauss method) and d-dimer (immuno-turbidimetric method). Biochemical blood tests were done on a Beckman Coulter AU5800 Biochemical Analyzer (Beckman Coulter, Brea, CA, USA) using heparin-anticoagulated blood samples. Blast counts and promyelocyte percentages were determined by microscopic examination of the BM by two experienced physicians separately. Fusion gene transcripts from chromosomal aberrations were analyzed by reverse transcription-polymerase chain reaction. FLT3-ITD mutations and the PML–RARα gene fusion were detected in BM samples collected at the time of APL diagnosis.\n\nStatistical analysis\nThe prognostic risk stratification of APL is based on a widely recognized risk evaluation standard that originated from the Italian GIMEMA and the Spanish PETHEMA trials:26 low risk, WBC ≤10×109/L and PLT >40×109/L; intermediate risk, WBC ≤10×109/L and PLT ≤40×109/L; and high risk, WBC >10×109/L.1 The outline of bleeding scores in idiopathic immune thrombocytopenia in China is based on the immune thrombocytopenia-specific bleeding assessment tool.9 Bleeding manifestations were classified (with gradations of severity) based on age and three major domains: skin, visible mucosae, and deep organs. Severity was scored from 1 to either 3 or 5, with a score of 8 assigned for any fatal bleeding (Table 1). We classified ≥6 as major bleeding and <6 as minor bleeding. Statistical analysis was conducted using SPSS software 16.0 (SPSS Inc., Chicago, IL, USA). The results are presented as the mean ± standard deviation for normally distributed data and as the median for nonnormally distributed data. Comparisons were made using Student’s t-test, Fisher’s exact test, and analysis of variance. P-values less than 0.05 indicated statistical significance.\n\nResults\nIn our study, 112 patients were newly diagnosed with APL based on morphology and detection of the PML–RARα mutation and/or t(15;17)(q22;q21). Sixty-six of the 112 evaluated patients (58.93%) were male and 46 (41.07%) were female (ratio: 1.43:1). The median age at diagnosis was 41 years (range: 12–75 years). Among the entire cohort, 22 patients (19.64%) were classified as low risk, 63 (56.25%) were intermediate risk, and 27 (24.11%) were high risk. The patient characteristics are summarized in Table 2. The ED rate in our study was 5.36% (6/112). Among these six deaths, five were extremely early (<7 days of induction). The causes of ED in these 5 cases were intracranial hemorrhage (3), pulmonary hemorrhage (1), and acute renal failure (1). One of the patients with intracranial bleeding also had concomitant pulmonary hemorrhage. The sixth patient died of severe infection, and he also suffered from type 2 diabetes with poor glycemic control. All the patients who survived past 1 week achieved remission. Thus, the CR rate was 95.53% (107/112). Hemorrhagic events account for the majority (66.67%) of the EDs.\n\nWe analyzed the clinical characteristics of all 112 patients. The median age of the cohort was 43 years (range: 12–75 years). Stratification of APL risk according to the Sanz stratification, which is based on WBC and PLT counts, remains the most reliable and valid method for rapidly identifying high-risk APL patients. We divided the patients into two groups: 85 (75.89%) were low/intermediate risk, and 27 (24.11%) were high risk. Among the 27 high-risk patients, 18 were male, and 9 were female; there was no statistically significant difference in the gender distribution of the two risk groups (low/intermediate group: 48 males and 37 females, P=0.455). The median age of the high-risk patients was 43.19 years versus 40.32 years for the low/intermediate-risk patients (P=0.383). The WBC count at presentation was higher in the high-risk group (median: 38.30×109/L) than in the low/intermediate-risk group (median: 2.62×109/L, P=0.000). The average Fbg concentration was lower in high-risk patients than in low/intermediate-risk patients (0.90±0.51 vs 1.48±0.85; P=0.000). The levels of HB, LDH, and BMP at presentation were higher in high-risk patients (median: 94.44 g/L, 847.26 U/L, and 85.81%, respectively) than in low/intermediate-risk patients (median: 81.61 g/L, 287.45 U/L, and 81.61%, respectively; P=0.044, P=0.000, and P=0.038, respectively). The PT value at presentation was higher in high-risk patients (median: 17.33 s) than in low/intermediate-risk patients (median: 13.77 s, P=0.003). However, the PLT, APTT, and d-dimer levels at presentation were not significantly different in high-risk patients compared to low/intermediate-risk patients (Table 3). The bleeding scores of high-risk patients were all ≥10, and the percentage of low/intermediate-risk patients with severe bleeding (≥6) was 48.24% (41/85).\n\nThen 6 cases of ED were excluded, and the remaining 106 cases (61 males and 45 females) were analyzed in the subsequent studies. We divided the 106 patients into the major bleeding and minor bleeding groups based on the bleeding rating scale. Among the 60 patients with major bleeding, 35 were male and 25 were female; there was no statistically significant difference in the gender distribution of the two bleeding groups (minor bleeding: total 46, 26 males and 20 females, P=0.852). The median age of the patients who suffered from major bleeding was 40.77 years versus 41.15 years for those with minor bleeding (P=0.893). There was a significant difference in the number of WBCs (17.90×109/L vs 1.16×109/L, P=0.000) and PLTs (25.72×109/L vs 43.65×109/L, P=0.011) between the major bleeding group and the minor bleeding group. However, there was no significant difference in the mean HB level (86.62 g/L vs 85.54 g/L, P=0.828) or the APTT (26.36 s vs 26.79 s, P=0.544). There were significant differences in LDH (519.39 U/L vs 249.35 U/L, P=0.002), d-dimer (7.09 µg/mL vs 13.23 µg/mL, P=0.026), PT (15.39 s vs 13.60 s, P=0.004), Fbg (1.09 g/L vs 1.66 g/L, P=0.001), and BMP (84.04% vs 80.18%, P=0.033) (Table 4).\n\nWe also analyzed the changes in the hemostatic variables in 106 patients during induction therapy. The recorded time points were the time of diagnosis, before initial treatment, and at 0.5, 1, 1.5, 2, and 4 weeks after initiating treatment with ATO + ATRA and/or chemotherapy. All the observed variables showed statistically significant differences that quickly changed over time. The PLT, PT, APTT, and Fbg values appeared to significantly improve at 0.5 weeks after initiating induction therapy, and the d-dimers began to decrease after 1 week of therapy. There were significant differences in the changes in PLT, PT, and Fbg (P=0.005, P=0.018, and P=0.022) between the major and minor bleeding groups after 4 weeks of introduction therapy, but there were no significant differences in the changes in APTT and d-dimer (P=0.746, P=0.333). Further comparisons showed that differences in the Fbg levels were present only at diagnosis (P<0.001), with no significant difference between the two groups after initiating therapy (P0.5W =0.053, P1W =0.246, P1.5W =0.160, P2W =0.506, P4W =0.510). The PT differed between groups at 0 weeks (P0W =0.008) and 0.5 weeks (P0.5W =0.019), but there was no significant difference starting 1 week after initiating introduction therapy (P1W =0.563, P1.5W =0.615, P2W =0.857, P4W =0.070). However, differences in the PLT levels were present during the first 2 weeks (P0W =0.005, P0.5W =0.009, P1W =0.000, P1.5W =0.047, P2W =0.007) but disappeared by the end of the fourth week of therapy (P4W =0.740) (Figures 1–5).\n\nDiscussion\nAPL is a clinical and biological variant of acute myeloid leukemia that is characterized by a cytogenetic abnormality, t(15;17)(q22;q12); PML–RARα.1 APL has a good prognosis based on the high rates of CR and survival achieved with therapies containing ATRA and/or ATO. Unlike other subtypes of acute myeloid leukemia, the primary cause of treatment failure in patients with APL is ED, which is defined as death within the first 30 days of diagnosis. There are multiple causes of ED in patients with APL, although death during induction therapy is most frequently related to hemorrhagic diathesis due to hyperfibrinolysis, proteolysis, and disseminated intravascular coagulation, which is further complicated by thrombocytopenia.10 In this study, the overall ED rate was 5.36% (6/112). In comparison with developed countries, the mortality in the current study was within previously described ranges of 5%–10%.6,11–13 All the patients who succumbed to ED had a low PLT count, with a mean PLT count of 24.33×109/L at presentation. Hemorrhages have been reported to occur in 90% of APL patients.14 ED due to hemorrhage before and during induction therapy currently remains the main cause of treatment failure in APL.6,15 Hemorrhage is responsible for most cases of death during the induction period, and it accounted for 66.67% (4/6) of the EDs in this study. Furthermore, most hemorrhagic mortalities in this study were attributed to intracranial and pulmonary hemorrhages. All these fatal events occurred within the first week of hospitalization.\n\nED is particularly frequent among high-risk patients, and a high WBC count (>10×109/L) was suggested as an adverse prognostic factor for bleeding complications in APL.16,17 Almost all patients had laboratory findings of intravascular coagulation, increased fibrinolysis, and decreased PLT production due to marrow invasion upon initial presentation. It is common for patients newly diagnosed with APL to present elevated d-dimer levels, fibrin split products, prolonged PT, and partial thromboplastin time and hypofibrinogenemia.14 These unusual indicators are related to the clinical manifestations of a high risk of bleeding and thrombosis. In addition to an elevated WBC count at presentation, high-risk patients with APL in our study also had high LDH, HB, and PT levels; increased BMP percentage; and low Fbg levels. Despite the rapid proliferation characteristics, high-risk patients had more abnormal coagulation variables. Based on bleeding score, all patients in the high-risk group had severe bleeding (score ≥10). There was no doubt that high-risk patients were more prone to severe bleeding.\n\nReported risk factors for severe hemorrhage include low initial Fbg levels, poor performance status, and high WBC count.18 We identified patients with major bleeding based on decreased values of Fbg, d-dimer, and PLT; high values of WBC, LDH, PT, and BMP; and positivity for FLT3-ITD. The repeated finding that total WBC count is an independent predictor of major bleeding complications is not surprising. Elevated BMP and LDH levels were also a reflection of excessive proliferation. The presence of coagulopathy and low PLT levels were associated with the development of hemorrhages. Low PLT counts are usually due to impaired PLT production and consumption. Increases in d-dimer and decreases in Fbg levels are evidence of hyperfibrinolysis.19,20 Notably, patients with major bleeding had lower d-dimer levels compared to patients with minor bleeding; this finding might explain why none of the randomized data showed a benefit of the clinical application of antifibrinolytics, which could block primary hyperfibrinolysis. Some studies have suggested a possible correlation between FLT3-ITD and the occurrence of ED in APL patients.21,22 Patients with major bleeding had a significantly higher prevalence of the FLT3-ITD mutation in the current study. Our results suggested that the bleeding score, which is mainly based on the hemorrhage severity, was a good approach to distinguish APL patients with different clinical and laboratory characteristics. The establishment of a bleeding scale that is more consistent with the bleeding characteristics of APL has realistic clinical value.\n\nLeukemic cells isolated from APL patients with the typical t(15;17) chromosomal balanced translocation exhibit high levels of PCA, including TF and cancer procoagulant, which are associated with the induction of hypercoagulability. ATRA induces cell differentiation of APL in vitro, which is associated with the loss of cancer procoagulant or TF expression. ATO, another effective agent for treating APL, also decreases TF expression and PCA in malignant APL cells both in vitro and in vivo.4 Therapy with ATRA and ATO leads to an improvement in the coagulopathy and a reduced risk of severe hemorrhage.23 After implementing the aggressive induction regimen, the hemostatic variables were significantly restored within 0.5–1 week compared to the initial levels. This confirmed that rapid initiation of therapy is important for treating APL. The ATO + ATRA regimen could quickly relieve the coagulopathy burden during the induction period. Thus, if an APL diagnosis is suspected based upon cytologic criteria, the recommendation is to immediately start introduction therapy without delay – even before obtaining definitive genetic confirmation of the diagnosis.\n\nAfter aggressive treatment, the recovery rates of PLT, PT, and Fbg levels were significantly slower in patients with major bleeding than in those with minor bleeding. In the major bleeding group, Fbg and PT levels increased to similar levels as those in the minor bleeding group after 0.5–1 week of induction therapy. Interestingly, the PLT levels in the major bleeding group were significantly lower than those in the minor bleeding group during the 2 weeks of induction therapy; this index was not similar in the two groups until after 4 weeks of treatment. Patients with major bleeding require aggressive prophylactic transfusions based on frequent complete blood count and clotting tests. Blood products consisting of PLT transfusions, FFP, and Fbg concentrate (typically cryoprecipitate) are the cornerstone of prohemostatic treatments. Our findings suggested that sustained low PLT levels were the most important factor in major bleeding. Possible causes of sustained low PLT levels include malignant clonal proliferation (which reduces PLT production), PLT infusion resistance (which causes ineffective infusion), and chemotherapy-induced BM suppression. Clinicians should aim for higher PLT counts in patients with APL during induction therapy, which may help prevent death due to hemorrhage in these patients. Therefore, in addition to aggressive induction therapy and supportive care, a reduction in the use of chemotherapy should also be considered. Lo-Coco et al have shown the efficacy and safety of ATRA in combination with ATO in patients with low/intermediate-risk APL. However, the ATRA + ATO regimen alone may be inadequate for high-risk patients.24,25 New immunotherapies such as CD33 monoclonal antibodies may be a viable method for better reducing the incidence of severe bleeding in APL.\n\nThis study had some limitations, including small sample size, short follow-up period, and single-center, retrospective design. There is an urgent need for more randomized, prospective trials of different induction regimens and new drug applications.\n\nIn conclusion, fatal hemorrhage remains the main cause of ED during the induction period in patients newly diagnosed with APL. High-risk patients had severe coagulopathy and were more prone to serious bleeding. The establishment of a bleeding scale that is more consistent with the bleeding characteristics of APL may better distinguish APL patients with different clinical and laboratory characteristics. Rapid onset of introduction therapy with the ATO + ATRA regimen could relieve the coagulopathy burden of APL patients. Aggressive prophylactic transfusion is the cornerstone of prohemostatic treatments. Finally, this study suggested that sustained low PLT levels were the most important factor in predicting severe bleeding. A higher PLT count should be the goal for patients with APL during induction therapy, as it may help prevent hemorrhagic death in these patients.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Changes in PLT level during the 4-week introduction period in different groups.\n\nNotes: The major bleeding group is represented as ●, and the minor bleeding group as ○. *The results of the major bleeding group were significantly different from the minor bleeding group at the same time. PTimes<0.001, PGroups=0.005.\n\nAbbreviation: PLT, platelet.\n\nFigure 2 Changes in PT during the 4-week introduction period in different groups.\n\nNotes: The major bleeding group is represented as ●, and the minor bleeding group as ○. *The results of the major bleeding group were significantly different from the minor bleeding group at the same time. PTimes<0.001, PGroups=0.018.\n\nAbbreviation: PT, prothrombin time.\n\nFigure 3 Changes in APTT level during the 4-week introduction period in different groups. The major bleeding group is represented as ●, and the minor bleeding group as ○. PTimes<0.001, PGroups=0.746.\n\nAbbreviation: APTT, activated partial thromboplastin time.\n\nFigure 4 Changes in d-dimer level during the 4-week introduction period in different groups.\n\nNotes: The major bleeding group is represented as ●, and the minor bleeding group as ○. PTimes<0.001, PGroups=0.333.\n\nFigure 5 Changes in Fbg level during the 4-week introduction period in different groups.\n\nNotes: The major bleeding group is represented as ●, and the minor bleeding group as ○. *The results of the major bleeding group were significantly different from the minor bleeding group at the same time. PTimes<0.001, PGroups=0.022.\n\nAbbreviation: Fbg, fibrinogen.\n\nTable 1 Outline of bleeding scores in idopathic immune thrombocytopenia\n\nScore\tAge (years)\n\tSkin bleeding\n\tMucosae bleeding\n\tVisceral bleeding\n\t\n≥65\t≥75\tPetechiae/ecchymosis/subcutaneous hematomas\n\tNose/gum/conjunctiva\n\tInternal organs (pulmonary, gastrointestinal, urinary)\n\tCentral nervous system\t\nHead and face\tOther parts\tOccasional, self-reliant\tMultiple, hard to stop\tWith anemia\tWithout anemia\tWith anemia\tLife-threatening\t\n1\t√\t\t\t√\t\t\t\t\t\t\t\t\n2\t\t√\t√\t\t√\t\t\t\t\t\t\t\n3\t\t\t\t\t\t√\t\t√\t\t\t\t\n5\t\t\t\t\t\t\t√\t\t√\t\t\t\n8\t\t\t\t\t\t\t\t\t\t√\t√\t\nTable 2 Baseline laboratory parameters in the APL cases\n\nLaboratory parameters\tValues\t\nAge (years), median (range)\t41 (12–75)\t\nGender, male/female\t66/46\t\nWBC (×109/L), median (range)\t11.22 (0.30–89.98)\t\nHB (g/L), median (range)\t86.03 (29–146)\t\nPLT (×109/L), median (range)\t33 (5–231)\t\nLDH (U/L), median (range)\t422.41 (121–3,571)\t\nBMP (%), median (range)\t82.62 (47.6–97.2)\t\nCR rate (%)\t95.53\t\nED rate (%)\t5.36\t\nAbbreviations: APL, acute promyelocytic leukemia; BMP, bone marrow leukemic promyelocytes; CR, complete remission; ED, early death; HB, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; WBC, white blood count.\n\nTable 3 Main characteristics of our series and comparison between the low/intermediate-risk group and the high-risk group\n\nCharacteristics\tLow/intermediate-risk group (n=85)\tHigh-risk group (n=27)\tP-value\t\nAge (years), median ± SD\t40.32±14.64\t43.19±15.44\t0.383\t\nGender, male/female\t48/37\t18/9\t0.379\t\nWBC (×109/L), median ± SD\t2.62±2.09\t38.30±25.48\t0.000\t\nHB (g/L), median ± SD\t83.35±24.61\t94.44±24.72\t0.044\t\nPLT (×109/L), median ± SD\t33.92±34.54\t30.15±23.79\t0.599\t\nLDH (U/L), median ± SD\t287.45±164.61\t847.26±867.12\t0.003\t\nPT (s), median ± SD\t13.77±1.67\t17.33±5.56\t0.003\t\nAPTT (s), median ± SD\t26.93±4.96\t27.76±5.29\t0.462\t\nFbg (g/L), median ± SD\t1.48±0.85\t0.90±0.51\t0.000\t\nD-D (µg/mL), median ± SD\t9.55±13.42\t10.47±13.12\t0.756\t\nBMP (%), median ± SD\t81.61±9.39\t85.81±7.82\t0.038\t\nFLT3-ITD (+)\t7/62\t3/17\t0.119\t\nAbbreviations: APTT, activated partial thromboplastin time; BMP, bone marrow leukemic promyelocytes; D-D, d-dimer; Fbg, fibrinogen; HB, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; PT, prothrombin time; SD, standard deviation; WBC, white blood count.\n\nTable 4 Main characteristics of our series and comparison between the major bleeding group and the minor bleeding group\n\nCharacteristics\tMinor bleeding group (n=46)\tMajor bleeding group (n=60)\tP-value\t\nAge, (years), median ± SD\t41.15±12.77\t40.77±15.83\t0.893\t\nGender, male/female\t26/20\t35/25\t0.852\t\nWBC (×109/L), median ± SD\t1.16±0.45\t17.90±22.33\t0.000\t\nHB (g/L), median ± SD\t85.54±25.24\t86.62±25.15\t0.828\t\nPLT (×109/L), median ± SD\t43.65±42.76\t25.72±19.74\t0.011\t\nLDH (U/L), median ± SD\t249.35±152.30\t519.39±612.15\t0.002\t\nPT (s), median ± SD\t13.60±1.68\t15.39±4.27\t0.004\t\nAPTT (s), median ± SD\t26.79±4.56\t26.36±4.89\t0.544\t\nFbg (g/L), median ± SD\t1.66±0.93\t1.09±0.66\t0.001\t\nD-D (µg/mL), median ± SD\t13.23±15.49\t7.09±11.31\t0.026\t\nBMP (%), median ± SD\t80.18±10.13\t84.04±8.23\t0.033\t\nFLT3-ITD (+)\t0/35\t10/40\t0.001\t\nAbbreviations: APTT, activated partial thromboplastin time; BMP, bone marrow leukemic promyelocytes; D-D, d-dimer; Fbg, fibrinogen; HB, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; PT, prothrombin time; SD, standard deviation; WBC, white blood count.\n==== Refs\nReferences\n1 Candoni A Damiani D Michelutti A Clinical characteristics, prognostic factors and multidrug-resistance related protein expression in 36 adult patients with acute promyelocytic leukemia Eur J Haematol 2003 71 1 8 12801292 \n2 Falanga A Barbui T Rickles FR Hypercoagulability and tissue factor gene upregulation in hematologic malignancies Semin Thromb Hemost 2008 34 2 204 210 18645927 \n3 Falanga A Rickles FR Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukemia Best Pract Res Clin Haematol 2003 16 3 463 482 12935963 \n4 Liu Y Wang Z Jiang M The expression of annexin II and its role in the fibrinolytic activity in acute promyelocytic leukemia Leuk Res 2011 35 7 879 884 21146216 \n5 Zhou J Shi J Hou J Phosphatidylserine exposure and procoagulant activity in acute promyelocytic leukemia J Thromb Haemost 2010 8 4 773 782 20102487 \n6 de la Serna J Montesinos P Vellenga E Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with alltrans retinoic acid and idarubicin Blood 2008 111 3395 3402 18195095 \n7 Vardiman JW Thiele J Arber DA The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2009 114 5 937 951 19357394 \n8 Hu J Liu YF Wu CF Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia Proc Natl Acad Sci U S A 2009 106 9 3342 3347 19225113 \n9 Wang L Hou M Outline of bleeding scores in idopathic immune thrombocytopenia Chin J Hematol 2015 36 12 1053 1055 \n10 Iland HJ Seymour JF Wei A Optimal approach for high-risk acute promyelocytic leukemia Curr Opin Hematol 2014 21 102 113 24378704 \n11 Lo-Coco F Avvisati G Vignetti M Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group Blood 2010 116 3171 3179 20644121 \n12 Avisati G Lo-Coco F Paoloni FP AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance Blood 2011 117 4716 4725 21385856 \n13 Ades L Guerci A Raffoux E Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience Blood 2010 115 1690 1696 20018913 \n14 Kwaan HC Wang J Boggio LN Abnormalities in hemostasis in acute promyelocytic leukemia Hematol Oncol 2002 20 33 41 11921015 \n15 Lehmann S Ravn A Carlsson L Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry Leukemia 2011 25 1128 1134 21502956 \n16 Dally N Hoffman R Haddad N Sarig G Rowe JM Brenner B Predictive factors of bleeding and thrombosis during induction therapy in acute promyelocytic leukemia–a single center experience in 34 patients Thromb Res 2005 116 2 109 114 15907524 \n17 Kwaan HC Cull EH The coagulopathy in acute promyelocytic leukemia – what have we learned in the past twenty years Best Pract Res Clin Haematol 2014 27 1 11 18 24907013 \n18 Yanada M Matsushita T Asou N Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome Eur J Haematol 2007 78 213 219 17241371 \n19 Stein E McMahon B Kwaan H The coagulopathy of acute promyelocytic leukemia revisited Best Pract Res Clin Haematol 2009 22 1 153 163 19285282 \n20 Kwaan HC The unique hemostatic dysfunction in acute promyelocytic leukemia Semin Thromb Hemost 2014 40 3 332 336 24590422 \n21 Gale RE Hills R Pizzey A Kottaridis PD Swirsky D Gilkes AF Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia Blood 2005 106 3768 3778 16105978 \n22 Kutny MA Moser BK Laumann K FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from Children’s Oncology Group Pediatr Blood Cancer 2012 59 662 667 22378655 \n23 Sanz MA Grimwade D Tallman MS Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood 2009 113 9 1875 1891 18812465 \n24 Estey E Garcia-Manero G Ferrajoli A Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia Blood 2006 107 3469 3473 16373661 \n25 Lo-Coco F Avvisati G Vignetti M Retinoic acid and arsenic trioxide for acute promyelocytic leukemia N Engl J Med 2013 369 2 111 121 23841729 \n26 Sanz MA Lo Coco F Martin G Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups Blood 2000 96 4 1247 1253 10942364\n\n",
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"keywords": "acute promyelocytic leukemia; all-trans retinoic acid; arsenic trioxide; coagulation; hemorrhage",
"medline_ta": "Onco Targets Ther",
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"title": "Low platelet count is potentially the most important contributor to severe bleeding in patients newly diagnosed with acute promyelocytic leukemia.",
"title_normalized": "low platelet count is potentially the most important contributor to severe bleeding in patients newly diagnosed with acute promyelocytic leukemia"
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"literaturereference": "SONG YH, PENG P, QIAO C, ZHANG R, LI JY, LU H. LOW PLATELET COUNT IS POTENTIALLY THE MOST IMPORTANT CONTRIBUTOR TO SEVERE BLEEDING IN PATIENTS NEWLY DIAGNOSED WITH ACUTE PROMYELOCYTIC LEUKEMIA. ONCO TARGETS THER. 2017 OCT 9?10:4917-4924.? SONG YH, QIAO C, XIAO LC, ZHANG R, LU H. HYPERFIBRINOLYSIS IS AN IMPORTANT CAUSE OF EARLY HEMORRHAGE IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA. MED SCI MONIT. 2018 MAY 17?24:3249-3255.",
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"abstract": "Raoultella planticola (R. planticola), considered an environmental organism, is a gram negative, motile, bacillus with phenotypic similarities to the genus Klebsiella. The organism remains a rare cause of human infection with a few cases reported in the literature. However, since its description in 1981 there have been increasing rates of infections caused by R. planticola with reports of conjunctivitis, liver abscess, cholangitis, pancreatitis, and necrotizing fasciitis. More concerning are reports of carbapenemase-producing isolates which have led to the only 2 mortalities associated with R. planticola infections. To our knowledge, we report the third case of R. planticola pneumonia in an immunocompromised patient with no known direct exposure to the reported risk factors.",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30208-810.1016/j.rmcr.2017.03.018Case ReportA Rare Case of Raoultella planticola Pneumonia: An Emerging Pathogen Westerveld Donevan MDaHussain Jonathan DOaAljaafareh Almotasembellah MDbAtaya Ali [email protected]∗a University of Florida College of Medicine, Department of Internal Medicine, USAb University of Florida College of Medicine, Division of Pulmonology, Critical Care and Sleep Medicine, USA∗ Corresponding author. University of Florida, Division of Pulmonology, Critical Care and Sleep Medicine, 1600 SW Archer Rd, M452, PO Box 100225, Gainesville, FL, 32610, USA.University of FloridaDivision of Pulmonology, Critical Care and Sleep Medicine1600 SW Archer RdM452PO Box 100225GainesvilleFL32610USA [email protected] 3 2017 2017 28 3 2017 21 69 70 12 12 2016 25 3 2017 27 3 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Raoultella planticola (R. planticola), considered an environmental organism, is a gram negative, motile, bacillus with phenotypic similarities to the genus Klebsiella. The organism remains a rare cause of human infection with a few cases reported in the literature. However, since its description in 1981 there have been increasing rates of infections caused by R. planticola with reports of conjunctivitis, liver abscess, cholangitis, pancreatitis, and necrotizing fasciitis. More concerning are reports of carbapenemase-producing isolates which have led to the only 2 mortalities associated with R. planticola infections. To our knowledge, we report the third case of R. planticola pneumonia in an immunocompromised patient with no known direct exposure to the reported risk factors.\n\nKeywords\nRaoultella planticolaBacterial pneumoniaRare lung diseaseImmunocompromised\n==== Body\n1 Introduction\nRaoultella planticola (R. planticola) is an aerobic, gram-negative, non-capsulated, motile bacillus that until recently was once a species of the genus Klebsiella, and is now distinguished into its own genera. It is a rare opportunistic pathogen primarily described in immunocompromised patients [1]. Although only a few cases of human infection have been reported, a growing body of literature demonstrates R. planticola's pathogenicity in its ability to infect various organs such as the pancreas, skin, liver, prostate, conjunctiva, and gallbladder [2], [3], [4], [5], [6]. To our knowledge we present the third reported case of R. planticola pneumonia in an immunocompromised patient with no direct history of attributable environmental exposure risks.\n\n2 Case\nA 36-year-old woman with a 20-pack year smoking history and medical history of invasive squamous cell carcinoma of the distal trachea with metastases to the lungs presented to our institution with complaints of shortness of breath, thick, purulent, and foul-smelling tracheal secretions. She had previously received palliative radiation therapy to the trachea that left her tracheostomy dependent. Her past chemotherapy consisted of 2 cycles of 5-Fluorouracil. Her most recent cycle of chemotherapy, a new regimen of cisplatin/paclitaxel, was administered 10 days prior to presentation.\n\nOn admission, her vitals were as follows: Temperature of 36.9° Celsius, blood pressure 82/54, pulse 132, and respiratory rate of 23 breaths per minute. The oxygen saturation was 96% on room air. Blood count showed a white blood cell count (WBC) of 1400/mm3, a hemoglobin of 8.5 g/dL, and a platelet count of 153 000/mm3. Auscultation of her lungs revealed rales bilaterally. A plain chest radiograph was concerning for a right sided pleural effusion and a superimposed infectious process. An axial chest computed tomography (CT) showed evidence of right lower lobe infiltrates (Fig. 1).Fig. 1 Axial CT of the chest with contrast showing confluent consolidation within the right lower lobe.\n\nFig. 1\n\nAn electrocardiogram did not reveal any changes suggestive of ischemia and her cardiac enzyme Troponin T was not elevated.\n\nGiven her immunocompromised status and recent hospitalization, our differential for her source of sepsis included bacterial, viral, or fungal pneumonia. We obtained a respiratory viral panel, blood, urine, fungal, and sputum cultures, and empirically started her on vancomycin and cefepime. A bronchoscopy revealed copious, mucopurulent, yellow, thin secretions in the right upper, middle, and lower lobe. Two days after admission her sputum culture revealed R. planticola with sensitivity to most antibiotics except for resistance to ampicillin and intermediate susceptibility to ciprofloxacin. The remainder of the cultures were negative. She was briefly transitioned to IV Ceftriaxone, but experienced clinical worsening with an increase in oxygen requirement. Repeat sputum cultures again grew R. planticola sensitive to ceftriaxone with no other isolates identified. Yet, she was transitioned back to IV piperacillin/tazobactam with clinical improvement and resolution of pneumonia after a 7-day total course. This may have been a coincidental outcome as other medical comorbidities were addressed with aggressive medical management.\n\n3 Discussion\nIdentified in 1981 by Bagley et al., R. planticola has traditionally been considered a nonclinical, aquatic, botanical and soil organism initially considered a species of the genus Klebsiella [7]. Further phylogenic analysis revealed major differential characteristics amongst the eight species of klebsiella. These differences included utilization of l-sorbose as a carbon source and the ability to grown on 10° Centigrade which became the hallmark of the new genus Raoultella. This new genus included the three species, Raoultella planticola, Raoultella ornithinolytica, and Raoultella terrigena [1]. The new genus remained relatively uncommon, although, R. planticola may be more prevalent than once thought with colonization rates ranging from 9 to 19% [8], [9].\n\nDue to the rare occurrence of human infection, risk factors associated with R. planticola infection are largely deduced from the few reported cases. These include, an immunocompromised state, invasive medical procedures, seafood consumption and exposure to aquatic or soil contaminants. Interestingly, R. planticola contamination of non-bacterial liquid hand soap in the hospital setting have been reported [10]. Our patient worked at a local call center and lived with her mother, who had a small garden. She denied tending to the plants, but noted that her mother spent time in her garden daily. Furthermore, she reported no recent seafood consumption or exposure to aquatic environments.\n\nSince its initial description in 1981, twenty-three cases of human infection with R. planticola have been reported, two of which have been fatal. The two fatalities were associated with a carbapenem resistant R. planticola with polymerase chain reaction (PCR) analysis detecting carbapenemase-encoding genes in the isolates [11]. Although there is growing concern of antibiotic resistant strains, most cases reported susceptibility to many antibiotics [12], [13].\n\n4 Conclusion\nWe report to our knowledge the third case of R. planticola pneumonia, an organism capable of infecting a wide range of hosts with multiple reported risk factors. Although our patient was not directly exposed to soil or aquatic contaminants, her mother with whom she lived, did spend time tending to her garden. Given that her sputum culture was only positive for R. planticola, it is likely that the isolate was the pathogenic cause of pneumonia rather than a colonizing organism. Though rarely a cause of infection, R. planticola has shown pathogenicity in many different organ systems. Currently, R. planticola remains widely susceptible to many antibiotics, but resistant strains causing significant mortality have been reported. Given the increasing reports concerning R. planticola, it would not be unreasonable to consider a future where this organism becomes a more prevalent pathogen in the healthcare setting. Practitioners should remain cognizant of the risk factors associated with acquiring an R. planticola infection, note the existence of carbapenemase resistant strains, and promptly diagnose and treat these potentially deadly infections.\n\nAcknowledgement\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector. The authors would like to thank Jessica M. Cope PharmD for her contribution.\n==== Refs\nReferences\n1 Drancourt M. Phylogenetic analyses of Klebsiella species delineate Klebsiella and Raoultella gen. nov., with description of Raoultella ornithinolytica comb. nov., Raoultella terrigena comb. nov. and Raoultella planticola comb. nov Int. J. Syst. Evol. Microbiol. 51 Pt 3 2001 925 932 11411716 \n2 O'Connell K. Kelly J. NiRiain U. A rare case of soft-tissue infection caused by Raoultella planticola Case Rep. Med. 2010 2010 Article ID 134086 \n3 Teo I. A rare case of cholecystitis caused by Raoultella planticola Case Rep. Med. 2012 2012 601641 22690225 \n4 Koukoulaki M. Acute prostatitis caused by Raoultella planticola in a renal transplant recipient: a novel case Transpl. Infect. Dis. 16 3 2014 461 464 24750300 \n5 Sitaula S. The first case report of Raoultella planticola liver abscess IDCases 5 2016 69 71 27516968 \n6 Vassallo J. Four cases of Raoultella planticola conjunctivitis Eye (Lond) 30 4 2016 632 634 26742869 \n7 Bagley S.T. Seidler R.J. Brenner D.J. Klebsiella planticola sp. nov.: a new species of enterobacteriaceae found primarily in nonclinical environments Curr. Microbiol. 6 2 1981 105 109 \n8 Westbrook G.L. Incidence and identification of Klebsiella planticola in clinical isolates with emphasis on newborns J. Clin. Microbiol. 38 4 2000 1495 1497 10747132 \n9 Podschun R. Isolation of Klebsiella planticola from newborns in a neonatal ward J. Clin. Microbiol. 36 8 1998 2331 2332 9666015 \n10 Garcia-San Miguel L. Contamination of liquid soap for hospital use with Raoultella planticola J. Hosp. Infect. 86 3 2014 219 220 24559578 \n11 Castanheira M. First descriptions of blaKPC in Raoultella spp. (R. planticola and R. ornithinolytica ): report from the SENTRY antimicrobial surveillance program J. Clin. Microbiol. 47 12 2009 4129 4130 19812278 \n12 Xu M. Nosocomial pneumonia caused by carbapenem-resistant Raoultella planticola : a case report and literature review Infection 43 2 2015 245 248 25595510 \n13 Gangcuangco L.M. Saul Z.K. A novel case of Raoultella planticola urinary tract infection in a female: comment on ‘Nosocomial pneumonia caused by carbapenem-resistant Raoultella planticola : a case report and literature review’ Infection 43 5 2015 621 622 25944570\n\n",
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"abstract": "BACKGROUND\nTo compare the efficacy and safety of imatinib and cytarabine (ara-c) combination versus imatinib monotherapy in newly diagnosed patients with chronic phase chronic myeloid leukemia (CML-CP).\n\n\nMETHODS\nThis prospective, randomized study included adult patients (age >18 years) with newly diagnosed CML-CP. Patients received either a single oral dose of imatinib 400 mg/day in combination with a subcutaneous injection of ara-c 20 mg/m2/day (imatinib + ara-c) or a single oral dose of imatinib 400 mg/day. Primary endpoints were hematological and molecular responses at 3 months and cytogenetic responses at 6 and 12 months. Secondary endpoints included grade 3/4 hematological and nonhematological adverse events (AEs).\n\n\nRESULTS\nOf 30 patients included, 14 were randomized to imatinib + ara-c and 16 to imatinib alone. Complete hematologic response (CHR) at 3 months was higher with imatinib + ara-c vs. imatinib alone (100% vs. 87.5%, P = 0.48). The median time to achieve CHR was significantly (P < 0.001) lower with imatinib + ara-c (32.07 vs. 23.43 days). Molecular response at 3 months was significantly higher (P = 0.04) with imatinib + ara-c vs. imatinib alone (100% vs. 68.75%). Complete cytogenetic response was also higher with imatinib + ara-c vs. imatinib alone (42.85% vs. 25% at 6 months and 71.4% vs. 62.5% at 12 months). Neutropenia followed by thrombocytopenia and anemia were the most common AEs. Grade 3/4 hematological and nausea events were significantly (P < 0.05) higher with imatinib + ara-c. Other nonhematological events were not significantly different between the treatments. The median follow-up duration was 20 months (range: 15-23 months).\n\n\nCONCLUSIONS\nImatinib with low-dose ara-c can be considered as a potential first-line treatment option for CML-CP.",
"affiliations": "Institute of Hematology and Transfusion Medicine (IHTM), Kolkata, West Bengal, India.;Institute of Hematology and Transfusion Medicine (IHTM), Kolkata, West Bengal, India.;Institute of Hematology and Transfusion Medicine (IHTM), Kolkata, West Bengal, India.",
"authors": "Samal|Priyanka|P|;Chakrabarti|Prantar|P|;Nath|Uttam K|UK|",
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"title_normalized": "a prospective randomized study to compare the combination of imatinib and cytarabine versus imatinib alone in newly diagnosed patients with chronic phase chronic myeloid leukemia"
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{
"abstract": "Primary central nervous system lymphoma (PCNSL) is more difficult to treat than other lymphomas. Recently, it has been suggested that high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is effective for treating PCNSL. In the present study, we retrospectively analyzed 12 patients with PCNSL at our hospital. Five young patients with good performance status (PS) received upfront ASCT. The conditioning regimen prior to ASCT with busulfan ＋ cyclophosphamide ＋ etoposide showed good prognosis (complete remission rate of 100%). In addition, the PS improved in patients treated with high-dose chemotherapy followed by ASCT, while it worsened in those treated without ASCT. Further investigations are needed to clarify inclusion/exclusion criteria and optimize conditioning regimens for ASCT.",
"affiliations": "Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.;Department of Hematology, Osaka Red Cross Hospital.",
"authors": "Okubo|Yukiko|Y|;Kaneko|Hitomi|H|;Shimizu|Takuya|T|;Nomura|Ryosuke|R|;Hyuga|Mizuki|M|;Mitsuyoshi|Takaya|T|;Tada|Kohei|K|;Ukyo|Naoya|N|;Mizutani|Chisato|C|;Hatanaka|Kazuo|K|;Imada|Kazunori|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.59.33",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "59(1)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Autologous stem cell transplantation; Conditioning regimen; Performance status; Primary central nervous system lymphoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "33-39",
"pmc": null,
"pmid": "29415935",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Autologous peripheral blood stem cell transplantation for treating primary central nervous system lymphoma: a single-center retrospective study.",
"title_normalized": "autologous peripheral blood stem cell transplantation for treating primary central nervous system lymphoma a single center retrospective study"
} | [
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"reactionmeddraversionpt": "21.0",
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},
{
"reactionmeddrapt": "Histiocytosis haematophagic",
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}
],
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"primarysource": {
"literaturereference": "OKUBO Y, KANEKO H, SHIMIZU T, ET AL. AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR TREATING PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A SINGLE-CENTER RETROSPECTIVE STUDY. THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY 2018?59(1):33-39.",
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},
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},
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},
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}
] |
{
"abstract": "BACKGROUND\nThe characterization of genetic abnormalities in non-small cell lung cancer (NSCLC) constitutes a theranostic revolution which is leading to rapid progress in the personalized management of this condition.\n\n\nMETHODS\nWe present the case of a patient with NSCLC harboring an activating mutation of the Epidermal Growth Factor Receptor (EGFR). After two years of treatment with a tyrosine kinase inhibitor (TKI), the development of a pleural effusion demonstrated that the NSCLC had progressed. The T790M mutation was identified in tumour cells from the pleural aspirate. This anomaly had not been observed in the initial lung biopsy sample.\n\n\nCONCLUSIONS\nThe genetic study of tumour cells contained in a biological fluid could be used to initiate molecular monitoring of the NSCLC tumour, without requiring repeated tissue biopsies and to customize the treatment in some patients with NSCLC.",
"affiliations": "LUNAM université, 49000 Angers, France; Pôle thorax-vaisseaux, université d'Angers, CHU d'Angers, 4, rue Larrey, 49933 Angers, France.",
"authors": "Rieux|C|C|;Boisdron-Celle|M|M|;Morel|A|A|;Fey|L|L|;Urban|T|T|;Hureaux|J|J|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8425",
"issue": "30(7)",
"journal": "Revue des maladies respiratoires",
"keywords": "Cancer bronchique non à petites cellules; Drug resistance neoplasm; Epidermal growth factor receptor (EGFR); Inhibiteur tyrosine kinase; Malignant pleural effusion; Non-small cell lung cancer; Pleurésie métastatique; Récepteur du facteur de croissance épidermique (EGFR); Résistance aux anticancéreux; Tyrosine kinase inhibitor",
"medline_ta": "Rev Mal Respir",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009154:Mutation; D016066:Pleural Effusion, Malignant; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D011799:Quinazolines",
"nlm_unique_id": "8408032",
"other_id": null,
"pages": "572-5",
"pmc": null,
"pmid": "24034463",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Biological diagnosis of resistance to erlotinib in a malignant pleural effusion.",
"title_normalized": "biological diagnosis of resistance to erlotinib in a malignant pleural effusion"
} | [
{
"companynumb": "FR-MYLANLABS-2015M1015423",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Dry skin",
"reactionmeddraversionpt": "18.0",
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},
{
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}
],
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"literaturereference": "RIEUX C, BOISDRON-CELLE M, MOREL A, FEY L, URBAN T, HUREAUX J. BIOLOGICAL DIAGNOSIS OF RESISTANCE TO ERLOTINIB IN A MALIGNANT PLEURAL EFFUSION. REV-MAL-RESPIR 2013; 30(7):572-575.",
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"abstract": "Toxoplasmosis may be transferred by organ transplantation. The most common clinical presentation is with multisystem disease, although isolated ocular toxoplasmosis has been described. Many centers have suggested that universal use of co-trimoxazole prophylaxis obviates the need for specific Toxoplasma testing. We report a case of donor-acquired ocular toxoplasmosis after liver transplantation despite co-trimoxazole prophylaxis. The diagnosis was confirmed by Toxoplasma polymerase chain reaction assay in conjunction with seroconversion. The fact that the infection was donor acquired was confirmed by serological mismatch and the absence of sporozoite-specific antigen antibody in the recipient.",
"affiliations": "National Institute of Health Research Birmingham Liver Biomedical Research Unit, Birmingham, UK.;National Institute of Health Research Birmingham Liver Biomedical Research Unit, Birmingham, UK.;Clinical Microbiology, Queen Elizabeth Hospital, Birmingham, UK.;St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK.;St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK.;National Institute of Health Research Birmingham Liver Biomedical Research Unit, Birmingham, UK. [email protected].",
"authors": "Webb|G J|GJ|http://orcid.org/0000-0002-0710-5644;Shah|H|H|;David|M D|MD|http://orcid.org/0000-0002-6756-0550;Tiew|S|S|;Beare|N|N|;Hirschfield|G M|GM|",
"chemical_list": "D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"doi": "10.1111/tid.12589",
"fulltext": "\n==== Front\nTranspl Infect DisTranspl Infect Dis10.1111/(ISSN)1399-3062TIDTransplant Infectious Disease1398-22731399-3062John Wiley and Sons Inc. Hoboken 10.1111/tid.12589TID12589Case ReportCase ReportsPost‐prophylaxis Toxoplasma chorioretinitis following donor–recipient mismatched liver transplantation Webb et alWebb G.J. http://orcid.org/0000-0002-0710-5644\n1\nShah H. \n1\nDavid M.D. http://orcid.org/0000-0002-6756-0550\n3\nTiew S. \n2\nBeare N. \n2\nHirschfield G.M. [email protected] \n1\n1 National Institute of Health Research Birmingham Liver Biomedical Research UnitBirminghamUK2 St Paul's Eye UnitRoyal Liverpool University HospitalLiverpoolUK3 Clinical MicrobiologyQueen Elizabeth HospitalBirminghamUK* \nCorrespondence to:\n\nGideon M. Hirschfield, Liver Biomedical Research Unit, NIHR Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, UK\n\nTel: +44 (0) 121 415 8700\n\nFax: +44 (0) 121 415 8701\n\nE‐mail: [email protected]\n04 10 2016 10 2016 18 5 10.1111/tid.2016.18.issue-5805 808 04 12 2015 19 4 2016 06 6 2016 © 2016 The Authors. Transplant Infectious Disease Published by John Wiley & Sons LtdThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nToxoplasmosis may be transferred by organ transplantation. The most common clinical presentation is with multisystem disease, although isolated ocular toxoplasmosis has been described. Many centers have suggested that universal use of co‐trimoxazole prophylaxis obviates the need for specific Toxoplasma testing. We report a case of donor‐acquired ocular toxoplasmosis after liver transplantation despite co‐trimoxazole prophylaxis. The diagnosis was confirmed by Toxoplasma polymerase chain reaction assay in conjunction with seroconversion. The fact that the infection was donor acquired was confirmed by serological mismatch and the absence of sporozoite‐specific antigen antibody in the recipient.\n\nToxoplasma gondiitoxoplasmosisocularchorioretinitisliver transplantationimmunosuppressiondisease transmissioninfectiousNational Institute for Health Research source-schema-version-number2.0component-idtid12589cover-dateOctober 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:06.10.2016\n\n\nG.J. \nWebb \n, \nH. \nShah \n, \nM.D. \nDavid \n, \nS. \nTiew \n, \nN. \nBeare \n, \nG.M. \nHirschfield \n. Post‐prophylaxis Toxoplasma chorioretinitis following donor–recipient mismatched liver transplantation . Transpl Infect Dis \n2016 : 18 : 805 –808 . All rights reserved27500398\n==== Body\nOcular toxoplasmosis is a major cause of uveitis worldwide and may be particularly aggressive in the immunosuppressed 1. Transfer of the causative agent Toxoplasma gondii through transplantation has been reported for all solid organs, although infection most commonly presents with multisystem disease 2. Incidences vary between transplant programs, and it has been suggested that universal prophylaxis with co‐trimoxazole (TMP/SMX) is sufficient to obviate the need for Toxoplasma testing 3. Here, we report a case of donor‐acquired isolated ocular toxoplasmosis despite TMP/SMX prophylaxis, occurring 7 months after liver transplantation.\n\nCase report\nA previously healthy 32‐year‐old British female patient presented with fulminant liver failure due to seronegative hepatitis. She received super‐urgent orthotopic liver transplantation from a brainstem dead UK donor. The recipient was seronegative for cytomegalovirus (CMV), but the donor was positive. The post‐transplant course was complicated by 2 episodes of acute rejection requiring high‐dose corticosteroids, in addition to standard immunosuppression with tacrolimus and mycophenolate. At discharge, liver biochemistry was normal. As per unit policy, she received 3 months of TMP/SMX and valganciclovir prophylaxis to prevent Pneumocystis jirovecii pneumonia and CMV infection, respectively.\n\nSeven months after transplantation, painless blurred vision affecting the left eye developed over several days. The patient had been well in the intervening period, with no other symptoms, and she was afebrile. External ocular examination was unremarkable. Fundoscopy of the left eye revealed 2 foci of chorioretinitis: an active nasal lesion and a temporal lesion that had largely progressed to chorioretinal atrophy. An overlying vitreous hazing was consistent with mild vitritis (Fig. 1).\n\nFigure 1 Wide‐field photograph of patient's left fundus, with eyelash artifacts inferiorly. Nasal region (left of the printed image) contains an active focus of chorioretinitis; the temporal region contains a region of chorioretinitis that has progressed to atrophy. Mild hazing caused by vitritis.\n\nAs the differential diagnosis included Toxoplasma or CMV chorioretinitis, empirical therapy with ganciclovir and clindamycin was commenced initially. An aqueous humor sample revealed the presence of leukocytes, but routine microbiological cultures and polymerase chain reaction (PCR) for CMV and varicella zoster virus were negative.\n\n\nToxoplasma gondii DNA was detected by real‐time PCR amplification of a region of the RE gene (GenBank Accession no. AF146527). Serum Toxoplasma immunoglobulin (Ig)M was positive and IgG negative; IgG became weakly positive 20 days later. Retrospective testing of stored pre‐transplant recipient serum showed absence of anti‐Toxoplasma IgG and IgM, whereas donor serology was Toxoplasma IgG positive.\n\nGanciclovir was discontinued, the patient completed a course of clindamycin, and her vision normalized over several weeks. Subsequently, testing for a sporozoite‐specific antibody, according to the method described by Hill et al. 4, was negative (anti‐TgERP O.D. 0.198; positive cutoff >0.4).\n\nLong‐term TMP/SMX secondary prophylaxis was commenced to prevent future recurrences, although was subsequently withdrawn because of myelosuppression. The patient went on to have a successful pregnancy while taking only tacrolimus and prednisolone immunosuppression.\n\nOn review of possible risk factors for acquiring toxoplasmosis, it was established that the patient had been given and followed routine advice to wash vegetables and to cook meat thoroughly. She had contact with her mother's healthy adult cat, but did not provide care for it.\n\nDiscussion\nThis is the first reported case, to our knowledge, of Toxoplasma chorioretinitis occurring after liver transplantation despite TMP/SMX prophylaxis. Donor–recipient Toxoplasma serological mismatch (seropositive donor to seronegative recipients; D+R−), the onset of symptoms occurring 4 months after discontinuing prophylaxis, the absence of sporozoite‐specific antibody, and the lack of other obvious routes of acquisition suggest that our case could represent donor‐acquired infection. Of particular interest in suggesting the route of acquisition is the negative sporozoite‐specific antibody. In contrast, in a large US series of congenital toxoplasmosis, positive results of this assay suggested that the majority of such cases represent oocyst ingestion, even in the absence of risk behaviors 5.\n\n\nToxoplasma donor–recipient mismatch was a significant risk factor for post solid organ transplant toxoplasmosis across multiple solid organ types in a case–control series 6. The rate of infection appeared to be highest with heart transplantation, and this has been attributed to the Toxoplasma bradyzoite cysts' predilection for muscle tissue including myocardium 7. Furthermore, reports of separate recipients developing toxoplasmosis from kidney grafts from the same donor suggest that transferred infection can occur 6, 8.\n\nThe incidence of new Toxoplasma infection in the UK population is 0.25–0.5% per year, while toxoplasmosis of any presentation in donor–recipient mismatch has been reported at up to 40% across all solid organs 6, 9. Given that the cat in this case was adult and healthy, that living with fewer than 3 kittens is not a significant risk factor for acquisition of Toxoplasma, that other family members remained well, and that serum sporozoite‐specific antibody was negative, we believe feline contact to be an unlikely route of infection in this case 10.\n\nA November 2015 Medline/PubMed search for “toxoplasmosis” and “transplantation” returned 506 abstracts, with 3 previous cases of possible donor‐derived ocular toxoplasmosis following orthotopic liver transplantation 11, 12, 13, 14. None received prophylaxis (Table 1). Our patient presented 7 months after transplantation and 4 months after cessation of prophylaxis. This is in contrast to a median of 31 days after transplantation for a series of all presentations of toxoplasmosis in liver transplant recipients 6 and 86.5 days among all solid organ transplants 12; however, details of prophylaxis are incomplete in the former study. The reported onset of isolated Toxoplasma chorioretinitis ranges from 21 days 11 to 9 months 6, and toxoplasmosis among all solid organ transplants is reported to be delayed in its presentation by prophylaxis (476.28 ± 415.70 days with prophylaxis vs. 48.81 ± 28.93 without), with no patients presenting while on prophylaxis 15. We hypothesize that our case's presentation may have been altered by prophylaxis and/or corticosteroids given for rejection.\n\nTable 1 Reported cases of Toxoplasma chorioretinitis after liver transplantation\n\nFirst author (reference)\tRecipient age, gender; indication\tLocation\tImmunosuppression\tDiagnosis\tProphylaxis\tDelay from transplant to onset\tTherapy\tOutcome\t\nSinger 11\n\t48, female; hepatitis C\tUSA\tAza, CsA\tPathological\tNone\t8 months; 3 weeks after cataract surgery\tNone\tEye enucleated\t\nChiquet 12, 13\n\t43, female; fulminant liver failure, possibly drug‐induced\tFrance\tPred, CsA\tFundoscopic findings, serum anti‐Toxoplasma IgM\tNone\t3 weeks\tPyri, Sulfad, Fol\tNo relapse for 1 year\t\nGalván Ramírez 14\n\t7, male; glycogen storage disease type IV\tSpain\tPred, CsA\tFundoscopic findings, serum anti‐IgM and IgG\tNone\t5 months\tPyri, Sulfad, Fol\tNo relapse 1 year; subsequent CMV retinitis\t\nWebb (Present case)\t32, female; fulminant seronegative hepatitis\tUnited Kingdom\tPred, Tac, MMF\tFundoscopic findings, serum anti‐Toxoplasma IgM; PCR of aqueous humor\t3 months TMP/SMX\t7 months\tClind\tNo relapse 2 years\t\nAZA, azathioprine; CsA, cyclosporine; Pred, prednis(ol)one; IgM, immunoglobulin M; Pyri, pyrimethamine; Sulfad, sulfadiazine; Fol, folinic acid; IgG, immunoglobulin G; CMV, cytomegalovirus; Tac, tacrolimus; MMF, mycophenolate mofetil; PCR, polymerase chain reaction assay; TMP/SMX, trimethoprim/sulfamethoxazole; Clind, clindamycin.\n\nJohn Wiley & Sons, LtdIn this case, chorioretinitis was multifocal and vitritis was mild. These findings are consistent with those seen in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) ocular toxoplasmosis patients 16. This presentation is in contrast to the immunocompetent host, where chorioretinitis is usually unifocal, may be accompanied by scars from previous resolved episodes, and may have severe overlying vitritis.\n\nLaboratory diagnosis of toxoplasmosis traditionally relies on the presence of IgM antibodies or on IgG seroconversion. However, in immunocompromised patients, seroconversion may be delayed and even absent. The specificity and sensitivity of PCR is, therefore, particularly useful 3.\n\nPrimary prophylaxis for the prevention of toxoplasmosis is used by many heart transplant centers. Some advocate indefinite prophylaxis in donor–recipient mismatch. For other solid organ transplant programs, especially in the presence of a low background rate of Toxoplasma IgG seropositivity in the population, and where TMP/SMX Pneumocystis jirovecii prophylaxis is routine, donors and recipients are not routinely tested for the presence of evidence of past Toxoplasma infection 15.\n\nLittle experience has been published on the need for secondary prophylaxis after completing a treatment course for a confirmed Toxoplasma infection in the context of immunosuppression outside the HIV/AIDS population 17. Further studies are warranted given the side effect profile and costs associated with agents such as TMP/SMX; regular monitoring by blood PCR may be an alternative strategy.\n\nIn summary, we present a case of toxoplasmosis chorioretinitis in a liver transplant recipient. This is the first such case, to our knowledge, reported after prophylaxis, and we believe that it is likely to represent graft transmission. The onset months after transplantation, the relative rarity of the condition, and its atypical presentation may delay diagnosis in similar cases. We note the utility of parallel donor–recipient serology and of PCR analysis of aqueous fluid. Toxoplasma infection is still a potential risk for the liver transplant population despite widespread use of TMP/SMX prophylaxis.\n\nAcknowledgements\nThe authors thank Dr Dolores Hill of the United States Department of Agriculture's Agricultural Research Service for her assistance with the sporozoite‐specific antibody assay and Prof Edward Guy of the Toxoplasma Reference Laboratory, Swansea, for advice and for processing the Toxoplasma PCR assay.\n\n\nFunding: G.J.W. is the recipient of a UK Medical Research Council Clinical Research Training Fellowship. G.J.W. and G.M.H. are supported by the National Institute for Health Research.\n\n\nDisclaimer: This report presents independent research supported by the National Institute for Health Research (NIHR). The views expressed are those of the authors(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.\n\n\nConflicts of interest: None declared.\n==== Refs\nReferences\n1 \n\nCommodaro \nAG \n, \nBelfort \nRN \n, \nRizzo \nLV \n, et al. Ocular toxoplasmosis: an update and review of the literature . Memórias do Instituto Oswaldo Cruz \n2009 ; 104 (2 ): 345 –350 .19430662 \n2 \n\nDerouin \nF \n, \nPelloux \nH \n; ESCMID Study Group on Clinical Parasitology \n. Prevention of toxoplasmosis in transplant patients . Clin Microbiol Infect \n2008 ; 14 (12 ): 1089 –1101 .19018809 \n3 \n\nGourishankar \nS \n, \nDoucette \nK \n, \nFenton \nJ \n, \nPurych \nD \n, \nKowalewska‐Grochowska \nK \n, \nPreiksaitis \nJ \n. The use of donor and recipient screening for Toxoplasma in the era of universal trimethoprim sulfamethoxazole prophylaxis . Transplantation \n2008 ; 85 (7 ): 980 –985 .18408578 \n4 \n\nHill \nD \n, \nCoss \nC \n, \nDubey \nJP \n, et al. Identification of a sporozoite‐specific antigen from Toxoplasma gondii\n . J Parasitol \n2011 ; 97 (2 ): 328 –337 .21506817 \n5 \n\nBoyer \nK \n, \nHill \nD \n, \nMui \nE \n, et al. Unrecognized ingestion of Toxoplasma gondii oocysts leads to congenital toxoplasmosis and causes epidemics in North America . Clin Infect Dis \n2011 ; 53 (11 ): 1081 –1089 .22021924 \n6 \n\nFernandez‐Sabe \nN \n, \nCervera \nC \n, \nFarinas \nMC \n, et al. Risk factors, clinical features, and outcomes of toxoplasmosis in solid‐organ transplant recipients: a matched case‐control study . Clin Infect Dis \n2012 ; 54 (3 ): 355 –361 .22075795 \n7 \n\nRobert‐Gangneux \nF \n, \nDarde \nML \n. Epidemiology of and diagnostic strategies for toxoplasmosis . Clin Microbiol Rev \n2012 ; 25 (2 ): 264 –296 .22491772 \n8 \n\nRogers \nNM \n, \nPeh \nCA \n, \nFaull \nR \n, \nPannell \nM \n, \nCooper \nJ \n, \nRuss \nGR \n. Transmission of toxoplasmosis in two renal allograft recipients receiving an organ from the same donor . Transpl Infect Dis \n2008 ; 10 (1 ): 71 –74 .17605745 \n9 \nAd Hoc Group on Vulnerable Groups: Advisory Committee on the Microbiological Safety of Food, Food Standards Agency \n. Risk profile in relation to toxoplasma in the food chain , 2012 Available at: http://multimedia.food.gov.uk/multimedia/pdfs/committee/acmsfrtaxopasm.pdf (Accessed 29 October 2015).\n10 \n\nJones \nJL \n, \nDargelas \nV \n, \nRoberts \nJ \n, \nPress \nC \n, \nRemington \nJS \n, \nMontoya \nJG \n. Risk factors for Toxoplasma gondii infection in the United States . Clin Infect Dis \n2009 ; 49 (6 ): 878 –884 .19663709 \n11 \n\nSinger \nMA \n, \nHagler \nWS \n, \nGrossniklaus \nHE \n. \nToxoplasma gondii retinochoroiditis after liver transplantation . Retina \n1993 ; 13 (1 ): 40 –45 .8460279 \n12 \n\nChiquet \nC \n, \nFleury \nJ \n, \nBlanc‐Jouvan \nM \n, \nWallon \nM \n, \nBoibieux \nA \n. Toxoplasmose oculaire acquise (panuvéite) après transplantation hépatique . J Francaise D'Ophtalmol \n2000 ; 23 (4 ): 375 –379 .\n13 \n\nBlanc‐Jouvan \nM \n, \nBoibieux \nA \n, \nFleury \nJ \n, et al. Chorioretinitis following liver transplantation: detection of Toxoplasma gondii in aqueous humor . Clin Infect Dis \n1996 ; 22 (1 ): 184 .8825000 \n14 \n\nGalván Ramírez \nML \n, \nCastillo‐de‐León \nY \n, \nEspinoza‐Oliva \nM \n, et al. Acute infection of Toxoplasma gondii and cytomegalovirus reactivation in a pediatric patient receiving liver transplant . Transpl Infect Dis \n2006 ; 8 (4 ): 233 –236 .17116139 \n15 \n\nCunningham \nJ \n, \nEmmett \nT \n, \nMargolis \nTP \n. Ocular manifestations of HIV infection . N Engl J Med \n1998 ; 339 (4 ): 236 –244 .9673303 \n16 \n\nHolliman \nRE \n, \nJohnson \nJ \n, \nBurke \nM \n, \nAdams \nS \n, \nPepper \nJR \n. False‐negative dye‐test findings in a case of fatal toxoplasmosis associated with cardiac transplantation . J Infect \n1990 ; 21 (2 ): 185 –189 .2230177 \n17 \n\nCaner \nAE \n, \nDöşkaya \nM \n, \nKarasu \nZ \n, et al. Incidence and diagnosis of active Toxoplasma infection among liver transplant recipients in Western Turkey . Liver Transplant \n2008 ; 14 (10 ): 1526 –1532 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1398-2273",
"issue": "18(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nToxoplasma gondii\n; chorioretinitis; disease transmission; immunosuppression; infectious; liver transplantation; ocular; toxoplasmosis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D064591:Allografts; D019072:Antibiotic Prophylaxis; D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D002825:Chorioretinitis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D016133:Polymerase Chain Reaction; D000069078:Seroconversion; D012698:Serologic Tests; D014122:Toxoplasma; D014126:Toxoplasmosis, Ocular; D014184:Transplantation, Homologous; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"references": "9673303;10794988;22491772;19018809;19663709;17605745;17116139;22021924;22075795;27500398;8825000;18825713;18408578;8460279;21506817;19430662;2230177",
"title": "Post-prophylaxis Toxoplasma chorioretinitis following donor-recipient mismatched liver transplantation.",
"title_normalized": "post prophylaxis toxoplasma chorioretinitis following donor recipient mismatched liver transplantation"
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"literaturereference": "WEBB G J, SHAH H, DAVID M D, TIEW S, BEARE N, HIRSCHFIELD G M. POST-PROPHYLAXIS TOXOPLASMA CHORIORETINITIS FOLLOWING DONOR-RECIPIENT MISMATCHED LIVER TRANSPLANTATION.. TRANSPLANT INFECTIOUS DISEASE. 2016;18(5):805-808",
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"abstract": "OBJECTIVE\nCeftriaxone is a commonly used antibiotic among the paediatric population. Various reports have associated high doses of Ceftriaxone with the development of nephrolithiasis; our aim was to test this association with a 5 day course of treatment.\n\n\nMETHODS\nOur study group consisted of 120 patients divided into two groups. The first group included 60 patients who underwent treatment with Ceftriaxone therapy that was started empirically and continued for 5 days at the dose of 80 mg/kg per day. The second group (60 patients) who received treatment with other antibiotics (other than Ceftriaxone), as recommended by hospital protocols. Patients with urinary tract infections (UTI) were excluded as UTI may be a predisposing cause for nephrolithiasis. Baseline and follow up after 5 days were done with; abdominal ultrasound, serum urea, creatinine, serum calcium, 24 h urinary calcium and urinary calcium/ creatinine ratio. Extended metabolic tests were done for cases that developed nephrolithiasis.\n\n\nRESULTS\nFive cases out of the 60 patients treated with Ceftriaxone developed calculi; that were small and were eliminated spontaneously in four cases at mean duration of 3 weeks. In these cases renal ultrasonography examinations were normal prior to treatment; and none of them had metabolic disturbances or risk factors leading to stone formation. By multiple regression analysis, only age was related to nephrolithiasis formation being higher in the group that has developed stones.\n\n\nCONCLUSIONS\nOnly patients who underwent Ceftriaxone therapy have developed renal stones, even with a short course of therapy (5 days), and in the absence of a known predisposing cause for nephrolithiasis. We have thus concluded that Ceftriaxone by itself maybe a predisposing factor for nephrolithiasis.",
"affiliations": "Pediatrics, Zagazig University, Egypt.;Pediatrics, Zagazig University, Egypt.;Pediatrics, Zagazig University, Egypt.;Pediatrics, Zagazig University, Egypt.;Pediatrics, Zagazig University, Egypt.;Radio-Diagnosis, Zagazig University, Egypt.;Departments of Pediatrics, Ain Shams University, Egypt.",
"authors": "Youssef|Doaa Mohammed|DM|;Sherief|Laila Metwaly|LM|;Sherbiny|Hanan Saker|HS|;ElAttar|Mai Yehia|MY|;Sheikh|Abdel Razek Mohammed El|AR|;Fawzy|Faten Mohammed|FM|;Adham|Tamer|T|",
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"issue": "21(5)",
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"keywords": "Ceftriaxone; children; renal stones; ultrasound",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D016022:Case-Control Studies; D002443:Ceftriaxone; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007668:Kidney; D008297:Male; D053040:Nephrolithiasis; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors",
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"publication_types": "D016428:Journal Article",
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"title": "Prospective study of nephrolithiasis occurrence in children receiving cefotriaxone.",
"title_normalized": "prospective study of nephrolithiasis occurrence in children receiving cefotriaxone"
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},
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},
{
"companynumb": "EG-LUPIN PHARMACEUTICALS INC.-2016-02718",
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{
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},
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],
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},
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},
{
"companynumb": "EG-LUPIN PHARMACEUTICALS INC.-2016-02716",
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"patient": {
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{
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"activesubstancename": "CEFTRIAXONE"
},
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"medicinalproduct": "CEFTRIAXONE."
}
],
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}
],
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},
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},
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},
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}
] |
{
"abstract": "OBJECTIVE\nMany comorbid conditions occur among people with epilepsy. These comorbid conditions can be divided into physical, psychiatric, and cognitive groups. This article examines the common comorbid conditions associated with epilepsy and identifies management strategies to mitigate these health concerns.\n\n\nRESULTS\nSudden unexpected death in epilepsy (SUDEP) is an important and common cause of epilepsy-related mortality, with the most important identified predictor being recurrent seizures. Psychiatric and cognitive comorbidities of epilepsy are also particularly common. Individuals with epilepsy need to be screened and treated for psychiatric comorbidities.\n\n\nCONCLUSIONS\nThis article explains common comorbid conditions such as depression, anxiety, and memory difficulties; outlines treatment approaches; and discusses functional restrictions such as driving. SUDEP and the risk factors that contribute to it are also discussed.",
"affiliations": null,
"authors": "Sirven|Joseph I|JI|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1212/CON.0000000000000268",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-2371",
"issue": "22(1 Epilepsy)",
"journal": "Continuum (Minneapolis, Minn.)",
"keywords": null,
"medline_ta": "Continuum (Minneap Minn)",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D003072:Cognition Disorders; D015897:Comorbidity; D003645:Death, Sudden; D019468:Disease Management; D004827:Epilepsy; D006801:Humans; D008297:Male; D001523:Mental Disorders; D012307:Risk Factors",
"nlm_unique_id": "9509333",
"other_id": null,
"pages": "191-203",
"pmc": null,
"pmid": "26844737",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Management of Epilepsy Comorbidities.",
"title_normalized": "management of epilepsy comorbidities"
} | [
{
"companynumb": "US-UCBSA-2016008898",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
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"medicinalproduct": "LEVETIRACETAM."
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{
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"activesubstancename": "LAMOTRIGINE"
},
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"medicinalproduct": "LAMOTRIGINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
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"drugcumulativedosagenumb": null,
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"medicinalproduct": "LACOSAMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
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"drugdosagetext": "UNKNOWN DOSE",
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"drugindication": "SEIZURE",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PHENOBARBITAL."
}
],
"patientagegroup": null,
"patientonsetage": "42",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Loss of personal independence in daily activities",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anger",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SIRVEN JI. MANAGEMENT OF EPILEPSY COMORBIDITIES. CONTINUUM LIFELONG LEARNING IN NEUROLOGY. 2016?22(1):191-203",
"literaturereference_normalized": "management of epilepsy comorbidities",
"qualification": "1",
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},
"primarysourcecountry": "US",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
}
] |
{
"abstract": "A woman in her late 40s presented with excessive per vagina (PV) bleeding and uterine fibroid. She reported excessive PV bleeding after starting Esmya; she was brought in by ambulance to the emergency department with profuse bleeding. Abnormal uterine bleeding (AUB) developed after selective progesterone receptor modulator (SPRM) administration in this symptomatic patient with uterine fibroid. The drug was withheld and surgical treatment considered. Progressive deterioration of PV bleeding after receiving SPRM led to an urgent laparoscopic total hysterectomy, which had to be postponed due to severe anaemia. Surgery took place regardless because the excessive bleeding continued. Histology revealed a 6 cm submucosal uterine fibroid (SMUF) and adenomyosis. Physicians prescribing SPRMs to stop PV bleeding should be aware of potential AUB, which could lead to urgent hysterectomy. The mechanism of action of SPRMs is not clearly understood. Awareness of the side effects of Esmya, such as AUB, must be kept in mind when administering SPRMs.",
"affiliations": "ECCSH, MDGH, Macclesfield, Cheshire, UK.;Nevill Hall Hospital, Aneurin Bevan Health Board, Abergavenny, UK.",
"authors": "Matytsina-Quinlan|Lyubov|L|;Matytsina|Laura|L|",
"chemical_list": "D003270:Contraceptive Agents; D009649:Norpregnadienes; C555622:ulipristal acetate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000740:Anemia; D003270:Contraceptive Agents; D000075202:Contraindications; D005260:Female; D006801:Humans; D007044:Hysterectomy; D010535:Laparoscopy; D007889:Leiomyoma; D008875:Middle Aged; D009649:Norpregnadienes; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014592:Uterine Hemorrhage",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25976198",
"pubdate": "2015-05-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20406552;22844281;23833530;24457604",
"title": "Abnormal excessive per vagina (PV) bleeding on Esmya-selective progesterone receptor modulator (SPRM) in a symptomatic patient with uterine fibroid.",
"title_normalized": "abnormal excessive per vagina pv bleeding on esmya selective progesterone receptor modulator sprm in a symptomatic patient with uterine fibroid"
} | [
{
"companynumb": "GB-ACTAVIS-2016-06167",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "NORETHINDRONE"
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"medicinalproduct": "NORETHISTERONE"
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"drugdosagetext": "500 MG, TID",
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"drugindication": "MENORRHAGIA",
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"medicinalproduct": "MEFENAMIC ACID."
},
{
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"activesubstancename": "LEVOTHYROXINE"
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},
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"reactionmeddraversionpt": "19.0",
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{
"abstract": "BACKGROUND\nThe echinocandins have shown anti-Pneumocystis jiroveci activity in nonhuman animal models; however, the corresponding human clinical experience has been rarely reported. We report a clinical picture of P jiroveci pneumonia (PJP) and determine the effects of concomitant therapy with echinocandins and trimethoprim (TMP)-sulfamethoxazole (SMZ).\n\n\nMETHODS\nWe investigated a retrospective case series of heart transplantation (HT) recipients with PJP from July 1988 to December 2015. Recipient charts were reviewed for their demographic characteristics, underlying conditions, concomitant infections, PJP prophylaxis, TMP-SMZ dosages, adverse events, echinocandin use, oxygenation, and outcomes.\n\n\nRESULTS\nEleven of 451 HT recipients developed PJP after a median duration of 2.8 years after transplantation. All 11 were treated with TMP-SMZ; 5 of them were treated with echinocandins added to the standard TMP-SMZ regimen. The longest interval between transplantation and PJP development was 16.3 years. The mortality rate was 33.3% in recipients receiving TMP-SMZ alone, whereas it was 20% in those receiving echinocandins as well. The most common side effects of TMP-SMZ include nausea and vomiting, metabolic acidosis, and hyperkalemia. Five recipients developed acute psychosis after a median duration of 6 days of TMP-SMZ therapy. The incidence of psychosis increased from 25% in recipients receiving TMP at ≤15 mg/kg/d to 100% in those receiving TMP at >15 mg/kg/d.\n\n\nCONCLUSIONS\nEchinocandins along with the standard TMP-SMZ regimen may effectively alleviate PJP developed after HT. The ideal prophylaxis duration is lifelong owing to the late onset of PJP. The typically intolerable adverse effects of TMP-SMZ therapy for PJP may necessitate dosage adjustments in some cases.",
"affiliations": "Division of Pharmacy, Cheng Hsin General Hospital, Taipei, Taiwan.;Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan.;Division of Pharmacy, Cheng Hsin General Hospital, Taipei, Taiwan.;Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan.;Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan.;Division of Pharmacy, Cheng Hsin General Hospital, Taipei, Taiwan.;Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan. Electronic address: [email protected].",
"authors": "Lu|Y-M|YM|;Lee|Y-T|YT|;Chang|H-C|HC|;Yang|H-S|HS|;Chang|C-Y|CY|;Huang|C-M|CM|;Wei|J|J|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.04.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D004359:Drug Therapy, Combination; D054714:Echinocandins; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011183:Postoperative Complications; D011605:Psychoses, Substance-Induced; D012189:Retrospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1893-1898",
"pmc": null,
"pmid": "28923644",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combination of Echinocandins and Trimethoprim/Sulfamethoxazole for the Treatment of Pneumocystis jiroveci Pneumonia After Heart Transplantation.",
"title_normalized": "combination of echinocandins and trimethoprim sulfamethoxazole for the treatment of pneumocystis jiroveci pneumonia after heart transplantation"
} | [
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"abstract": "Heroin can be adulterated with various substances that may or may not have pharmacological effects. Here we report a case series of 8 patients who presented to the emergency department after overdose with intravenous heroin preparation adulterated with the synthetic cannabinoid methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (5F-MDMB-PINACA).\nExcept for one patient, all of them presented with a typical initial opioid toxidrome consisting of central nervous system and respiratory depression along with pinpoint pupils. Naloxone was given to them, triggering severe agitation and combative behavior along with overlapping features of anticholinergic and sympathomimetic toxidrome. All patients required multiple doses of benzodiazepines. Three were successfully treated with physostigmine.\n5F-MDMB-PINACA is a synthetic cannabinoid that was added to heroin in samples obtained from patients reported in this case series. Patients demonstrated significant agitation after receiving naloxone for opioid toxidrome, presumably because of the removal of the depressant effect of opioids, which unmasked the excitatory effects of the synthetic cannabinoids. Three patients required physostigmine along with the benzodiazepines for control of their agitation, urine retention and abnormal vitals, suggesting the possibility of an anticholinergic toxidrome to have developed in these patients.\nHeroin contaminated with 5F-MDMB-PINACA exhibits variable severities of anticholinergic effects, some on presentation and others only after opiate antagonism.",
"affiliations": "Drexel University College of Medicine, Department of Emergency Medicine, Division of Medical Toxicology, Philadelphia, Pennsylvania.;Drexel University College of Medicine, Department of Emergency Medicine, Division of Medical Toxicology, Philadelphia, Pennsylvania.;Drexel University College of Medicine, Department of Emergency Medicine, Division of Medical Toxicology, Philadelphia, Pennsylvania.;Drexel University College of Medicine, Department of Emergency Medicine, Division of Medical Toxicology, Philadelphia, Pennsylvania.;Drexel University College of Medicine, Department of Emergency Medicine, Philadelphia, Pennsylvania.;Drexel University College of Medicine, Department of Emergency Medicine, Philadelphia, Pennsylvania.",
"authors": "Ershad|Muhammed|M|;Dela Cruz|Maricel|M|;Mostafa|Ahmed|A|;Khalid|Muhammad M|MM|;Arnold|Ryan|R|;Hamilton|Richard|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5811/cpcem.2020.2.45060",
"fulltext": "\n==== Front\nClin Pract Cases Emerg Med\nClin Pract Cases Emerg Med\nClinical Practice and Cases in Emergency Medicine\n2474-252X University of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine \n\n10.5811/cpcem.2020.2.45060\ncpcem-04-121\nCase Series\nHeroin Adulterated with the Novel Synthetic Cannabinoid, 5F-MDMB-PINACA: A Case Series\nErshad Muhammed MD* Dela Cruz Maricel MD* Mostafa Ahmed MD* Khalid Muhammad M. MD* Arnold Ryan MD† Hamilton Richard MD† \n* Drexel University College of Medicine, Department of Emergency Medicine, Division of Medical Toxicology, Philadelphia, Pennsylvania\n\n† Drexel University College of Medicine, Department of Emergency Medicine, Philadelphia, Pennsylvania\nAddress for Correspondence: Muhammed Ershad, Einstein Healthcare Network, Division of Medical Toxicology, 5501 Old York Rd., Philadelphia, PA 19141. Email: [email protected].\n5 2020 \n23 4 2020 \n4 2 121 125\n03 9 2019 20 2 2020 21 2 2020 Copyright: © 2020 Ershad et al.2020This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Introduction\nHeroin can be adulterated with various substances that may or may not have pharmacological effects. Here we report a case series of 8 patients who presented to the emergency department after overdose with intravenous heroin preparation adulterated with the synthetic cannabinoid methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (5F-MDMB-PINACA).\n\nCase Series\nExcept for one patient, all of them presented with a typical initial opioid toxidrome consisting of central nervous system and respiratory depression along with pinpoint pupils. Naloxone was given to them, triggering severe agitation and combative behavior along with overlapping features of anticholinergic and sympathomimetic toxidrome. All patients required multiple doses of benzodiazepines. Three were successfully treated with physostigmine.\n\nDiscussion\n5F-MDMB-PINACA is a synthetic cannabinoid that was added to heroin in samples obtained from patients reported in this case series. Patients demonstrated significant agitation after receiving naloxone for opioid toxidrome, presumably because of the removal of the depressant effect of opioids, which unmasked the excitatory effects of the synthetic cannabinoids. Three patients required physostigmine along with the benzodiazepines for control of their agitation, urine retention and abnormal vitals, suggesting the possibility of an anticholinergic toxidrome to have developed in these patients.\n\nConclusion\nHeroin contaminated with 5F-MDMB-PINACA exhibits variable severities of anticholinergic effects, some on presentation and others only after opiate antagonism.\n\nsynthetic cannabinoidsheroinphysostigmine\n==== Body\nINTRODUCTION\nHeroin is often adulterated with a variety of substances including baking soda, caffeine, crushed analgesics, and scopolamine.1 We present a consecutive patient case series with similar presentations after overdose with intravenous (IV) heroin adulterated with the synthetic cannabinoid (SC) methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (5F-MDMB-PINACA). Within three months, eight patients presented to the emergency department (ED) after use of IV heroin with symptoms consistent with anticholinergic toxicity and variable requirement for naloxone administration by emergency medical services (EMS).\n\nCASE SERIES\nCase 1\nA 28-year-old man with a past medical history of bipolar disorder and polysubstance abuse including IV heroin, presented to the hospital by EMS after being found at home unresponsive. Family members found packets of drugs near the patient labelled “Santa Muerte (Image 1). On arrival, vital signs included a heart rate (HR) of 122 beats per minute, blood pressure (BP) 134/78 millimeters of mercury (mm Hg), respiratory rate (RR) of 38 breaths per minute, oral temperature 98.2 degrees Fahrenheit (F), and oxygen saturation (SpO2) 78% on non-rebreather mask. Physical exam included tachycardia, flushing, dry mucous membranes and mydriasis. The patient was initially given two milligrams (mg) of intranasal (IN) naloxone in the field by EMS secondary to central nervous system (CNS) and respiratory depression, with no response. He was given a second dose of two mg IN naloxone and became agitated and combative. The patient was intubated upon ED arrival for hypoxic respiratory failure. Chest radiograph showed signs of aspiration pneumonitis, which developed into acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). Head computed tomography was negative for acute intracranial abnormality. Complete blood count (CBC) and basic metabolic panel (BMP) were unremarkable. Urine drug screen immunoassay was positive for cocaine, opiates, fentanyl, tetrahydrocannabinol (THC) and benzodiazepines. Comprehensive drug screen of the serum by liquid chromatography tandem mass spectrometry (LC-MS-MS) was positive for cocaine, heroin, 6-monoacetylmorphine (6-MAM), fentanyl, THC, and alprazolam. The patient remained intubated on VV-ECMO for 12 days, after which he was extubated, removed off of VV-ECMO, and discharged on day 17. Laboratory analysis of the patient’s confiscated drug by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LCQ-TOF-MS) was positive for the novel SC 5F-MDMB-PINACA, heroin, and fentanyl.\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nSynthetic cannabinoids (SC) may be added as adulterants to opiates sold on the street, which can contribute to unpredictable clinical consequences.\n\nWhat makes this presentation of disease reportable?\n\nWe report a case series of eight patients who had predominantly anticholinergic features after using heroin containing the SC 5F-MDMB-PINACA.\n\nWhat is the major learning point?\n\nPatients using heroin containing SCs may exhibit severe agitation and hyperactive behavior following naloxone administration.\n\nHow might this improve emergency medicine practice?\n\nConsider using physostigmine along with benzodiazepines in treating patients with severe agitation following naloxone-induced reversal of an opioid toxidrome.\n\nCase 2\nA 25-year-old man with a past medical history of IV heroin use, presented to the ED by EMS after IV heroin use. The patient initially had CNS and respiratory depression in the field and was first given two mg of IN naloxone with no response, followed by a second dose of two mg IN naloxone, which made him anxious and tachycardic. Vital signs on arrival to the ED included a HR of 102 beats per minute, BP of 146/89 mmHg, RR 24 breaths per minute, SpO2 98% on room air, and oral temperature 97.5º F. Physical exam was positive for flushing, tachycardia, and agitation. The patient was given 4 mg of lorazepam IV in the ED. He admitted to the use of an adulterated heroin “Santa Muerte.” CBC and BMP were unremarkable. Urine drug screen immunoassay was positive for opiates, amphetamine, barbiturates and cocaine. Symptoms improved after benzodiazepine treatment, IV fluids, and supportive care. He was admitted for 24 hours and discharged the following day with no further complications. Laboratory analysis of the patient’s confiscated drug by GC-MS and LCQ-TOF was positive for the novel SC 5F-MDMB-PINACA, heroin, and fentanyl.\n\nCase 3\nA 31-year-old man with a past medical history of IV heroin use, presented to the ED by EMS for CNS and respiratory depression after IV heroin use. The patient’s girlfriend provided the history that the patient was using a new type of heroin called “Santa Muerte.” The patient was given a total of four mg IN naloxone in the field, after which he became agitated, combative, and tachycardic. His vital signs on arrival included a HR of 163 beats per minute, BP of 131/81 mmHg, RR of 29 breaths per minute, SpO2 99% on room air, and oral temperature 98.8 degrees F. While in the ED, he continued to be agitated and combative. On examination, he was tachycardic and flushed with dilated pupils and a palpable full bladder in the suprapubic region. The patient was given a total of 10 mg of lorazepam with minimal improvement of his agitation, and he was later intubated for airway protection. Complete blood count (CBC) and basic metabolic panel (BMP) were unremarkable, and urine drug screening immunoassay was positive for opiates. Serum comprehensive drug screen by LC-MS-MS was positive for heroin, 6-MAM, fentanyl, and negative for any SCs. The patient later developed ARDS, requiring increased ventilator setting and was transferred to a tertiary center for VV-ECMO. Specialty laboratory testing of the patient’s confiscated drug by GC-MS and LCQ-TOF was positive for the novel SC 5F-MDMB-PINACA, heroin, and fentanyl.\n\nCase 4\nA 25-year-old man presented to the hospital by EMS after IV heroin use. The patient was found with a drug packet labeled “Santa Muerte” in his pocket and had CNS and respiratory depression. He was given a total of four mg of IN naloxone, after which he became flushed, tachycardic, and agitated with dilated pupils. On arrival to the ED, his HR was 158 beats per minute, BP was 215/158 mmHg, RR was 26 breaths per minute, SpO2 was 99% on room air, and oral temperature was 102.1º F. On exam, he had urinary retention and anhidrosis. He was given four mg of lorazepam and two mg of IV physostigmine, which treated his agitation. There was also marked improvement in anhidrosis and urine retention. He was admitted for 24 hours and discharged the following day with no further complications. Urine drug screen was positive for cocaine, opiates, and THC. Serum comprehensive toxicology analysis by LC-MS-MS was positive for 5F-MDMB-PICA(5F-ADB), heroin, 6-MAM, and fentanyl. Laboratory analysis of the patient’s confiscated drug by GC-MS and LCQ-TOF was positive for the novel SC 5F-MDMB-PINACA, heroin, and fentanyl.\n\nCase 5\nA 45-year-old man was found down in the field agitated and tachycardic. On arrival to the ED, his HR was 124 beats per minute, BP 140/82 mm Hg, RR 22 breaths per minute, oxygen saturation 99%, and oral temperature 99.3º F. On exam, he had pinpoint pupils with flushing of skin. He received midazolam five mg and olanzapine 20 mg intramuscular followed by diazepam 10 mg IV after which he calmed down. He was eventually started on dexmedetomidine infusion when his agitation returned. He was admitted for 24 hours and discharged the following day with no complications. Urine drug screen was positive for opiates and fentanyl. He was found with a drug packet named “50 CAL” (Image 2), which was sent for GC-MS and LCQ-TOF and was found to be positive for 5F-MDMB-PINACA, heroin, and fentanyl.\n\nCase 6\nA 36-year-old man was found lying in the street unresponsive. He received eight mg of naloxone IN after which he became agitated. On arrival to the ED, his HR was 130 beats per minute, BP 160/100 mm Hg, RR 24 breaths per minute, oxygen saturation 95% on 100 % oxygen, and oral temperature 98.6º F. Initial physical examination revealed restlessness, confusion, and picking behavior. Patient also had bilaterally dilated pupils with urine retention on point-of-care ultrasound. Considering an anticholinergic toxidrome, the emergency provider administered physostigmine two mg IV with improvement in agitation, picking behavior, urine retention, and relative constriction in pupillary diameter. He had received multiple doses of benzodiazepines prior to physostigmine. He was eventually intubated due to risk of aspiration from vomiting in the setting of altered mental status. His mental status and vitals improved the next day, following which he was extubated. CBC and BMP were unremarkable and urine drug screen was positive for opiates and fentanyl. The patient was found with a blue packet labeled “50 CAL,” which was found to be positive for fentanyl, heroin, and 5F-MDMB-PINACA on GC-MS and LCQ-TOF.\n\nCase 7\nA 23-year-old woman was brought to the ED with severe agitation and combative behavior. Her initial vitals were HR 156 beats per minute, BP 147/64 mm Hg, RR 20 breaths per minute, and oral temperature 101.5º F. Examination revealed bilaterally dilated pupils, flushed and dry skin, and urine retention on point-of-care ultrasound. The patient received Lorazepam four mg IV and physostigmine two mg IV after which her agitation subsided, urine retention improved, pupillary diameter decreased, and skin appeared less flushed and less dry. CBC and BMP were unremarkable while her urine drug screen was positive for opiates and fentanyl. She was admitted to the floor and discharged the next day. The patient reported consuming a substance from packets labeled “50 CAL.” The drug packets were not available for analysis. We were also unable to send her serum or urine for further comprehensive toxicology analysis.\n\nCase 8\nA 27-year-old man was brought to the ED after IV heroin use. He was found to be in respiratory and CNS depression with pinpoint pupils in the field by the EMS. Naloxone four mg IN was given after which he became agitated. His vitals were HR 130 beats per minute, BP 130/94 mm Hg, RR 22 breaths per minute, and temperature of 99º F. Initial examination revealed dilated pupils, dry oral mucous membrane, and flushed skin. He received lorazepam 4 mg IV and physostigmine two mg IV after which he calmed down, pupils returned back to normal size, and heart rate came down to normal; he was admitted to the floor. Urine drug screen was positive for opiates and fentanyl. He reported having ingested drugs from packets labeled “Nick” and “50 CAL,” but they were unavailable for analysis.\n\nDISCUSSION\nHeroin has been historically adulterated with a variety of substances including baking soda, caffeine, acetaminophen, diphenhydramine, scopolamine, fentanyl, and clenbuterol.1 These adulterants are usually added to increase profits by incorporating any substance that looks like the original substance and/or would have the same effect. In the months of April and August 2018, consumption of heroin that had been laced with the newer SC 5F-MDMB-PINACA gave rise to a series of patients presenting to our ED with unique clinical manifestations.\n\nSCs, by themselves, have been widely used as drugs of abuse since the early 2000s. They have been found to have more adverse clinical presentations than the active compound marijuana itself, owing to its full agonistic action on the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) receptors, as compared to marijuana, which is only a partial agonist.2 Clinical effects of SC overlap with anticholinergic and sympathomimetic toxidromes.3,4 There have also been reported fatalities with SCs including 5F-ADB, 5F-PB-22, and AB-CHMINACA.5\n\nThe patients reported in our case series took opioids containing 5F-MDMB-PINACA (Figure), which is a new generation SC. Except for patient 5, all of them presented with a typical initial opioid toxidrome consisting of CNS and respiratory depression along with pinpoint pupils. Naloxone, an opioid antagonist, was given to them, which triggered severe agitation and combative behavior along with overlapping features of anticholinergic and sympathomimetic toxidrome. This was presumably because of the removal of the depressant effect of opioids by the administration of naloxone that unmasked the effects of SC.\n\nAll the patients required multiple doses of benzodiazepines. Three of the eight patients were successfully treated with physostigmine, which helped control the abnormal psychomotor activity and anticholinergic manifestations.\n\nThe initial urine drug screen test used for all eight patients was an immunoassay-based screening test. Apart from morphine (opiates), it tests for fentanyl, buprenorphine, methadone, tramadol, cocaine, oxycodone, phencyclidine, amphetamines, barbiturates, benzodiazepines, and cannabinoids. The comprehensive serum drug screen performed in cases 1, 3 and 4 was through LC-MS-MS, which is an exceedingly sensitive and specific analytical technique that can precisely estimate the identities and concentrations of molecules within a sample.\n\nThe seized drug packets were analyzed at the Center for Forensic Science Research and Education, using GC-MS and LCQ-TOF. The samples were prepared using acid/base extraction prior to the analysis.6 The drug packets that were analyzed at this facility did not turn positive for any of the anticholinergic agents, thereby leading us to conclude that 5F-MDMB-PINACA potentially has anticholinergic manifestations that seem to be responding to physostigmine in our clinical experience.\n\nCONCLUSION\nHeroin contaminated with 5F-MDMB-PINACA exhibits variable severities of anticholinergic effects, some on presentation and others only after opiate antagonism. Synthetic cannabinoids affect cannabinoid CB1 and CB2 receptors, potentially causing adrenergic stimulation, sedation, hallucinations, catecholamine release, and severe tachycardia.2–4 It is also possible that synthetic cannabinoids and/or their metabolites interact directly with acetylcholine receptors to cause anticholinergic effects. In our case series, we found that physostigmine was effective in reversing the anticholinergic effects and agitation in three out of the eight patients.\n\nSection Editors: Steven Walsh, MD\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nThe authors attest that their institution requires neither Institutional Review Board approval, nor patient consent for publication of this case report. Documentation on file.\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n\nFigure Chemical structure of the synthetic cannabinoid methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate.\n\nImage 1 Packets of “Santa Muerte,” a street heroin adulterated with synthetic cannabinoid, that were retrieved from a patient found unresponsive at home.\n\nImage 2 A “50 CAL” drug packet retrieved from a patient, which contained heroin, synthetic cannabinoid, and fentanyl.\n==== Refs\nREFERENCES\n1 Hamilton RJ Perrone J Hoffman R A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine Clin Toxicol 2000 38 6 597 608 \n2 Le Boisselier R Alexandre J Lelong-Boulouard V Focus on cannabinoids and synthetic cannabinoids Clin Pharmacol Ther 2017 101 2 220 9 27861784 \n3 Schwartz MD Trecki J Edison LA A common source outbreak of severe delirium associated with exposure to the novel synthetic cannabinoid ADB-PINACA J Emerg Med 2015 48 5 573 80 25726258 \n4 Zhang MW Ho RC The cannabis dilemma: a review of Its associated risks and clinical efficacy J Addict Med 2015 2015 707596 \n5 Angerer V Jacobi S Franz F Three fatalities associated with the synthetic cannabinoids 5F-ADB, 5F-PB-22, and AB-CHMINACA Forensic Sci Int 2017 281 e9 15 29133010 \n6 Krotulski AJ Mohr ALA Logan BK [Ahead of Print] Emerging synthetic cannabinoids: development and validation of a novel liquid chromatography quadrupole time-of-flight mass spectrometry assay for real-time detection J Anal Toxicol 1 7 2020\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-252X",
"issue": "4(2)",
"journal": "Clinical practice and cases in emergency medicine",
"keywords": "heroin; physostigmine; synthetic cannabinoids",
"medline_ta": "Clin Pract Cases Emerg Med",
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"nlm_unique_id": "101718968",
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"pages": "121-125",
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"pmid": "32426651",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "26539302;31909808;11185966;27861784;29133010;25726258",
"title": "Heroin Adulterated with the Novel Synthetic Cannabinoid, 5F-MDMB-PINACA: A Case Series.",
"title_normalized": "heroin adulterated with the novel synthetic cannabinoid 5f mdmb pinaca a case series"
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"abstract": "BACKGROUND\nDespite neoadjuvant/adjuvant chemotherapy, women with resectable stage II/III breast cancer (BC) have high risk of recurrent disease. Recent data suggest that zoledronic acid (ZOL) therapy concurrent with adjuvant treatments may improve cancer-related outcomes in patients with BC.\n\n\nMETHODS\nDisease-free survival (DFS; secondary end point) and overall survival (OS; tertiary end point) were evaluated in 119 women with stage II/III BC randomised to intravenous ZOL 4 mg every 3 weeks for 1 year or no ZOL (control) starting with the first chemotherapy cycle.\n\n\nRESULTS\nAt 61.9 months' median follow-up, there was no significant difference in recurrence or survival between study arms. However, time to recurrence or death (DFS) was significantly different between subgroups defined by oestrogen receptor (ER) status (interaction P=0.010 for DFS and 0.025 for OS). Hazard ratios (HRs) for disease recurrence and death were significantly less among patients with ER-negative (ER(-)) tumours who received ZOL vs no ZOL (DFS: HR=0.361, 95% confidence interval (CI) 0.148, 0.880; OS: HR=0.375, 95% CI 0.143, 0.985).\n\n\nCONCLUSIONS\nZOL administered with chemotherapy may improve DFS and OS in a subset of BC patients with ER(-) tumours. This study was not powered to compare subgroups of patients; thus, these findings should be considered hypothesis generating.",
"affiliations": "Department of Surgery, Washington University School of Medicine, Campus Box 8109, 660 South Euclid Avenue, St Louis, MO 63110, USA. [email protected]",
"authors": "Aft|R L|RL|;Naughton|M|M|;Trinkaus|K|K|;Weilbaecher|K|K|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D011960:Receptors, Estrogen; D000077211:Zoledronic Acid",
"country": "England",
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"doi": "10.1038/bjc.2012.210",
"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\nbjc2012210\n10.1038/bjc.2012.210\n22617128\nClinical Study\nEffect of (Neo)adjuvant zoledronic acid on disease-free and overall survival in clinical stage II/III breast cancer\n(Neo)adjuvant zoledronic acid in breast cancer\nAft R L *123\nNaughton M 24\nTrinkaus K 25\nWeilbaecher K 24\n1 Department of Surgery, Washington University School of Medicine, Campus Box 8109, 660 South Euclid Avenue, St Louis, MO 63110, USA\n2 Siteman Cancer Center, Washington University, 660 South Euclid Avenue, St Louis, MO 63110, USA\n3 John Cochran Veterans Administration Hospital, 915 North Grand Boulevard, St Louis, MO 63106, USA\n4 Department of Medicine, Washington University, 660 South Euclid Avenue, St Louis, MO 63110, USA\n5 Division of Biostatistics, Washington University, 660 South Euclid Avenue, St Louis, MO 63110, USA\n* E-mail: [email protected]\n26 06 2012\n22 05 2012\n26 6 2012\n107 1 711\n13 12 2011\n09 04 2012\n18 04 2012\nCopyright © 2012 Cancer Research UK\n2012\nCancer Research UK\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/\nBackground:\n\nDespite neoadjuvant/adjuvant chemotherapy, women with resectable stage II/III breast cancer (BC) have high risk of recurrent disease. Recent data suggest that zoledronic acid (ZOL) therapy concurrent with adjuvant treatments may improve cancer-related outcomes in patients with BC.\n\nMethods:\n\nDisease-free survival (DFS; secondary end point) and overall survival (OS; tertiary end point) were evaluated in 119 women with stage II/III BC randomised to intravenous ZOL 4 mg every 3 weeks for 1 year or no ZOL (control) starting with the first chemotherapy cycle.\n\nResults:\n\nAt 61.9 months’ median follow-up, there was no significant difference in recurrence or survival between study arms. However, time to recurrence or death (DFS) was significantly different between subgroups defined by oestrogen receptor (ER) status (interaction P=0.010 for DFS and 0.025 for OS). Hazard ratios (HRs) for disease recurrence and death were significantly less among patients with ER-negative (ER−) tumours who received ZOL vs no ZOL (DFS: HR=0.361, 95% confidence interval (CI) 0.148, 0.880; OS: HR=0.375, 95% CI 0.143, 0.985).\n\nConclusion:\n\nZOL administered with chemotherapy may improve DFS and OS in a subset of BC patients with ER− tumours. This study was not powered to compare subgroups of patients; thus, these findings should be considered hypothesis generating.\n\nbisphosphonate\nbreast cancer\nchemotherapy\nhormone receptor\nneoadjuvant\nzoledronic acid\n==== Body\npmcBreast cancer (BC) is the most commonly diagnosed malignancy and the leading cause of cancer-related mortality among women worldwide (Ferlay et al, 2010). Despite the use of neoadjuvant and adjuvant therapies in patients with localised BC, recent trials report ∼8% incidence of disease recurrence overall within the first few years after treatment, with even higher recurrence rates for patients with certain BC subtypes (Gnant et al, 2009; Eidtmann et al, 2010). The development of recurrent disease is thought to be the result of persistent micro-metastatic disease that is chemotherapy resistant (Pantel et al, 2009). The presence and persistence of disseminated tumour cells (DTCs), also known as bone marrow micro-metastases, have been associated with poor outcomes and recurrent disease in patients with early-stage BC, regardless of hormone receptor status and other established prognostic features such as nodal status (Braun et al, 2005). We and others have reported that the bone-targeted bisphosphonate, zoledronic acid (ZOL), which is currently used to treat osteoporosis and to reduce the risk of skeletal morbidity in patients with bone metastases, can also reduce the persistence of DTCs in the bone marrow of women with early BC (Lin et al, 2008; Solomayer et al, 2009; Aft et al, 2010; Rack et al, 2010).\n\nZoledronic acid has been reported to decrease tumour burden in the breast when administered with neoadjuvant chemotherapy (Coleman et al, 2010). In addition, we observed that subsets of patients with triple-negative BC were more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy if they received concurrent ZOL, suggesting that bisphosphonates may provide potential anti-cancer benefits in addition to their established bone-protective activities (Neville-Webbe et al, 2010). Numerous studies have evaluated the impact of bisphosphonates on disease-free survival (DFS) and overall survival (OS) in localised BC. Although the results have been mixed, consensus is emerging that certain subsets of patients with early-stage BC may benefit from bisphosphonate therapy. Zoledronic acid administration increased DFS in premenopausal women with oestrogen receptor-positive (ER+) BC who were treated with ovarian suppression and endocrine-targeted therapies (Gnant et al, 2011a). Likewise, ZOL increased DFS in postmenopausal women with ER+ tumours who received endocrine-targeted therapies (Eidtmann et al, 2010; Coleman et al, 2011). The mechanisms of the anti-cancer effects of bisphosphonates are under intense investigation.\n\nIn this study, we report the effect of ZOL administered every 3 weeks for 1 year, beginning at the start of neoadjuvant chemotherapy, on DFS and OS outcomes in a phase II trial of 120 women with stage II/III BC, which included pre- and postmenopausal women and patients with ER+ and ER-negative (ER−) tumours (Aft et al, 2010).\n\nPatients and methods\n\nPatients\n\nEligible patients had clinical stage II/III (⩾T2 and/or ⩾N1) newly diagnosed BC with inclusion of all tumour biomarker subtypes, Eastern Cooperative Oncology Group performance status score of 0 or 1, and normal cardiac, renal and liver function. Menopausal status was defined as 1 year with no menstrual activity, previous bilateral oophorectomy, or age >56 years. Inclusion criteria for this study were as previously described (Aft et al, 2010).\n\nStudy design and treatment\n\nThis single-centre, open-label, phase II trial evaluated the efficacy and safety of adding ZOL to standard therapy in women with stage II/III BC. This study is registered with ClinicalTrials.gov, NCT00242203. Eligible women were randomly assigned to receive either 4 mg intravenous ZOL every 3 weeks for 1 year (total 17 doses) commencing with the first dose of chemotherapy, or no ZOL (chemotherapy alone; Figure 1). The randomisation process was as previously described (Aft et al, 2010).\n\nThe primary end point was the number of patients with detectable DTCs in bone marrow, measured at baseline, 3 months (after four cycles of chemotherapy), and 12 months. These results have been reported earlier (Aft et al, 2010). Respective secondary and tertiary end points were DFS, defined as the time interval between surgery (the time point of all residual disease removal) and first detectable disease recurrence or death, and OS, defined as the time from diagnosis to death from any cause or to last follow-up.\n\nThe approved dosing schedule of ZOL (4 mg via 15-min intravenous infusion every 3 weeks) for bone metastasis was used (Hillner et al, 2003). All women received four cycles of intravenous neoadjuvant epirubicin (75 mg m−2) plus docetaxel (75 mg m−2) every 3 weeks, with granulocyte-stimulating factor support and oral dexamethasone premedication (20 mg), followed by surgery and two cycles of adjuvant epirubicin plus docetaxel administered every 3 weeks. Adjuvant radiation, endocrine, and trastuzumab therapies were administered when indicated. The recommended follow-up was every 3 months for years 1 and 2 after randomisation, then every 6 months for years 3–5 after randomisation. It was recommended that all radiological exams (i.e., mammogram, computed tomography, bone or positron emission tomography) be performed annually.\n\nAll patients were encouraged to take 1000 mg calcium with 800 IU vitamin D daily. Adverse events were assessed at each follow-up. Patients were removed from the study for safety reasons, progression during chemotherapy or recurrent disease development. The Internal Review Board of Washington University approved the study, and patients provided written consent.\n\nStudy assessments\n\nImmunostaining for ER, progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER2) was performed at Washington University. ER and PgR were considered positive if there was any detectable staining by immunohistochemistry (Ventana, Inc., Tucson, AZ, USA). HER2 was considered positive if HercepTest (Dako North America, Inc., Carpinteria, CA, USA) was 3+ or if the fluorescence in situ hybridisation (FISH) score was >2.0. The FISH analysis was done for all specimens scored as 2+ by HercepTest.\n\nPre-treatment tumour size was defined as the largest tumour dimension documented by mammogram, breast ultrasound, or magnetic resonance imaging. Pre-treatment lymph-node status was defined as any abnormal lymph nodes on computed tomography or ultrasound imaging, or on clinical exam, or by the presence of metastatic disease from fine-needle aspiration or sentinel lymph-node biopsy. Pathologic complete response was defined as no residual invasive tumour in the breast specimen at the time of surgery.\n\nStatistical analysis\n\nKaplan–Meier estimates were generated for DFS and OS in each treatment arm, and patient subsets were defined by ER and HER2 status. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. A propensity score, adjusting for differences in age, race, menopausal status, ER, PgR, and HER2, was found to be a significant predictor of DFS and OS; thus, all reported analyses were adjusted using the propensity score. P-values <0.05 were considered significant.\n\nResults\n\nPatients\n\nOf the 120 eligible women enrolled in this study, 119 were evaluated, and of those patients ∼55% had ER+ tumours, 20% had HER2+ tumours, and 33% had ER−/HER2− tumours (Table 1; Aft et al, 2010). One patient withdrew consent before receiving treatment, one patient did not have tumour biomarkers, and two patients did not undergo surgery for their cancer. Thirty-seven patients developed recurrent disease, of whom 27 died and 10 were alive with disease at last follow-up. There were 18 deaths among the 52 ER− patients and 9 deaths among the 66 ER+ patients. The remaining 82 patients were alive without disease at last follow-up. No deaths were identified within this cohort as having a cause unrelated to BC.\n\nEfficacy\n\nAfter a median follow-up of 61.9 months, DFS (P=0.92) and OS (P=0.92) were similar in the ZOL and no-ZOL arms for the overall study population (Figure 2). ER status is an independent predictor of OS (Berry et al, 2006) and, as expected in our study, times to recurrence and death were significantly different between patient subgroups defined by ER status in the no-ZOL arm (interaction P=0.010 for DFS and 0.025 for OS; Table 2). However, in the ZOL treatment arm we failed to find a differences among the ER+ and ER− patients. The hazards of disease recurrence and of death were significantly less among patients with ER− tumours who received ZOL vs those who did not (DFS: HR=0.361; 95% CI 0.148, 0.880; OS: HR=0.375; 95% CI 0.143, 0.985). There was no evidence that ZOL treatment altered DFS or OS vs no ZOL in patients with ER+ tumours (Table 3). In Kaplan–Meier analyses, there were significant differences in DFS (P=0.0007) and OS (P=0.0018) based on treatment arms (Figure 3).\n\nAs HER2+ status has significant effects on DFS and OS, especially with the recent adoption of HER2-targeted therapy, and to analyse more uniform subsets of BC patients, we analysed the effects of ER status on DFS and OS in the subset of patients with HER2− tumours (n=95). In the subset of HER2− tumours, the effect of ZOL on OS and DFS was not shown to be significantly different in ER+ and ER− patients (DFS interaction P=0.052 and OS interaction P=0.064; Table 2). However, among patients with ER−/HER2− tumours, only 58% were alive at last follow-up in the no-ZOL arm compared with 81% in the ZOL arm. The corresponding DFS rates were 47% (no ZOL) and 71% (ZOL).\n\nSafety\n\nAs previously reported, ZOL was generally well tolerated; toxicities were similar in the two treatment groups, with no observed cases of nephrotoxicity resulting in dose modifications. One of the 60 patients (1.7%) developed osteonecrosis of the jaw after receiving 11 infusions of ZOL (Aft et al, 2010).\n\nDiscussion\n\nWith a median follow-up of 62 months, the addition of neoadjuvant ZOL to standard therapy did not significantly change median DFS or OS in women with stage II/III BC treated in this study. This is consistent with our earlier report in which we did not observe significant differences in the 1- and 2-year disease recurrence and survival rates (Aft et al, 2010). Analysis of survival rates stratified according to BC subtype revealed significant improvements in DFS and OS in women with ER− tumours randomised to receive ZOL. Our data are consistent with a recent report demonstrating a survival benefit of bisphosphonates in ER− patients with metastatic disease (Park et al, 2009). In most adjuvant trials with bisphosphonates in non-metastatic BC, the predominant tumour type is ER+. Our trial was intentionally geared to patients at high risk of metastasis; >40% of patients treated in our trial had ER− tumours and were premenopausal at diagnosis.\n\nThree recently reported large phase III trials, which included women with all tumour subtypes, did not demonstrate an overall DFS or OS benefit from bisphosphonate treatment in women receiving adjuvant chemotherapy. These trials were the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 trial, which compared clodronate vs placebo in women with early BC treated with adjuvant chemotherapy or endocrine therapy, the German Adjuvant Intergroup Node-positive (GAIN) study, which compared ibandronate vs placebo in women receiving adjuvant chemotherapy, and the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) study, which compared ZOL vs placebo in women receiving adjuvant chemotherapy or endocrine therapy (Coleman et al, 2011; Mobus et al, 2011; Paterson et al, 2011). In contrast, other trials evaluating the addition of ZOL (4 mg every 6 months) to endocrine therapy demonstrated significant improvement in DFS compared with adjuvant endocrine therapy alone in premenopausal women with ovarian suppression in phase III trials (N=1803; DFS HR=0.64; P=0.01; Gnant et al, 2009) and postmenopausal (N=1065; DFS HR=0.59; P=0.03; Eidtmann et al, 2010) women with stage I to III BC. However, clinical data indicate that ER status may be a variable for clinical benefit from bisphosphonates in this setting.\n\nIn a subset analysis of the AZURE trial in patients who were unequivocally postmenopausal at the time of starting the trial, ZOL provided a benefit for DFS to those patients with ER+ tumours (Coleman et al, 2011). We await OS data from the planned subgroup analysis by tumour subtype of the NSABP B-34 and GAIN trials. Meanwhile, in the ABCSG-12 trial, those women who derived the greatest benefit from the addition of ZOL were >40 years of age at study entry (Gnant et al, 2011b). These studies suggest that women with ER+ tumours and low oestrogen levels (postmenopausal, or premenopausal women with ovarian suppression) experience a survival benefit when ZOL is administered in the adjuvant setting. In this study, we did not observe any DFS benefit with the addition of ZOL to standard therapy in the subset of patients with ER+ tumours. The lack of DFS benefit in ER+ patients may be related to the small number of events in this subgroup with a more favourable prognosis compared with ER− patients. The ER+ patients in this study were relatively young (median age, 47 years) and may have benefitted from upfront neoadjuvant chemotherapy because of their high-risk status (tumour size and other risk factors). As 60% of the patients with ER+ tumours in this trial were premenopausal at diagnosis, in contrast to the AZURE population, and were not given ovarian suppression, in contrast to the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12) population, it is difficult to extrapolate the results of our trial to others (Gnant et al, 2009).\n\nMany bisphosphonate trials have focused on patients with ER+ disease or have not included a large population of patients with ER− disease. Few studies have examined the effects of bisphosphonates on ER− BCs. In a retrospective study, Park et al (2009) found significantly prolonged survival in ER− stage IV BC patients who received bisphosphonate treatment. In our trial, we found a significant decreased risk of recurrent disease development and death in patients with ER− disease who received ZOL (HR=0.361 and 0.375, respectively). We observed 21 recurrences among the 50 ER− patients. This population was composed of predominantly premenopausal (55%) and African American (45%) women. Thus, in contrast to ER+ tumours, the effect does not seem to be dependent on a low oestrogen environment and may be the result of a more direct anti-tumour effect of ZOL on ER− tumour cells.\n\nIn the primary report of this study, it was shown that adding ZOL to neoadjuvant chemotherapy was associated with increased rates of pCR vs no ZOL, although this difference was not significant (Aft et al, 2010). For Luminal B, HER2+, and ER−/HER2− BC subtypes, response in the breast correlates with OS, which is thought to reflect the response of systemic micro-metastatic disease (Von Minckwitz et al, 2011). Thus, patients who achieve a pCR in the breast with chemotherapy have a better prognosis than patients who have residual breast disease (Chavez-MacGregor and Gonzalez-Angulo, 2010). Pathologic complete response in the breast has been used as a surrogate for response to therapy. As previously reported, in our patient population the between-group differences in the pCR rate were most pronounced in the triple-negative subset (ER−/PgR−/HER2−; ZOL group=28% no-ZOL group=10%), although, as with the overall population, this difference was not statistically significant (Aft et al, 2010). These data are consistent with previous clinical data from the neoadjuvant therapy subset (n=205) of the ongoing AZURE trial, wherein the addition of ZOL (4 mg every 3 to 4 weeks) to 6 cycles of neoadjuvant chemotherapy improved pCR rates approximately two-fold in a multivariate analysis of the entire neoadjuvant cohort and significantly reduced the residual invasive tumour size at surgery (relative decrease of 43% P=0.006) vs chemotherapy alone (Coleman et al, 2010).\n\nAs previously reported, among patients without detectable DTCs at baseline, a larger proportion of ZOL-treated patients (87%) remained DTC− at 3 months compared with patients receiving chemotherapy alone (60% P=0.03; Aft et al, 2010). Similarly, among patients who were DTC+ at baseline, a larger proportion of patients transitioned to DTC− status in the ZOL group (48%) compared with chemotherapy alone (43% P=0.05 vs no ZOL; Aft et al, 2010). Emerging data suggest that there is a complex interaction between the tumour and bone marrow (McAllister and Weinberg, 2010). Primary tumours release cytokines that are thought to prime the bone marrow for receipt of micro-metastasis disease, interrupt the delicate balance between bone formation and destruction with the release of growth factors, and recruit bone marrow-derived cells to enhance tumour growth and invasion. Similarly, bone marrow-derived myeloid cells can promote tumour growth at primary and distant sites (Weilbaecher et al, 2011). It is possible that drugs such as ZOL affect this interaction with the observed results of tumour growth inhibition and reduction of DTCs and metastases formation (Aft, 2011).\n\nAlthough multiple statistical models used in the current study show a trend of increased clinical benefit in ER− patients treated with ZOL, our findings are limited in that time to relapse (i.e., DFS) and OS were secondary and tertiary end points, respectively, and the study was not designed or powered to compare subgroups of patients. Thus, our findings should be regarded as hypothesis generating, and interpretation should be regarded with appropriate caution.\n\nIn summary, in this study, adding ZOL (4 mg every 3 weeks) to neoadjuvant chemotherapy reduced DTC persistence (Aft et al, 2010), improved pCR rates in specific patient subsets (Aft et al, 2010), and improved DFS and OS vs chemotherapy alone in the patient subset with ER− tumours. These observations in the ER− subset suggest that neoadjuvant or adjuvant ZOL may be a beneficial addition to current treatment paradigms in patients with ER− tumours, and may warrant further investigation in larger clinical trials in this high-risk patient population with few targeted therapy options.\n\nWe would like to thank our patients and their families for being active and enthusiastic participants in this study. We thank Ms Susan Fox and Ms Farley Johnson who provided outstanding assistance with the data and clinical trial management. We would also like to thank the doctors and nurses of Surgical Oncology, Medical Oncology, and Radiation Oncology at the Washington University School of Medicine and Siteman Cancer Center for the exceptional care provided to study patients. Research support was provided by KNW (R01-CA097250, PPG-CA100730), St Louis Men’s Group against Cancer. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Jerome F Sah, PhD, ProEd Communications, Inc., for his medical editorial assistance with this manuscript.\n\nFigure 1 Study design. Abbreviations: DFS=disease-free survival; DTC=disseminated tumour cells; IV=intravenous; OS=overall survival; ZOL=zoledronic acid (4 mg every 3 weeks).\n\nFigure 2 Disease-free survival (A) and overall survival (B) were similar between the ZOL and no-ZOL arms for the overall trial population. Abbreviations: DFS=disease-free survival; OS=overall survival; ZOL=zoledronic acid (4 mg every 3 weeks); ○=censored.\n\nFigure 3 Kaplan–Meier estimates of (A) disease-free survival and (B) overall survival in all patients according to the ER status of their tumours. Abbreviations: DFS=disease-free survival; ER=oestrogen receptor; ZOL=zoledronic acid (4 mg every 3 weeks); ○=censored.\n\nTable 1 Patient demographics and baseline disease characteristics\n\nCharacteristic\tNo ZOL ( n =59)\tZOL ( n =60)\t\nMean age, years (range)\t49.1 (32–69)\t50 (30–68)\t\n \t \t \t\nRace, n (%)\t\n Caucasian\t45 (76.3)\t39 (65)\t\n African American\t11 (18.6)\t20 (33)\t\n \t \t \t\nMenopausal status, n (%)\t\n Premenopausal\t33 (55.9)\t31 (51.7)\t\n Postmenopausal\t26 (44.1)\t29 (48.3)\t\n \t \t \t\nPathology, n (%)\t\n Ductal carcinoma\t49 (83.1)\t47 (78.3)\t\n Lobular carcinoma\t7 (11.8)\t7 (11.7)\t\n Other\t3 (5.1)\t6 (10)\t\n \t \t \t\nMean tumour size, cm (s.d.)\t3.56 (2.41)\t3.81 (2.03)\t\nLymph-node positive, n (%)\t33 (55.9)\t38 (63.3)\t\n \t \t \t\nGrade, n (%)\t\n I\t2 (3.4)\t7 (11.7)\t\n II\t28 (47.5)\t20 (33.3)\t\n III\t29 (49.2)\t33 (55)\t\n \t \t \t\nReceptor status, n (%)\t\n ER+/HER2+\t5 (8.5)\t6 (10)\t\n ER+/HER2−\t29 (49.2)\t26 (43.3)\t\n ER−/HER2+\t5 (8.5)\t7 (11.7)\t\n ER−/HER2−\t19 (32.2)\t21 (35)\t\n Unknown\t1 (1.7)\t—\t\nAbbreviations: ER=oestrogen receptor; HER2=human epidermal growth factor receptor-2; s.d.=standard deviation; ZOL=zoledronic acid.\n\nSome of these patient data were previously published (Aft et al, 2010).\n\nTable 2 Proportional hazards by tumour subtype and treatment arm adjusted for propensity score\n\n \tP -value\t\nParameter\tOverall DFS ( N =119)\tOverall OS ( N =119)\tHER2− DFS (N=95)\tHER2− OS (N=95)\t\nTreatment, ZOL vs no ZOL\t0.14\t0.17\t0.36\t0.32\t\nPropensity score\t0.038\t0.02\t0.026\t0.023\t\nER status, ER+ vs ER−\t0.0012\t0.0042\t0.025\t0.022\t\nTreatment by ER status, interaction\t0.01\t0.025\t0.064\t0.052\t\nAbbreviations: DFS=disease-free survival; ER=oestrogen receptor; HER2=human epidermal growth factor receptor-2; OS=overall survival; ZOL=zoledronic acid.\n\nTable 3 Risk of recurrence or death by tumour subtype and treatment arm\n\n \tHazard ratio (95% confidence interval)\t\nParameter\tOverall DFS\tOverall OS\tHER2− DFS\tHER2− OS\t\nTreatment in ER−\t0.361 (0.148, 0.880)\t0.375 (0.143, 0.985)\t0.374 (0.125, 1.12)\t0.306 (0.091, 1.04)\t\nTreatment in ER+\t2.43 (0.748, 7.90)\t3.07 (0.626, 15.1)\t1.78 (0.512, 6.21)\t2.32 (0.440, 12.2)\t\n \t \t \t \t \t\nER− vs ER+ in ZOL\t0.958 (0.377, 2.43)\t1.12 (0.391, 3.18)\t0.832 (0.262, 2.64)\t0.835 (0.222, 3.14)\t\nER− vs ER+ in no ZOL\t6.45 (2.08, 20.0)\t9.15 (2.01, 41.6)\t3.96 (1.19, 13.2)\t6.32 (1.31, 30.4)\t\n \t \t \t \t \t\nPropensity score, per 0.01 increase\t1.03 (1.002, 1.06)\t1.04 (1.01, 1.08)\t1.05 (1.01, 1.09)\t1.06 (1.01, 1.11)\t\nAbbreviations: DFS=disease-free survival; ER=oestrogen receptor; HER2=human epidermal growth factor receptor-2; OS=overall survival; ZOL=zoledronic acid.\n\nTreatment is ZOL vs no ZOL.\n\nR Aft and M Naughton have received honoraria from Novartis. The remaining authors have no conflict of interest.\n==== Refs\nAft R (2011) Bisphosphonates in breast cancer: clinical activity and implications of preclinical data. Clin Adv Hematol Oncol 9 (3): 194–20521475125\nAft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-Macgregor M, Zhai J, Kuo S, Shannon W, Diemer K, Herrmann V, Dietz J, Ali A, Ellis M, Weiss P, Eberlein T, Ma C, Fracasso PM, Zoberi I, Taylor M, Gillanders W, Pluard T, Mortimer J, Weilbaecher K (2010) Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 11 (5): 421–42820362507\nBerry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295 (14): 1658–166716609087\nBraun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353 (8): 793–80216120859\nChavez-MacGregor M, Gonzalez-Angulo AM (2010) Breast cancer, neoadjuvant chemotherapy and residual disease. Clin Transl Oncol 12 (7): 461–46720615822\nColeman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, Gil M, Houston SJ, Grieve RJ, Barrett-Lee PJ, Ritchie D, Pugh J, Gaunt C, Rea U, Peterson J, Davies C, Hiley V, Gregory W, Bell R (2011) Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365 (15): 1396–140521995387\nColeman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H (2010) The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 102 (7): 1099–110520234364\nEidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R (2010) Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Ann Oncol 21 (11): 2188–219420444845\nFerlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127 (12): 2893–291721351269\nGnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rucklinger E, Greil R, Marth C (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360 (7): 679–69119213681\nGnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R (2011a) Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12 (7): 631–64121641868\nGnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Poestlberger S, Dubsky PC, Jakesz R, Singer CF, Eidtmann H, Greil R (2011b) Overall survival with adjuvant zoledronic acid in patients with premenopausal breast cancer with complete endocrine blockade: long-term results from ABCSG-12 (abstract). J Clin Oncol 29 (Suppl): Abstract 520\nHillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21 (21): 4042–405712963702\nLin AY, Park JW, Scott J, Melisko M, Goga A, Moasser MM, Moore DH, Rugo HS (2008) Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow (abstract). J Clin Oncol 26 (S15): 559\nMcAllister SS, Weinberg RA (2010) Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28 (26): 4022–402820644094\nMobus V, Diel IJ, Elling D, Harbeck N, Jackisch C, Thomssen C, Untch M, Conrad B, Schneeweiss A, Kreienberg R, Huober J, Muller V, Luck HJ, Bauerfeind I, Loibl S, Nekljudova V, von Minckwitz G (2011) GAIN study: a phase III trial to compare ETC vs EC-TX and ibandronate vs observation in patients with node-positive primary breast cancer – 1st interim efficacy analysis (abstract). 34th Annual San Antonio Breast Cancer Symposium 6–10 December, 2011; San Antonio, TX. Abstract S2–4\nNeville-Webbe HL, Gnant M, Coleman RE (2010) Potential anticancer properties of bisphosphonates. Semin Oncol 37 (Suppl 1): S53–S6520682373\nPantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6 (6): 339–35119399023\nPark IH, Ro J, Nam BH, Kwon Y, Lee KS (2009) Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases. BMC Cancer 9 : 154 19454038\nPaterson AHG, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE, Swain SM, Costantino JP, Mamounas EP, Wolmark N (2011) NSABP protocol B-34: a clinical trial comparing adjuvant clodronate vs placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy—final analysis. 34th Annual San Antonio Breast Cancer Symposium 6–10 December, 2011; San Antonio, TX. Abstract S2–3\nRack B, Juckstock J, Genss EM, Schoberth A, Schindlbeck C, Strobl B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese K, Janni W (2010) Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 30 (5): 1807–181320592383\nSolomayer E, Gebauer G, Hirnle P, Janni W, Lück H-J, Becker S, Huober J, Kraemer B, Wackwitz B, Fehm T (2009) Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients (abstract). Cancer Res 69 (2 Suppl 1): 170s–171s, . Abstract 2048\nVon Minckwitz G, Kaufmann M, Kuemmel S, Fasching PA, Eiermann W, Blohmer JU, Costa SD, Hilfrich J, Jackisch C, Gerber B, Du Bois A, Huober JB, Hanusch CA, Konecny GE, Fett W, Stickeler E, Harbeck N, Mehta K, Loibl S, Untch M (2011) Correlation of various pathologic complete response (pCR) definitions with long-term outcome and the prognostic value of pCR in various breast cancer subtypes: results from the German neoadjuvant meta-analysis. J Clin Oncol 29 (S15): 1028\nWeilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11 (6): 411–42521593787\n\n",
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"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D004164:Diphosphonates; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009376:Neoplasms, Hormone-Dependent; D011960:Receptors, Estrogen; D000077211:Zoledronic Acid",
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"title": "Effect of (Neo)adjuvant zoledronic acid on disease-free and overall survival in clinical stage II/III breast cancer.",
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"abstract": "Distant metastases (DM) from childhood differentiated thyroid carcinoma (DTC) are uncommon and published studies are limited.\n\n\n\nThis work aimed to describe the outcomes of patients with DM from childhood DTC and to evaluate the molecular landscape of these tumors.\n\n\n\nA retrospective study was conducted at a tertiary cancer center including patients with pediatric DTC (diagnosed at age ≤ 18 years from 1946 to 2019) and DM.\n\n\n\nWe identified 148 patients; 144 (97%) had papillary thyroid carcinoma (PTC) and 104 (70%) were female. Median age at DTC diagnosis was 13.4 years (interquartile range [IQR], 9.9-15.9 years). Evaluable individuals received a median of 2 (IQR, 1-3) radioactive iodine (RAI) treatments at a median cumulative administered activity of 238.0 mCi (IQR, 147.5-351.0 mCi). The oncogenic driver was determined in 64 of 69 PTC samples: RET fusion (38/64; 59%), NTRK1/3 fusions (18/64; 28%), and the BRAF V600E mutation (8/64; 13%). At last evaluation, 93% had persistent disease. The median overall and disease-specific survival after DTC diagnosis were 50.7 and 52.8 years, respectively. Eight (5%) PTC patients died of disease after a median of 30.7 years (IQR, 20.6-37.6 years).\n\n\n\nChildhood DTC with DM persists in most patients despite multiple courses of RAI, but disease-specific death is uncommon, typically occurring decades after diagnosis. Fusion genes are highly prevalent in PTC, and all identified molecular alterations have appropriate targeted therapies. Future studies should focus on expanding genotype-phenotype correlations, determining how to integrate molecularly targeted therapy into treatment paradigms, and relying less on repeated courses of RAI to achieve cure in patients with DM from childhood DTC.",
"affiliations": "Department of Endocrinology, Internal Medicine, University of Groningen, University Medical Center Groningen, GZ Groningen, the Netherlands.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Abdominal Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrinology, Internal Medicine, University of Groningen, University Medical Center Groningen, GZ Groningen, the Netherlands.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Nies|Marloes|M|;Vassilopoulou-Sellin|Rena|R|;Bassett|Roland L|RL|;Yedururi|Sireesha|S|;Zafereo|Mark E|ME|;Cabanillas|Maria E|ME|;Sherman|Steven I|SI|;Links|Thera P|TP|;Waguespack|Steven G|SG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/clinem/dgaa935",
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"issn_linking": "0021-972X",
"issue": "106(4)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": "fusion gene; lung metastasis; pediatric thyroid cancer; prognosis; somatic mutation; stage II",
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D002454:Cell Differentiation; D002648:Child; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D012189:Retrospective Studies; D013964:Thyroid Neoplasms",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "e1683-e1697",
"pmc": null,
"pmid": "33382403",
"pubdate": "2021-03-25",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27129982;20553841;26963949;19355831;7990760;17011421;31456750;28209747;19631341;16919778;28476228;27494611;18929686;30924609;25417114;24795243;10873043;26649796;27849443;20860418;32813019;31533238;25201796;30022382;31085772;31072837;29108474;25900731;9702543;32517539;32556222;9170425;27824297;21113590;23533233;32190019;32737449;17724004;25316293;20087589;25210762;28521635;31363334;15072704;16552205;26367451;17536106;3680475;23678260;14752883;26717936;30272236;19777194;31540418;18502335;26307021;31078660;21626048;32495721;27482611;23616148;31012956;29030676;10197078;21484047;8435810;27809646;23327804",
"title": "Distant Metastases From Childhood Differentiated Thyroid Carcinoma: Clinical Course and Mutational Landscape.",
"title_normalized": "distant metastases from childhood differentiated thyroid carcinoma clinical course and mutational landscape"
} | [
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"literaturereference": "Nies M, Vassilopoulou-Sellin R, Bassett RL, Yedururi S, Zafereo ME, Cabanillas ME, Sherman SI, Links TP, Waguespack SG. Distant Metastases From Childhood Differentiated Thyroid Carcinoma: Clinical Course and Mutational Landscape. J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1683-e1697. doi: 10.1210/clinem/dgaa935.",
"literaturereference_normalized": "distant metastases from childhood differentiated thyroid carcinoma clinical course and mutational landscape",
"qualification": "1",
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"receiptdate": "20211001",
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{
"abstract": "BACKGROUND\nUntil now, the prevalence of macrolide-resistant Mycoplasma pneumoniae (MP) infection among adult patients has been low, and severe MP pneumonia due to a macrolide-resistant strain has seldom been reported. Here, we describe a rare case of severe life-threatening MP pneumonia due to a macrolide-resistant strain in an adult, which was finally treated with fluoroquinolone and tetracycline after failed treatment with macrolide and corticosteroid.\n\n\nMETHODS\nA 39-year-old apparently healthy woman complained of fever and productive cough. Three days after onset, she was admitted to a local general hospital. On admission, her vital signs were stable except for high-grade fever. The patient's chest X-ray and chest computed tomography images revealed subsegmental consolidation in her right lower lobe. Treatment with ampicillin/sulbactam, and azithromycin were initiated under a clinical diagnosis of community-acquired pneumonia. After treatment initiation, her fever had not subsided, and the pulmonary lesion had extended to the entire lower lobe. Thus, treatment with prednisolone as steroid pulse therapy was initiated from clinical day 7. However, neither her symptoms nor her pulmonary lesion improved; therefore, she was transferred to our hospital for further examination and treatment. On admission (clinical day 14), her indirect hemagglutination titer for MP was elevated at 1:2560, and bronchoalveolar fluid examination yielded positive results for the mycoplasma antigen. Based on these clinical findings, we confirmed a case of severe life-threatening MP pneumonia. Since her respiratory condition was extremely severe, we initiated levofloxacin and tetracycline. Two days later (clinical day 16), her fever, malaise, and hypoxia resolved, and her pulmonary lesions had significantly improved. Further molecular identification yielded the DNA of MP from her bronchoalveolar fluid, and mutation of A2063G in the 23S rRNA gene was revealed. Based on these results and the clinical course, we confirmed our case as severe MP pneumonia due to a macrolide-resistant strain.\n\n\nCONCLUSIONS\nMore awareness is needed on the emergence of macrolide-resistant MP infection in adults, because severe infection could develop despite initial treatment with macrolide and steroid therapy, which are generally considered as standard therapy for MP.",
"affiliations": "Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. [email protected].;Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Division of Respiratory Medicine, Iwamizawa Municipal General Hospital, Iwamizawa, Japan.;Division of Respiratory Medicine, Iwamizawa Municipal General Hospital, Iwamizawa, Japan.;Department of Infection Control, Hokkaido University Hospital, Sapporo, Japan.;Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.",
"authors": "Matsumoto|Munehiro|M|;Nagaoka|Kentaro|K|http://orcid.org/0000-0003-3484-4554;Suzuki|Masaru|M|;Konno|Satoshi|S|;Takahashi|Kei|K|;Takashina|Taichi|T|;Ishiguro|Nobuhisa|N|;Nishimura|Masaharu|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides; D012338:RNA, Ribosomal, 23S; D064704:Levofloxacin; D017963:Azithromycin; D013752:Tetracycline",
"country": "England",
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"doi": "10.1186/s12879-019-3846-1",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 384610.1186/s12879-019-3846-1Case ReportAn adult case of severe life-threatening Mycoplasma pneumoniae pneumonia due to a macrolide-resistant strain, Japan: a case report Matsumoto Munehiro [email protected] 1http://orcid.org/0000-0003-3484-4554Nagaoka Kentaro [email protected] 1Suzuki Masaru [email protected] 1Konno Satoshi [email protected] 1Takahashi Kei [email protected] 2Takashina Taichi [email protected] 2Ishiguro Nobuhisa [email protected] 3Nishimura Masaharu [email protected] 11 0000 0001 2173 7691grid.39158.36Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2 Division of Respiratory Medicine, Iwamizawa Municipal General Hospital, Iwamizawa, Japan 3 0000 0004 0378 6088grid.412167.7Department of Infection Control, Hokkaido University Hospital, Sapporo, Japan 28 2 2019 28 2 2019 2019 19 20424 8 2018 22 2 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nUntil now, the prevalence of macrolide-resistant Mycoplasma pneumoniae (MP) infection among adult patients has been low, and severe MP pneumonia due to a macrolide-resistant strain has seldom been reported. Here, we describe a rare case of severe life-threatening MP pneumonia due to a macrolide-resistant strain in an adult, which was finally treated with fluoroquinolone and tetracycline after failed treatment with macrolide and corticosteroid.\n\nCase presentation\nA 39-year-old apparently healthy woman complained of fever and productive cough. Three days after onset, she was admitted to a local general hospital. On admission, her vital signs were stable except for high-grade fever. The patient’s chest X-ray and chest computed tomography images revealed subsegmental consolidation in her right lower lobe. Treatment with ampicillin/sulbactam, and azithromycin were initiated under a clinical diagnosis of community-acquired pneumonia. After treatment initiation, her fever had not subsided, and the pulmonary lesion had extended to the entire lower lobe. Thus, treatment with prednisolone as steroid pulse therapy was initiated from clinical day 7. However, neither her symptoms nor her pulmonary lesion improved; therefore, she was transferred to our hospital for further examination and treatment. On admission (clinical day 14), her indirect hemagglutination titer for MP was elevated at 1:2560, and bronchoalveolar fluid examination yielded positive results for the mycoplasma antigen. Based on these clinical findings, we confirmed a case of severe life-threatening MP pneumonia. Since her respiratory condition was extremely severe, we initiated levofloxacin and tetracycline. Two days later (clinical day 16), her fever, malaise, and hypoxia resolved, and her pulmonary lesions had significantly improved.\n\nFurther molecular identification yielded the DNA of MP from her bronchoalveolar fluid, and mutation of A2063G in the 23S rRNA gene was revealed. Based on these results and the clinical course, we confirmed our case as severe MP pneumonia due to a macrolide-resistant strain.\n\nConclusion\nMore awareness is needed on the emergence of macrolide-resistant MP infection in adults, because severe infection could develop despite initial treatment with macrolide and steroid therapy, which are generally considered as standard therapy for MP.\n\nKeywords\nMycoplasma pneumoniaePneumoniaMacrolide-resistanceAdultissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMycoplasma pneumoniae (M. pneumoniae; MP) is a major cause of community-acquired pneumonia in children and adults [1]. MP pneumonia (MPP), often described as a self-limiting disease, is typically mild and cured without medication. However, approximately 0.5–2% of all MPP cases is known to present a fulminant course with severe complications such as respiratory failure [2]. For the treatment of severe life-threatening MPP, early administration of anti-mycoplasma drugs, such as macrolides (erythromycin, clarithromycin, and azithromycin), and corticosteroids has been recognized as advantageous [2–4]. Recently, the prevalence of macrolide-resistant MP has emerged in several countries, including Asia, Europe, and the United States [5–7]. More than 60% of MP strains among pediatric patients in Japan have been reported to possess a macrolide-resistance mutation [8]. In contrast, the prevalence of macrolide-resistant MP infection among adult patients has, thus far, been considered low [9], and severe MPP due to a macrolide-resistant strain has rarely been reported. Here, we describe a case of severe life-threatening MPP due to a macrolide-resistant strain (23S rRNA gene A2063G) in an adult, which was finally treated with fluoroquinolone and tetracycline after failed treatment with macrolide and corticosteroid therapy.\n\nCase presentation\nA 39-year-old apparently healthy woman complained of fever and productive cough, in March, 2017. Her medical history did not reveal any specific illness, including acquired immune deficiency syndrome, collagen disease, and congenital immunodeficiency. She neither smoked nor consumed alcohol. Three days after onset (clinical day 3), she was admitted to a local general hospital, owing to progressive fever, malaise, and anorexia. On admission, her vital signs were as follows: body temperature, 39.2 °C; blood pressure, 106/64 mmHg; pulse, 80 beats/min with a regular rhythm; SpO2, 97% in an air-conditioned room; and respiratory rate, 16 breaths/min. Cyanosis, cardiac murmur, and abnormal breath sounds were absent. The patient’s liver, spleen and lymph nodes were not palpable. Her white blood cell count was 5600/μL, with a shift to the left (81.2% neutrophils). Her aspartate aminotransferase level was 23 IU/L; alanine aminotransferase, 12 IU/L; lactate dehydrogenase, 206 IU/L; and C-reactive protein, 2.4 mg/dL (normal range, 0–0.3 mg/dL). Moreover, the patient’s chest X-ray and chest computed tomography (CT) images revealed subsegmental consolidation in her right lower lobe (Figs. 1a, f). After admission, administration of ampicillin/sulbactam (ABPC/SBT), at 6 g/day, was initiated under a clinical diagnosis of severe community-acquired pneumonia. Azithromycin (AZM) was also given at 2 g/day p.o. stat on clinical day 3 (Fig. 2). Her indirect hemagglutination titer for MP was negative (1:40) on clinical day 4. After admission (clinical day 7), her fever had not subsided, and the pulmonary lesions had extended to the entire right lower lobe as well as to the left lower lobe (Figs. 1b, g). Thus, bronchoalveolar lavage (BAL) and a transbronchial biopsy of the right lower lobe were performed. These examinations revealed nonspecific inflammation with neutrophil infiltration, but no pathogen was identified on pathological or microbiological examination. Contrary to the extremely rapid progression of the pulmonary lesions, her general condition had not significantly deteriorated, which was not compatible with severe bacterial infection. Owing to the unique clinical presentation, organizing pneumonia was considered. Therefore, treatment with prednisolone (PSL) was initiated at 40 mg/day from clinical day 7, and steroid pulse therapy (methylprednisolone 1 g/day) was given on clinical days 10–12. However, neither her symptoms nor her pulmonary lesion improved (Figs. 1 c, h). Rather, her respiratory failure had worsened significantly, after steroid pulse therapy (clinical day 14), as she required oxygen inhalation at 15 L/min on her motion; therefore, she was transferred to our hospital (Hokkaido University hospital) for further examination and treatment. Considering the existence of lower respiratory tract infection due to any rare pathogens, ABPC/SBT was changed to meropenem (MEPM) on clinical day 14, and levofloxacin (LVFX) and minocycline (MINO) were also initiated concurrently. On admission (clinical day 14), her indirect hemagglutination titer for MP had elevated to 1:2560, which was more than that identified on clinical day 4 at the referring hospital. Moreover, BAL fluid (BALF) examination, which was performed on the day of admission to our hospital, using Ribotest™ Mycoplasma (Asahi Kasei Pharma Corporation, Japan), yielded positive results for the mycoplasma antigen. No other pathogen was identified on microbiological examination of the BALF. Based on these clinical findings, we confirmed our case as severe life-threatening MP pneumonia. Thereafter, we continued empirical antibiotic therapy with LVFX, MINO and MEPM, and corticosteroid therapy with PSL at 40 mg/day. Two days later (clinical day 16), her fever, malaise, and hypoxia had resolved, and her pulmonary lesions had significantly improved (Fig. 1d). Therefore, we replaced the antibiotics with garenoxacin (GRNX) as monotherapy, at 400 mg/day, and reduced the dosage of PSL from clinical day 18. The patient was discharged on day 24, and administration of GRNX and corticosteroid therapy were continued until clinical day 30 (Fig. 2). Subsequently, she had an uneventful recovery with no recurrence of fever or pneumonia.Fig. 1 Chest X-ray image (A, B, C and D) and chest CT image (F, G and H) of the thorax. 10 days before admission to our hospital (clinical day 3), the chest images revealed sub-segmental infiltration in the right lower lobe, which enlarged to bilateral lower lung field from clinical day 7 to 14. After switching the antibiotics, the chest images improved until clinical day 16\n\nFig. 2 Treatment course. m-PSL: methylprednisolone, PSL: prednisolone, AZM: azithromycin, ABPC/SBT: ampicillin/sulbactam, MEPM: meropenem, LVFX: levofloxacin, MINO: minomycin, GRNX: garenoxacin\n\n\n\nDue to the rarity of our patient’s clinical course, we performed further molecular identification using DNA extracted from her BALF. DNA of MP was identified by real-time polymerase chain reaction (PCR) with Mp181-F and Mp181-R primer pairs and an Mp181-P probe [10]. A previously described RFLP analysis of point mutation in domain V of MP 23SrRNA gene [11] was used to identify mutations known to confer macrolide resistance (2063, 2064, and 2617 in the MP 23S rRNA gene domain V region). The result of the molecular analysis was positive for A2063G mutation, which was, at that time, a common macrolide-resistant mutant of MP in Japan. Based on these results and the clinical course, we confirmed our case as severe MP pneumonia due to a macrolide-resistant strain.\n\nDiscussion and conclusions\nIn this report, we describe a severe life-threatening case of MPP due to a macrolide-resistant strain. In our case, the initial therapy involving high-dose administration of AZM and corticosteroids was ineffective, and LVFX and MINO were necessary for an improvement in clinical symptoms and reduction in pulmonary lesions. The possibility of bacterial co-infection remained; thus, another antibiotic (MEPM) was administered. However, the clinical course and CT manifestations were not compatible with general bacterial infection, and the repetitively negative bacterial culture from respiratory tract specimens could not fully explain the presence of extensive pulmonary lesions. Hence, we considered that the extreme deterioration noted until clinical day 14 was largely due to macrolide-resistant MPP.\n\nRecently, the prevalence of macrolide-resistant MP isolates has increased worldwide. The most frequent mechanism underlying the resistance is an A-to-G mutation at position 2063 of MP 23S rRNA gene domain V (A2063G), followed by A2063T, A2064G, and A2063C [12]. As previously reported, failure of the initial treatment with macrolides against macrolide-resistant MPP often results in prolonged fever and cough; however, respiratory failure or a fatal course are rare [12–14]. Macrolide-resistant MPP likely did not progress to severe infection owing to its less efficient protein synthesis, caused by a point mutation within its rRNA [15]. Because MP has only one rRNA operon for constructing ribosomes, a point mutation in a macrolide-resistant strain might exclusively affect ribosomal activity.\n\nSome cases of MPP may be life-threatening, involving severe respiratory failure or fatality, and are occasionally defined as fulminant MPP [2–4]. In those life-threatening MPP cases, the average duration from the onset of infection to the development of respiratory failure is reported to be 9–15 days [2]; these cases include those involving deterioration after the administration of certain therapies, such as macrolide or steroid therapy. As respiratory failure development was noted in our case until clinical day 14, we considered that this case was likely of the severe life-threatening/fulminant type.\n\nRecognized as the mechanism and etiology of severe/fulminant MPP, the host’s cellular hyper-immune response to MP is considered to play a central role in disease progression [2]. As MP has no bacterial cell wall, antibiotics that inhibit DNA synthesis, such as macrolides, tetracycline, and fluoroquinolone, are commonly used to treat MP infection. In addition, corticosteroids are broadly recommended for severe/fulminant MPP cases, which present with a hyperactive immune response [2–4]. Izumikawa et al. reported that a relatively high dose of methylprednisolone (> 500 mg/day) combined with appropriate anti-mycoplasma agents effectively improved symptoms in a majority of fulminant MPP cases within 3–5 days [16]. Miyashita et al. recommended the initiation of corticosteroid therapy for severe MPP cases with a serum LDH level above 364 IU/L [17]. However, a definitive treatment for fulminant MPP, in particular that caused by a macrolide-resistant strain, has not been established.\n\nTo date, there exist only few reports describing fulminant MPP cases resistant to macrolide and steroid therapy. In a pediatric case, Shen et al. described fulminant MPP due to a macrolide-resistant strain, in which drug-susceptibility was confirmed by cultures [18]. In this case, MPP exacerbated after the administration of AZM and standard-dose methylprednisolone (2 mg/kg/day), and improvement was finally noted after switching antibiotic treatment to moxifloxacin with intravenous immunoglobulin. In an adult case, Kawakami et al. reported that fulminant MPP exacerbated despite the administration of AZM and prednisolone 30 mg/day, but that improvement was noted after minocycline administration [19]. Similar to these cases, our case of MPP also showed rapid improvement after fluoroquinolone and minocycline addition. Overall, we propose that not only hyper-immune activity, but also MP proliferation, may play a critical role in severe/fulminant MPP due to a macrolide-resistant strain. Thus, treatment using fluoroquinolone or tetracycline for suppressing MP proliferation might be indispensable in these cases.\n\nIn our case, rapid antigen test was not available in the referring hospital, and definite diagnosis was confirmed on clinical day 14. Although serological antibody test is generally accepted as a standard method for the diagnosis of MPP, it is not suitable for MPP-diagnosis during the acute phase since it requires paired serum samples with a 2–4-week interval [20]. In this situation, immunochromatography-based rapid mycoplasma antigen test, Ribotest™ Mycoplasma, has become available in Japan, since 2013 [21]. This test detects the M. pnuemoniae L7/12 ribosomal protein, a component of the 50S ribosome, and its diagnostic sensitivity for MPP has been reported as approximately 60% that of real-time PCR [21]. Until now, the clinical experience and data on Ribotest are still limited only to Japan, and its utility in the management of adult MPP remains unclear. In our case, the Ribotest on BALF performed on clinical day 14 was positive, which proved the existence of a longer-lasting MP pulmonary infection. Since MP has been found to be larger amount in sputum than in upper respiratory tract samples [22, 23], it might be more useful to examine BALF, which is the most directly sampled lower respiratory tract specimen, using Ribotest. At least, had an immediate diagnosis been made for our patient, we could have selected appropriate antibiotics at an earlier stage, which might have achieved more rapid improvement. Considering the difficulty of MPP diagnosis, in particular cases due to macrolide-resistant strains, we suggest that further study might be necessary, which examine the utility of rapid antigen test.\n\nTo the best of our knowledge, the present report is the first documented case of severe life-threatening MPP due to a macrolide-resistant strain, which macrolide-resistance was confirmed by genetic analysis. Based on the experience gained from our present case, we suggest that severe MPP due to a macrolide-resistant strain should be considered as a differential diagnosis, when one encounters cases of deteriorating community-acquired pneumonia. This is particularly important when antibiotics other than fluoroquinolone or tetracycline have been administered. The high prevalence of macrolide-resistant MP worldwide should also be recognized, because similar cases of life-threatening MPP may be substantially underdiagnosed.\n\nIn conclusion, we report the rare case of severe life-threatening MPP caused by a macrolide-resistant strain in an adult. It highlights the importance of appropriate selection of anti-mycoplasma drugs in the treatment of this condition. In addition, more awareness is needed on the emergence of macrolide-resistant MPP infection, especially in cases where severe infection develops after initial treatment failure.\n\nAbbreviations\nABPC/SBTAmpicillin/sulbactam\n\nAZMAzithromycin\n\nBALBronchoalveolar lavage\n\nBALFBronchoalveolar lavage fluid\n\nCTComputed tomography\n\nGRNXGarenoxacin\n\nLVFXLevofloxacin\n\nMEPMMeropenem\n\nMINOMinocycline\n\nMP\nMycoplasma pneumoniae\n\n\nPSLPrednisolone\n\nAcknowledgements\nThe authors thank Miki Kaiho of the Department of Pediatrics, Hokkaido University Hospital, Japan for her excellent technical support.\n\nFunding\nNo funding received.\n\nAvailability of data and materials\nAll the information supporting our conclusions and relevant references are included in the manuscript. There are no datasets related to this case report.\n\nAuthors’ contributions\nMM, KN, MS, SK, KT, and TT contributed to the management of this patient. KN was the leader of the clinical team. MM and KN conducted the literature review and wrote the manuscript. MN revised the article. NI contributed to molecular identification. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Principi N Esposito S Macrolide-resistant Mycoplasma pneumoniae : its role in respiratory infection J Antimicrob Chemother 2013 68 506 511 10.1093/jac/dks457 23169891 \n2. Izumikawa K Clinical features of severe or fatal Mycoplasma pneumoniae pneumonia Front Microbiol 2016 1 7 800 10.3389/fmicb.2016.00800.eCollection2016. \n3. Chan ED Welsh CH Fulminant Mycoplasma pneumoniae pneumonia West J Med 1995 162 133 142 7725685 \n4. Miyashita N Obase Y Ouchi K Kawasaki K Kawai Y Kobashi Y Oka M Clinical features of severe Mycoplasma pneumoniae pneumonia in adults admitted to an intensive care unit J Med Microbiol 2007 56 1625 1629 10.1099/jmm.0.47119-0 18033831 \n5. Li X Atkinson TP Hagood J Makris C Duffy LB Waites KB Emerging macrolide resistance in Mycoplasma pneumoniae in children: detection and characterization of resistant isolates Pediatr Infect Dis J 2009 28 693 696 10.1097/INF.0b013e31819e3f7a 19633515 \n6. Pereyre S Charron A Renaudin H Bébéar C Bébéar CM First report of macrolide-resistant strains and description of a novel nucleotide sequence variation in the P1 adhesin gene in Mycoplasma pneumoniae clinical strains isolated in France over 12 years J Clin Microbiol 2007 45 3534 3539 10.1128/JCM.01345-07 17881549 \n7. Eshaghi A, Memari N, Tang P, Olsha R, Farrell DJ, Low DE, Gubbay JB, Patel SN. Macrolide-resistant Mycoplasma pneumoniae in humans, Ontario, Canada, 2010-2011. Emerg Infect Dis. 2013;19.\n8. Kawai Y Miyashita N Kubo M Akaike H Kato A Nishizawa Y Saito A Kondo E Teranishi H Wakabayashi T Ogita S Tanaka T Kawasaki K Nakano T Terada K Ouchi K Nationwide surveillance of macrolide-resistant Mycoplasma pneumoniae infection in pediatric patients Antimicrob Agents Chemother 2013 57 4046 4049 10.1128/AAC.00663-13 23716043 \n9. Miyashita N Oka M Atypical pathogen study group, Kawai Y, Yamaguchi T, Ouchi K. Macrolide-resistant Mycoplasma pneumoniae in adults with community-acquired pneumonia Int J Antimicrob Agents 2010 36 384 385 10.1016/j.ijantimicag.2010.06.009 20674283 \n10. Winchell JM Thurman KA Mitchell SL Thacker WL Fields BS Evaluation of three real-time PCR assays for detection of mycoplasma pneumoniae in an outbreak investigation J Clin Microbiol 2008 46 3116 3118 10.1128/JCM.00440-08 18614663 \n11. Matsuoka M Narita M Okazaki N Ohya H Yamazaki T Ouchi K Suzuki I Andoh T Kenri T Sasaki Y Horino A Shintani M Arakawa Y Sasaki T Characterization and molecular analysis of macrolide-resistant Mycoplasma pneumoniae clinical isolates obtained in Japan Antimicrob Agents Chemother 2004 48 4624 4630 10.1128/AAC.48.12.4624-4630.2004 15561835 \n12. Kawai Y Miyashita N Kubo M Akaike H Kato A Nishizawa Y Saito A Kondo E Teranishi H Ogita S Tanaka T Kawasaki K Nakano T Terada K Ouchi K Therapeutic efficacy of macrolides, minocycline, and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae pneumonia in pediatric patients Antimicrob Agents Chemother 2013 57 2252 2258 10.1128/AAC.00048-13 23459497 \n13. Ishiguro N Koseki N Kaiho M Ariga T Kikuta H Togashi T Oba K Morita K Nagano N Nakanishi M Hara K Hazama K Watanabe T Yamanaka T Sasaki S Furuyama H Shibata M Shida S Ishizaka A Tabata Y Aoyagi H Naito H Yoshioka M Horino A Kenri T Hokkaido pediatric respiratory infection study group. Therapeutic efficacy of azithromycin, clarithromycin, minocycline and tosufloxacin against macrolide-resistant and macrolide-sensitive Mycoplasma pneumoniae pneumonia in pediatric patients PLoS One 2017 12 3 e0173635 10.1371/journal.pone.0173635.eCollection2017 28288170 \n14. Miyashita N Akaike H Teranishi H Ouchi K Okimoto N Macrolide-resistant Mycoplasma pneumoniae pneumonia in adolescents and adults: clinical findings, drug susceptibility, and therapeutic efficacy Antimicrob Agents Chemother 2013 57 5181 5185 10.1128/AAC.00737-13 23896480 \n15. Narita M Two unexpected phenomena in macrolide-resistant Mycoplasma pneumoniae infection in Japan and the unique biological characteristics of Mycoplasma pneumoniae J Infect Chemother 2011 17 735 736 10.1007/s10156-011-0235-0 21437678 \n16. Izumikawa K Izumikawa K Takazono T Kosai K Morinaga Y Nakamura S Kurihara S Imamura Y Miyazaki T Tsukamoto M Yanagihara K Hara K Kohno S Clinical features, risk factors and treatment of fulminant Mycoplasma pneumoniae pneumonia: a review of the Japanese literature J Infect Chemother 2014 20 181 185 10.1016/j.jiac.2013.09.009 24462437 \n17. Miyashita N Kawai Y Inamura N Tanaka T Akaike H Teranishi H Wakabayashi T Nakano T Ouchi K Okimoto N Setting a standard for the initiation of steroid therapy in refractory or severe Mycoplasma pneumoniae pneumonia in adolescents and adults J Infect Chemother 2015 21 153 160 10.1016/j.jiac.2014.10.008 25533771 \n18. Shen Y Zhang J Hu Y Shen K Combination therapy with immune-modulators and moxifloxacin on fulminant macrolide-resistant Mycoplasma pneumoniae infection: a case report Pediatr Pulmonol 2013 48 519 522 10.1002/ppul.22650 22949411 \n19. Kawakami N Namkoong H Ohata T Sakaguchi S Saito F Yuki H A fulminant case of acute respiratory distress syndrome associated with Mycoplasma Pneumonia treated with nasal high-flow oxygen therapy Case Rep Crit Care 2018 2018 1067593 30420924 \n20. Thurman KA Walter ND Schwartz SB Mitchell SL Dillon MT Baughman AL Deutscher M Fulton JP Tongren JE Hicks LA Winchell JM Comparison of laboratory diagnostic procedures for detection of Mycoplasma pneumoniae in community outbreaks Clin Infect Dis 2009 48 1244 1249 10.1086/597775 19331586 \n21. Miyashita N Kawai Y Kato T Tanaka T Akaike H Teranishi H Nakano T Ouchi K Okimoto N Rapid diagnostic method for the identification of mycoplasma pneumoniae respiratory tract infection J Infect Chemother 2016 22 327 330 10.1016/j.jiac.2016.02.005 26993174 \n22. Dorigo-Zetsma JW Verkooyen RP van Helden HP van der Nat H van den Bosch JM Molecular detection of mycoplasma pneumoniae in adults with community-acquired pneumonia requiring hospitalization J Clin Microbiol 2001 39 1184 1186 10.1128/JCM.39.3.1184-1186.2001 11230455 \n23. Räty R Rönkkö E Kleemola M Sample type is crucial to the diagnosis of mycoplasma pneumoniae pneumonia by PCR J Med Microbiol 2005 54 287 291 10.1099/jmm.0.45888-0 15713613\n\n",
"fulltext_license": "CC BY",
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"issue": "19(1)",
"journal": "BMC infectious diseases",
"keywords": "Adult; Macrolide-resistance; Mycoplasma pneumoniae; Pneumonia",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D007564:Japan; D064704:Levofloxacin; D018942:Macrolides; D009154:Mutation; D009177:Mycoplasma pneumoniae; D011019:Pneumonia, Mycoplasma; D012338:RNA, Ribosomal, 23S; D013752:Tetracycline",
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"pmc": null,
"pmid": "30819124",
"pubdate": "2019-02-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11230455;15561835;15713613;17881549;18033831;18614663;19331586;19633515;20674283;21437678;22949411;23169891;23459497;23716043;23896480;23968896;24462437;25533771;26993174;27313568;28288170;30420924;7725685",
"title": "An adult case of severe life-threatening Mycoplasma pneumoniae pneumonia due to a macrolide-resistant strain, Japan: a case report.",
"title_normalized": "an adult case of severe life threatening mycoplasma pneumoniae pneumonia due to a macrolide resistant strain japan a case report"
} | [
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],
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},
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"literaturereference": "NAGAOKA K, MATSUMOTO M, SUZUKI M, KONNO S, TAKAHASHI K, TAKASHINA T. AN ADULT CASE OF SEVERE LIFE-THREATENING MYCOPLASMA PNEUMONIAE PNEUMONIA DUE TO A MACROLIDE-RESISTANT STRAIN, JAPAN: A CASE REPORT. BMC INFECT DIS. 2019 FEB 01?19(1):.",
"literaturereference_normalized": "an adult case of severe life threatening mycoplasma pneumoniae pneumonia due to a macrolide resistant strain japan a case report",
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},
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},
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},
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}
] |
{
"abstract": "BACKGROUND\nAnaphylaxis often misdiagnosed and treated as acute asthma, especially when it has a predominant respiratory symptom, and there are no obvious precipitants or previous allergic history. This morbid outcome is preventable if the level of suspicion for anaphylaxis is high among healthcare provider when treating a patient who is not responding to the standard management of acute asthma. A proportion of anaphylactic patient shows a biphasic reaction which potentially fatal when it is under-anticipated and prematurely discharge without adequate observation period after the recovery of the initial episode.\n\n\nMETHODS\nHere, we present a case of a young man who has childhood asthma with the last attack more than 10 years ago presented with symptoms suggestive of acute exacerbation of bronchial asthma. As the symptoms failed to improve after standard asthma management, anaphylaxis was suspected, and he was given intramuscular adrenaline 0.5 mg which leads to symptom improvement. However, he developed another attack shortly after improvement while under observation.\n\n\nCONCLUSIONS\nThe objective of this case report is to emphasise the importance of keeping anaphylaxis in mind whenever a patient has treatment-refractory asthma, and also the anticipation of biphasic reaction that warrants adequate observation period especially those who are likely to have developed it.",
"affiliations": "Faculty of Medicine and Health Science, Universiti Malaysia Sabah (UMS), Jalan UMS, 88400 Kota Kinabalu, Sabah, Malaysia.;Department of Internal Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.;Department of Internal Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.",
"authors": "Payus|Alvin Oliver|AO|;Ibrahim|Azliza|A|;Mustafa|Norlaila|N|",
"chemical_list": null,
"country": "North Macedonia",
"delete": false,
"doi": "10.3889/oamjms.2018.317",
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"issn_linking": "1857-9655",
"issue": "6(11)",
"journal": "Open access Macedonian journal of medical sciences",
"keywords": "Acute asthma; Anaphylaxis; Biphasic reaction; Intramuscular adrenaline 0.5 mg; Shortness of breath",
"medline_ta": "Open Access Maced J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101662294",
"other_id": null,
"pages": "2136-2138",
"pmc": null,
"pmid": "30559876",
"pubdate": "2018-11-25",
"publication_types": "D002363:Case Reports",
"references": "12204988;16453966;20143649;24909803",
"title": "\"Two Stones on One Bird\": A Case Report on Severe Biphasic Anaphylaxis Masquerading as Life-Threatening Acute Asthma.",
"title_normalized": "two stones on one bird a case report on severe biphasic anaphylaxis masquerading as life threatening acute asthma"
} | [
{
"companynumb": "MY-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-008150",
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"medicinalproduct": "COMBIVENT"
},
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{
"abstract": "We report here a case of esophageal cancer patient who developed tumor lysis syndrome after chemotherapy. A 57- year-old man received esophagectomy for advanced esophageal cancer. CT study revealed multiple lymphnode metastases, multiple bone metastases and multiple lung metastases after 15 months from the operation. So, chemotherapy was performed for the patient. Eleven days following the administration of docetaxel: 30 mg/m2 and nedaplatin: 30 mg/m2, the patient developed TLS (serum creatinine: 8.57 mg/dL, uric acid: 11.0 mg/dL, serum potassium: 6.3 mEq/L, serum phosphorus: 7.18 mg/dL). The patient responded well to an appropriate treatment with a combination of vigorous intravenous hydration, carperitide, allpurinol and potassium citrate sodium citrate. This case report describes the first patient to develop TLS following chemotherapy for esophageal cancer.",
"affiliations": "Dept. of Digestive Surgery and Surgical Oncology (Dept. of Surgery II), Yamaguchi University Graduate School of Medicine.",
"authors": "Tokunou|Kazuhisa|K|;Takeda|Shigeru|S|;Yoshino|Shigefumi|S|;Nishimura|Taku|T|;Oka|Masaaki|M|",
"chemical_list": "D009944:Organoplatinum Compounds; D043823:Taxoids; D000077143:Docetaxel; C053989:nedaplatin",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "35(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000077143:Docetaxel; D004938:Esophageal Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D043823:Taxoids; D014057:Tomography, X-Ray Computed; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2030-2",
"pmc": null,
"pmid": "19106513",
"pubdate": "2008-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of esophageal cancer patient who developed tumor lysis syndrome after chemotherapy.",
"title_normalized": "a case of esophageal cancer patient who developed tumor lysis syndrome after chemotherapy"
} | [
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"reaction": [
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"reactionmeddrapt": "Tumour lysis syndrome",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
"summary": null
},
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"literaturereference": "TOKUNOU, K.. A CASE OF ESOPHAGEAL CANCER PATIENT WHO DEVELOPED TUMOR LYSIS SYNDROME AFTER CHEMOTHERAPY. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY. 2008?35 (12):2030-2032",
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] |
{
"abstract": "Post-transplant lymphoproliferative disease (PTLD) often exhibits poor prognosis and high mortality, and there are no uniform guidelines for the treatment of this disease. Anti-CD19 chimeric antigen receptor (CAR) T cells show significant efficacy in treatment of relapse/refractory diffuse large B-cell lymphoma (DLBCL). Treatment using anti-CD19-CAR T-cell therapy in PTLD has been limited by immunosuppressants and has not been widely employed. In this study, a refractory post kidney transplant DLBCL patient with a high tumor burden was enrolled in a clinical trial of anti-CD19-CAR T-cell therapy. The tacrolimus dose was not decreased during combination chemotherapy, as the creatinine level of the patient increased. To improve the function of autologous T cells, combination therapy with anti-CD19-CAR T cells and programmed cell death 1 (PD-1) inhibitors was selected. After treatment with the combination therapy, the patient was diagnosed with grade 1 cytokine release syndrome and grade 3 immune effector cell-associated neurotoxicity syndrome. The amplification peak of anti-CD19-CAR T cells reached 9.01% on day 7. With PD-1 inhibitor maintenance therapy, his disease was maintained in partial remission for 18 weeks. However, his tumor suddenly increased in size, and he discontinued the treatment, including radiation therapy. The anti-CD19-CAR T cell and PD-1 inhibitors have a combined effect on PTLD, and this combination therapy needs to be further explored.",
"affiliations": "Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.;Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.;Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.;Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.;Shanghai Genbase Biotechnology Co. Ltd., Shanghai, China.;Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.;Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.",
"authors": "Feng|Gang|G|;Li|Qing|Q|;Zhu|Haibo|H|;Jiang|Yanyu|Y|;Yuan|Jijun|J|;Fu|Yingxin|Y|;Deng|Qi|Q|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.726134",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.726134\nOncology\nCase Report\nSafety and Efficacy of Anti-CD19-Chimeric Antigen Receptor T Cell Combined With Programmed Cell Death 1 Inhibitor Therapy in a Patient With Refractory Post-Transplant Lymphoproliferative Disease: Case Report and Literature Review\nFeng Gang 1\nLi Qing 2\n\nZhu Haibo 2\nJiang Yanyu 2\n\nYuan Jijun 3\nFu Yingxin 1 *\n\nDeng Qi 1 *\n\n1Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China\n2Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China\n3Shanghai Genbase Biotechnology Co. Ltd., Shanghai, China\nEdited by: Ling Xu, Jinan University, China\n\nReviewed by: Tijana Martinov, Fred Hutchinson Cancer Research Center, United States; Li Xuan, Southern Medical University, China\n\n*Correspondence: Qi Deng, [email protected]; Yingxin Fu, [email protected]\nThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n16 9 2021\n2021\n11 72613416 6 2021\n27 8 2021\nCopyright © 2021 Feng, Li, Zhu, Jiang, Yuan, Fu and Deng\n2021\nFeng, Li, Zhu, Jiang, Yuan, Fu and Deng\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nPost-transplant lymphoproliferative disease (PTLD) often exhibits poor prognosis and high mortality, and there are no uniform guidelines for the treatment of this disease. Anti-CD19 chimeric antigen receptor (CAR) T cells show significant efficacy in treatment of relapse/refractory diffuse large B-cell lymphoma (DLBCL). Treatment using anti-CD19-CAR T-cell therapy in PTLD has been limited by immunosuppressants and has not been widely employed. In this study, a refractory post kidney transplant DLBCL patient with a high tumor burden was enrolled in a clinical trial of anti-CD19-CAR T-cell therapy. The tacrolimus dose was not decreased during combination chemotherapy, as the creatinine level of the patient increased. To improve the function of autologous T cells, combination therapy with anti-CD19-CAR T cells and programmed cell death 1 (PD-1) inhibitors was selected. After treatment with the combination therapy, the patient was diagnosed with grade 1 cytokine release syndrome and grade 3 immune effector cell-associated neurotoxicity syndrome. The amplification peak of anti-CD19-CAR T cells reached 9.01% on day 7. With PD-1 inhibitor maintenance therapy, his disease was maintained in partial remission for 18 weeks. However, his tumor suddenly increased in size, and he discontinued the treatment, including radiation therapy. The anti-CD19-CAR T cell and PD-1 inhibitors have a combined effect on PTLD, and this combination therapy needs to be further explored.\n\npost-transplant lymphoproliferative disease\ndiffuse large B-cell lymphoma\nprogrammed cell death 1\nchimeric antigen receptor\nT cells\n==== Body\npmcIntroduction\n\nPost-transplant lymphoproliferative disease (PTLD) is a common complication after solid organ transplantation (SOT) (1). PTLD is a group of heterogeneous lesions characterized by uncontrolled proliferation of lymphocytes due to immunosuppression (2) and includes a variety of histopathological types, ranging from reactive polyclonal B-cell benign proliferation to malignant invasive lymphoma. Malignant and invasive lymphoma types have rapid progression, poor prognosis, and high mortality (3). More than 70% of PTLD cases are associated with Epstein-Barr virus (EBV) infection (4). Owing to the heterogeneity of PTLD and the lack of prospective studies, there are no uniform guidelines for the treatment of this disease. Reduction of immunosuppressive therapy is the first and most important step in the treatment of PTLD and should be started as early as possible (5). Rituximab, an anti-CD20 monoclonal antibody, has become the standard treatment for patients with PTLD who do not respond to immunosuppressant reduction (6–8). Chemotherapy is usually required as a concurrent or sequential therapy in typical PTLD, whereas surgical resection or radiotherapy might be used as adjuvant treatment (9, 10). However, some patients with PTLD develop relapsed/refractory (R/R) disease after standard combination therapy. In particular, PTLD patients with high tumor burden diagnosed with diffuse large B-cell lymphoma (DLBCL) have a poor prognosis (1).\n\nAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable effects in R/R non-hodgkin lymphoma, especially in R/R DLBCL (11, 12). However, some R/R DLBCL patients, particularly those with a high tumor burden, responded poorly to this therapy (13). Treatment of PTLD using anti-CD19-CAR T-cell therapy has been limited by immunosuppressants and has not been widely employed. Programmed cell death 1 (PD-1) is an important central checkpoint in tumor progression (14). A recent study showed that overexpression of the PD-1 gene in DLBCL is associated with high tumor aggressiveness (15). Moreover, immunomodulatory agents such as PD-1 inhibitors may be used in patients with transplant-related malignancies. However, the problems of transplantation immunosuppression and cancer immunoregulation caused by PD-1 inhibitor therapy must be addressed.\n\nHere, we report the successful use of anti-CD19-CAR T cell with PD-1 inhibitor therapy followed by PD-1 inhibitor maintenance therapy conducted after kidney transplantation in a patient diagnosed with DLBCL who had a refractory case of PTLD with high tumor burden. After the combined treatment, the patient achieved partial remission despite undergoing continued treatment with immunosuppressives.\n\nCase Description\n\nA 46-year-old patient (deceased) received allogeneic kidney transplantation owing to a 10-year history of chronic kidney disease (stage 5) in July 2006. Baliximab was used at the induction of immunosuppression therapy for kidney transplantation. For immunosuppressive therapy after kidney transplantation, we administered 150 mg bid oral cyclosporine, 750 mg bid myfortic, and 20 mg Qd prednisone. The serum creatinine level decreased to 120 μmol/L after the transplantation. However, on the sixth day after the operation, the patient developed acute rejection with a serum creatinine level of 556 μmol/L. The immunosuppressive therapy was changed from 20 mg Qd prednisone to 250 mg Qd intravenous methylprednisolone for three consecutive days and from 150 mg bid cyclosporin to 150 mg bid tacrolimus. The patient’s serum creatinine level declined to 129 μmol/L 1 month after the operation, and he successfully recovered. After discharge, the immunosuppressive therapy included the following doses: 2.5 mg bid tacrolimus, 750 mg bid myfortic, and 15 mg Qd prednisone. Subsequently, the patient underwent regular outpatient reexamination and showed stable kidney transplant function.\n\nIn July 2020, the patient was admitted to our hospital with bloating and abdominal pain for 15 days. A large, irregularly shaped, untender mass was observed on his abdomen. Computed tomography (CT) of the abdomen revealed a large area of mixed density in the right middle and lower abdomen (Figure 1A). Laparoscopic biopsies of the mesentery and greater omentum were performed. Pathological results indicated germinal center B-cell-DLBCL, EBV-, and a Ki67 index >85%. The positive rate of MYC detected by fluorescence in situ hybridization was 70%, whereas the rates for Bcl-2, Bcl-6, and TP53 were negative. No abnormal B-lymphocyte phenotype was found in the bone marrow by flow cytometry (FCM); however, 4.78% abnormal B lymphocytes were found in drainage from the right lung pleural fluid. He was diagnosed with PTLD, germinal center B-cell-DLBCL (a histological classification of PTLD), stage IV, EBV-, with an international prognostic index score of 4.\n\nFigure 1 Results of the abdominal CT throughout the course of treatment. (A) Large area of mixed density in the right middle and lower abdomen when the patient was diagnosed with PTLD. (B) Before the anti-CD19-CAR T cell combined with PD-1 inhibitor therapy, he was refractory to all the combined chemotherapies. (C, D). One and 2 months after the combination therapy, CT scan showed a significantly smaller abdominal mass.\n\nMycophenolate mofetil was immediately discontinued in July 2020. Tacrolimus and prednisone doses were reduced from 4 mg/day and 20 mg/day to 1 mg/day and 10 mg/day, respectively. He received two cycles of frontline therapy with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP). However, his symptoms of abdominal distension and pain were not relieved, and CT still showed an enlarged abdominal mass. Subsequently, he underwent two cycles of R-CHOP combined with etoposide (R-ECHOP). However, the abdominal mass only showed a slight reduction in size after four cycles of chemotherapy. Rituximab combined with bendamustine, etoposide, vincristine, and methylprednisolone (R-BEVD) and rituximab combined with etoposide, carboplatin, and ifosfamide (R-ICE) were chosen as salvage therapies. However, the patient was refractory to all these combined chemotherapies (Figure 1B) and was therefore diagnosed with refractory PTLD. The tacrolimus dose was maintained at 1 mg/day during combination chemotherapy because of the increased creatinine levels.\n\nThe patient accepted our recommendation for treatment of refractory PTLD. He was enrolled in a clinical trial of anti-CD19-CAR T-cell therapy (ChiCTR1800019622) as a refractory DLBCL patient and signed an informed consent form. The expression of PD-1 in CD3+ T cells in the peripheral blood was 61.43% at the time of enrollment. Peripheral blood mononuclear cells (PBMCs) for the anti-CD19-CAR T-cell therapy were collected by leukapheresis and isolated by Ficoll density gradient centrifugation. Immunosuppressive therapy for the kidney transplant was adjusted again on the day of leukapheresis. Prednisone was discontinued, and the tacrolimus dose was maintained at 1 mg/day. He received lymphodepleting chemotherapy with fludarabine (30 mg/m2) and cyclophosphamide (400 mg/m2) from day -4 to day -2. Thereafter, he received PD-1 inhibitors (Sintilimab, 200 mg) on day -1. On the 12th day of cultivation, transduction efficiencies of anti-CD19-CAR were analyzed by FCM. The efficiency of anti-CD19-CAR transduction in this patient was 44.17%. The proportion of anti-CD19-CAR T cells on the harvest date was 5.38 × 106 cells/kg. Autologous humanized anti-CD19-CAR T cells were infused on day 0 (2 × 106 cells/kg) in December 2020 (Figure 2A).\n\nFigure 2 Monitoring the course of anti-CD19-CAR T cell combined with PD-1 inhibitor therapy. (A) Flowchart of combination and maintenance therapy. (B) The expression level of PD-1 in CD3+ T cells in peripheral blood detected by FCM declined to less than 2%. (C) The expression level of the anti-CD19-CAR gene remained more than 10 times higher than the baseline level before therapy. (D) The patient had a persistent deficiency of B lymphocytes in his peripheral blood.\n\nAdverse events (AEs) manifested as fever up to 37.8°C with chills on day 1 after anti-CD19-CAR T-cell infusion, accompanied by fatigue, dizziness, headache, and weakness. The highest temperature recorded was 38.4°C on day 7. He was diagnosed with grade 1 cytokine release syndrome (16) and grade 3 immune effector cell-associated neurotoxicity syndrome (17), which was relieved on day 14 with symptomatic treatments only. Anti-CD19-CAR T-cell expression level in CD3+ T cells in peripheral blood was detected by FCM on days 0, 4, 7, 14, and 28. The anti-CD19-CAR T-cell amplification peak reached 9.01% on day 7 (Table 1). There were no abnormal peaks of cytokines (including interleukin-6, -2R, or -10 or tumor necrosis factor-α) in the peripheral blood, as detected using enzyme-linked immunosorbent assay. Meanwhile, the proportion of CD3+ CD8+ T cells detected by FCM reached a peak of 79.65% on day 28, and CD19+ B-cell aplasia continued up to week 12 (Table 1). The DNA expression level of the anti-CD19-CAR gene detected by quantitative PCR reached its peak at 14500 copies/ng gDNA on day 14. The expression level of PD-1 in CD3+ T cells in peripheral blood detected by FCM declined to less than 2% during the combination therapy (Figure 2B).\n\nTable 1 Side effects during anti-CD19-CAR T cell combined with PD-1 inhibitor therapy.\n\n\tPrior therapy\tDay 4\tDay 7\tDay 14\tDay 28\t\nCAR-T(%)\t0.00\t0.67\t9.01\t3.94\t0.83\t\nIL-6(U/ml)\t3.10\t7.02\t13.76\t6.05\t3.13\t\nIL-2R(pg/ml)\t1.27\t0.47\t5.48\t2.3\t1.05\t\nIL-10(pg/ml)\t0.25\t0.19\t8.1\t2.79\t1.21\t\nTNF-α(pg/ml)\t1.02\t0.89\t4.07\t1.35\t1.36\t\nIFN-γ(pg/ml)\t0.56\t0.89\t5.15\t2.30\t1.78\t\nCD3+T(%)\t95.8\t95.4\t93.7\t89.4\t90.31\t\nCD3+CD4+T(%)\t44.72\t30.21\t16.63\t15.53\t13.71\t\nCD3+CD8+T(%)\t52.42\t62.25\t72.38\t70.47\t79.65\t\nTreg(%)\t6.02\t6.12\t8.41\t10.98\t7.05\t\nFerritin(ng/ml)\t1285\t1720\t1180\t979\t621\t\nHb(g/L)\t107\t112\t108\t106\t107\t\nWBC(×109/L)\t4.05\t5.2\t7.23\t8.35\t6.52\t\nPLT(×109/L)\t103\t95\t34\t229\t240\t\n\nKidney function of the patient remained stable, while immunosuppressive therapy for the kidney transplant was maintained with tacrolimus at a dose of 1 mg/day. His creatinine level rose to 102.3 μmol/L when the tacrolimus dose was reduced to 0.5 mg/day 4 weeks after the anti-CD19-CAR T cell + PD-1 inhibitor therapy. He was diagnosed with acute rejection and was readministered a 1 mg/day dose of tacrolimus. Subsequently, his renal function gradually declined (Figure 2A).\n\nBetween 1 and 2 months after the combination therapy, all his symptoms were relieved. The CT scan showed a significantly smaller abdominal mass than before (Figures 1C, D). The patient achieved partial remission 1 month after combination therapy, according to the Lugano Revised Criteria for Response Assessment (18).\n\nBecause the dose for immunosuppressive therapy could not be reduced owing to the kidney transplant, the patient received maintenance therapy with PD-1 inhibitors (Sintilimab, 200 mg) every 3 weeks starting at 28 days after the anti-CD19-CAR T-cell infusion to avoid further progression of the disease. The expression level of the anti-CD19-CAR gene detected 16 weeks after cell infusion remained more than 10 times higher than the baseline level before therapy (Figure 2C). The expression level of PD-1 in the peripheral blood remained below 3% throughout this period. The patient exhibited persistent B-lymphocyte deficiency in his peripheral blood (Figure 2D). During maintenance therapy (PD-1 inhibitors and tacrolimus 1 mg/day for 3 weeks), we observed a continued reduction in tumor volume (Figure 1). His disease was in partial remission for 18 weeks. However, his tumor then suddenly increased in size, and the patient did not elect to receive further treatment, including radiation therapy. When he was diagnosed with progressive disease and refused further treatment, his creatinine level was 98.6 μmol/L. The proportion of anti-CD19-CAR T cells within the CD3+ T-cell population in the peripheral blood was 0% at this time. Because of the rapid progression of the disease, we did not have the opportunity to obtain additional data on CD19 expression in the tumor tissue.\n\nDiscussion\n\nThe incidence of PTLD has increased as the number of SOT patients have increased. However, survival time has been simultaneously prolonged. In addition, an increasing number of cases of very late PTLD onset can occur more than 20 years after SOT (19). EBV infection, immunosuppression status, and genetic susceptibility are important factors for PTLD (20, 21). Increased malignancy and rapid progression are characteristics of EBV-negative PTLD, which usually develops several years after SOT (22, 23). In the EBV-negative PTLD patient in this study, the disease was refractory to conventional chemotherapy and progressed rapidly.\n\nAlthough anti-CD19-CAR T-cell therapy has achieved impressive results in R/R DLBCL, there are still many patients who do not benefit from this therapy. Patients with high tumor burden or immunodeficiency have poor response to chemotherapeutic drugs and immunotherapy (13, 24). Our patient exhibited EBV-negative PTLD, a high tumor burden, refractoriness to chemotherapeutic therapy, including rituximab, and was given continuous immunosuppressive therapy, all of which were disadvantages for the prospects of anti-CD19-CAR T-cell therapy.\n\nThe tumor microenvironment plays a major role in preventing durable responses to immunotherapy in hematologic malignancies (25). Macrophages, myeloid-derived suppressor cells, and regulatory T cells in the tumor microenvironment are major inhibitors of immunosuppression in anti-CD19 CAR T-cell therapy (26, 27). Patients with the highest PD-1/PD-L1 interaction scores did not respond to anti-CD19-CAR T-cell therapy or relapsed within 3–6 months (12). Anti-CD19 CAR T cells derived from T cells with high PD-1 expression result in failure of this therapy (28). Fortunately, PD-1 inhibitors combined with anti-CD19 CAR T cells may overcome such immunosuppressive effects (29). Our study also demonstrated the synergistic effects of PD-1 inhibitors combined with chemotherapeutic regimens or anti-CD19-CAR T cells in R/R B-cell lymphoma (30, 31). Some biological theoretical studies have been reported (32), providing a basis for the application of PD-1 inhibitors in DLBCL patients with MYC overexpression. Therefore, for this MYC-overexpressing R/R DLBCL patient, we predicted that PD-1 inhibitors might serve as an effective maintenance therapy after anti-CD19 CAR T-cell therapy. When the patient was enrolled in our clinical trial, the expression of PD-1 in the peripheral blood was 61.4%, and the positive rate of MYC was 70%. These are important factors associated with the poor efficacy of anti-CD19-CAR T-cell therapy. Therefore, we selected a combination therapy of anti-CD19-CAR T cells and PD-1 inhibitors. Although there was some benefit from the combination therapy, the proportion of anti-CD19-CAR T cells within the CD3+ T cell pool in the peripheral blood declined to 0.83% 28 days after CAR T-cell infusion. The rapid decline in the proportion of anti-CD19-CAR T cells might be one of the reasons for disease progression in this patient.\n\nThe infusion of PD-1 inhibitors following transplantation led to complete loss of the allograft in an animal model study (33). Another animal study suggested that PD-1 blockade aggravated the progression of EBV+ PTLD (34). Therefore, we encourage the use of additional agents for transplant recipients with tumors in clinical settings (35). However, some studies on the use of PD-1 inhibitors in organ transplant patients without rejection have been reported (36–38). A study was conducted on 69 cancer patients with kidney transplants receiving immune checkpoint inhibitors (39). Following this therapy, 42% of patients developed acute rejection, while 28% lost their allograft. No significant renal damage occurred throughout the course of treatment, although rejection occurred due to tacrolimus dose reduction. In this case, there was no significant rejection of PD-1 inhibitor therapy, which might be related to tacrolimus therapy. PD-1 inhibitors are associated with a high risk of rejection in patients with PTLD but may also lead to improved PTLD outcomes.\n\nAEs were another problem that affected the prognosis for this patient. AEs associated with PD-1 inhibitors are immune-associated events in the respiratory and circulatory systems (28). Fortunately, the safety of the combination therapy and subsequent PD-1 inhibitor maintenance therapy were acceptable. There were no interruptions in any of the therapies due to AEs. In particular, kidney function of the patient remained stable throughout the combination therapy. Until the disease progressed after the combination therapy, his creatinine level did not increase significantly.\n\nHis immunosuppressive therapy was maintained with tacrolimus 1 mg/day during the combination therapy and maintenance therapy. However, immunosuppressive therapy may lead to the recurrence of PTLD. Considering the patient history, we decided to continue immunosuppressive therapy with tacrolimus; meanwhile, we chose the PD-1 inhibitors in combination therapy and the subsequent maintenance therapy. We anticipated that the PD-1 inhibitors would overcome the immunosuppressive effects and enhance T-cell function (28) while simultaneously increasing the risk for acute rejection. Fortunately, there was no serious acute rejection due to increased T-cell function throughout the course of therapy. In contrast, the humoral immune response mediated by B cells plays an important role in rejection after SOT (40, 41). We hypothesized that the deficiency of B cells induced by anti-CD19-CAR T-cell therapy might prohibit acute rejection and protect renal function.\n\nPrevious studies have reported the efficacy and safety of anti-CD19-CAR T-cell therapy in R/R PTLD patients (42–46) (Table 2). All refractory PTLD patients to date received anti-CD19-CAR T-cell therapy with discontinuation or reduction in the dose of immunosuppressive therapy. They either did not respond to anti-CD19-CAR T-cell therapy or had disease progression within a few months after responding to anti-CD19-CAR T-cell therapy. Therefore, maintaining the efficacy of anti-CD19-CAR T-cell therapy is a problem that needs to be solved. None of these refractory PTLD patients received maintenance therapy after anti-CD19-CAR T-cell therapy.\n\nTable 2 Summary of PTLD cases received CD19 CAR-T therapy.\n\nPatient\tAge\tSex\tSOT, years\tTime of PTLD diagnosis\tEBV tumor status\tPathology\tTherapy before CAR-T\tImmunosuppressive therapy in CAR-T\tCRS\tICANS\tOutcome\tMaintenance therapy after CAR-T\tRef.\t\nPatient 1\t54\tM\tKidney,\nPancreas\t20 years\tNegative\tDLBCL\tRIS, Rituximan,\nR-CHOP, R-ICE\tNone\tGrade 1\tGrade 2\tSD, death at day 115\tNone\t(39)\t\nPatient 2\t54\tF\tHeart\t27 years\tNegative\tDLBCL\tRIS, R-CHOP,\nR-ICE\tLower dose of Sirolimus\tGrade 2\tGrade 3\tPD, death at day 44\tNone\t(39)\t\nPatient 3\t71\tM\tKidney\t10 years\tNegative\tDLBCL\tRIS, R-CHOP,\nR-DHAX, Ibrutinib\tLower dose of Prednisone\tGrade 2\tGrade 4\tPD, Death at day 15\tNone\t(39)\t\nPatient 4\t38\tM\tKidney\t10 years\tNegative\tDLBCL\tRIS, R-CHOP,\nR-GEM-Ox\tPrednisone\n(5 mg/day)\tGrade 1\tNone\tCR, Lasts up to +28 weeks\tNone\t(40)\t\nPatient 5\t44\tM\tKidney\t10 years\tNegative\tDLBCL\tRIS, R-CHOP\tNone\tGrade 1\tGrade 3\tCR, Refractory at +34 weeks.\tNone\t(40)\t\nPatient 6\t41\tM\tKidney\t7 years\tNegative\tDLBCL\tR-EPOCH, R-GDP,\nR-ESHAP, Pola+BR\tNone\tNone\tNone\tPR, PD at +12 weeks\tNone\t(40)\t\nPatient 7\t69\tM\tKidney\t25 years\tNegative\tDLBCL\tR-POCH, R-GDP\tLower dose of Tacrolimus\tGrade 1\tNone\tCR, Refractory at 3 months\tNone\t(41)\t\nPatient 8\t50\tF\tKidney\t5 years\tNegative\tDLBCL\tR-CHOP, R-ICE,\nASCT\tLower dose of Tacrolimus\tGrade 2\tNone\tCR, Lasts up to 9 months\tNone\t(41)\t\nPatient 9\t66\tM\tLiver\t8 years\tNegative\tDLBCL\tR-HOP, ICE\tLower dose of Tacrolimus\tGrade 1\tNone\tPR, Lasts up to 3 months\tNone\t(41)\t\nPatient 10\t4\tM\tLiver\t21 months\tPositive\tBL-PTLD\tR+CTX+\nMethylprednis\tNone\tGrade 2\tNone\tCR, Lasts up to 16 months\tNone\t(42)\t\nPatient 11\t17\tF\tHeart\t4 months\tPositive\tDLBCL\tRIS, R-COP,\nR-COPADM,\nR-CYVE, O-ICE\tLower dose of Tacrolimus and Prednisone\tGrade 1\tnone\tCR, Lasts up to 6 months.\tPlan to undergo HCT\t(43)\t\nPTLD, posttransplant lymphoproliferative disorders; DLBCL, diffuse large B cell lymphoma; EBV, Epstein Barr virus; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; RIS, reduction in immunosuppression; R, rituximab; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone; DHAX, dexamethasone, cytarabine, and oxaliplatin; ICE, ifosfamide, carboplatin, and etoposide; EPOCH, etoposide, adriamycin, vincristine, cyclophosphamide, prednisone; GDP, gemcitabine, cisplatin, dexamethasone; ESHAP, etoposide, methylprednisolone, cisplatin, cytarabine; Pola+BR, polatuzumab vedotin, bendamustine, rituximab; COPADM, cyclophosphamide, vincristine, prednisone, doxorubicin, and high dose methotrexate; O-ICE, obinutuzumab-ICE; CYVE, cytarabine, etoposide; ASCT, autologous stem cell transplantation; HCT, hematopoietic cell transplantation.\n\nIn our study, despite many obstacles, the patient achieved partial remission as a result of the anti-CD19-CAR T cell + PD-1 inhibitor therapy and subsequent PD-1 inhibitor maintenance therapy. The selection of PD-1 inhibitors might have antagonized the immunosuppressive effect of T cells and the overexpression of MYC in tumor cells. Combining anti-CD19-CAR T cells and PD-1 inhibitors as well as the application of tacrolimus might reduce the risk of acute rejection caused by PD-1 inhibitors. Although the refractory PTLD in this patient eventually progressed, this combination therapy could be attempted again with more success.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThis study was approved by the Medical Ethics Committee of the Department of Hematology, Tianjin First Center Hospital (Tianjin, China) (approved no. of ethic committee: 2018N105KY). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nConcept and design: QD and YF. Drafted or revised the manuscript: GF and QL. Acquisition of data: HZ and YJ. Analysis and interpretation of data: JY. Writing, review, and/or revision of manuscript: GF. Study supervision: QD. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by a grant (81970654) from National Natural Science Foundation of China to YF.\n\nConflict of Interest\n\nJY was employed by the company Shanghai Genbase Biotechnology Co., Ltd.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe thank our patient for his participation in our clinical trials. 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Pediatr Transplant (2021) 25 (5 ):e13861. doi: 10.1111/petr.13861 33002249\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "T cells; chimeric antigen receptor; diffuse large B-cell lymphoma; post-transplant lymphoproliferative disease; programmed cell death 1",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "726134",
"pmc": null,
"pmid": "34604065",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "33042618;24876563;21171509;20085936;33359528;21264909;23108141;16254143;33511078;33002249;28719552;33512386;30741059;30413665;20408848;11275994;27258579;28076715;27614165;29914976;25113753;14629278;33089906;30526160;28666406;27992268;23465004;31501612;15771580;29226764;30501490;15979320;28912137;33230187;30592986;29427591;32857184;22045767;33643299;17911605;26936508;32025577;31611950;33631963;22173060;10755535",
"title": "Safety and Efficacy of Anti-CD19-Chimeric Antigen Receptor T Cell Combined With Programmed Cell Death 1 Inhibitor Therapy in a Patient With Refractory Post-Transplant Lymphoproliferative Disease: Case Report and Literature Review.",
"title_normalized": "safety and efficacy of anti cd19 chimeric antigen receptor t cell combined with programmed cell death 1 inhibitor therapy in a patient with refractory post transplant lymphoproliferative disease case report and literature review"
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"abstract": "Denosumab is an antiresorptive agent widely used for treating osteoporosis. Atypical femur fractures, osteonecrosis of the jaw and hypocalcaemia are well-known possible adverse effects of this drug. We present, to our knowledge, the first case report in the English literature of clinically significant interstitial lung disease likely related to denosumab.\nDenosumab is a fully human monoclonal antibody which may rarely cause interstitial lung disease (ILD).The findings from this isolated case report of ILD in a patient taking denosumab do not prove causality.Nevertheless, we suggest that patient exposure to denosumab should be considered in a patient with ILD.",
"affiliations": "Department of Internal Medicine, Hospital of Laredo, Laredo, Spain.;Department of Internal Medicine, Hospital of Laredo, Laredo, Spain.;Department of Radiology, Hospital of Laredo, Laredo, Spain.;Department of Pulmonary Medicine, Hospital of Laredo, Spain.;Department of Pulmonary Medicine, Hospital of Laredo, Spain.",
"authors": "Ruiz|Ana Campo|AC|;Carrascosa|Miguel F|MF|;Concha|Sergio Tapia|ST|;Gil|Aníbal Hernández|AH|;Rivero|Juan García|JG|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_001131131-1-8398-1-10-20190701ArticlesInterstitial Lung Disease in a Patient Treated with Denosumab Ruiz Ana Campo 1Carrascosa Miguel F 1Concha Sergio Tapia 2Gil Aníbal Hernández 3Rivero Juan García 3\n1 Department of Internal Medicine, Hospital of Laredo, Laredo, Spain\n2 Department of Radiology, Hospital of Laredo, Laredo, Spain\n3 Department of Pulmonary Medicine, Hospital of Laredo, Spain2019 03 7 2019 6 7 00113129 4 2019 16 5 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseDenosumab is an antiresorptive agent widely used for treating osteoporosis. Atypical femur fractures, osteonecrosis of the jaw and hypocalcaemia are well-known possible adverse effects of this drug. We present, to our knowledge, the first case report in the English literature of clinically significant interstitial lung disease likely related to denosumab.\n\nLEARNING POINTS\nDenosumab is a fully human monoclonal antibody which may rarely cause interstitial lung disease (ILD).\n\nThe findings from this isolated case report of ILD in a patient taking denosumab do not prove causality.\n\nNevertheless, we suggest that patient exposure to denosumab should be considered in a patient with ILD.\n\nInterstitial lung diseasedenosumabosteoporosis\n==== Body\nINTRODUCTION\nDenosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts[1,2]. However, since RANKL and RANK are also expressed in the lung[3,4], there is theoretical concern that denosumab might have adverse pulmonary effects. We describe, as far as we know, the first case report of clinically significant interstitial lung disease (ILD) likely related to denosumab.\n\nCASE DESCRIPTION\nIn March 2018, an 87-year-old non-smoking woman presented with a 1-month history of dry cough and worsening exertional dyspnoea. Her past medical history was significant for arterial hypertension, atrial fibrillation and postmenopausal osteoporosis. She had been taking nebivolol, digoxin, acenocoumarol and pantoprazole for many years along with subcutaneous denosumab since May 2016 (60 mg every 6 months, the third dose having been given 4 months before admission). Physical examination was remarkable only for cardiac arrhythmia and fine, high-pitched bibasilar inspiratory crackles.\n\nMETHODS AND PROCEDURES\nOxygen therapy was prescribed since her arterial O2 partial pressure was 43 mmHg while breathing room air. The white blood cell count and differential, haemoglobin concentration and blood urea nitrogen were all normal; the ESR was 38 mm/hour. The chest radiograph revealed bilateral basal reticular abnormalities. An echocardiographic study was normal. A high-resolution CT scan of the chest displayed a pattern suggestive of hypersensitivity pneumonitis (Fig. 1).\n\nDiagnostic work-up for antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor and angiotensin-converting enzyme showed normal results. Serology for HIV was negative. ILD related to denosumab was suspected and so this drug was discontinued while the other habitual medications were maintained. The patient was started on prednisone (10 mg/day as initial dose) and discharged on the 7th hospital day with recommendations for zoledronic acid treatment. Six months after discharge (while on prednisone 5 mg/day), she denied having dyspnoea, ESR was normal, and a high-resolution CT scan of the chest displayed normal findings. At a follow-up visit in early December 2018, the patient remained well and prednisone was stopped. When last seen on 9 May 2019, she continued to be eupnoeic, her arterial oxygen saturation was 95% while breathing room air, lung auscultation revealed no abnormalities, and the serum level of C-reactive protein was within normal limits. Denosumab re-challenge was avoided because both the adverse reaction had been severe (grade 3: symptomatic, interfering with activities of daily living or oxygen indicated[5]) and denosumab was regarded as a non-essential medication.\n\nDISCUSSION\nDrug-induced ILD incidence rates vary between 4.1 and 12.4 cases/million/year and account for 3–5% of all prevalent ILD cases[5]. Over 350 drugs can cause drug-induced ILD, but this is often unrecognised until late in drug development or after launch[5]. Moreover, drug-induced ILD is a diagnosis of exclusion, which poses unique challenges for the treating physician. Cancer therapy agents (bleomycin, gemcitabine and others), followed by rheumatology drugs (methotrexate, leflunomide and others), amiodarone and antibiotics (nitrofurantoin, daptomycin) are the most common causes of drug-induced ILD[5].\n\nILD associated with denosumab seems to be an exceptional occurrence. In fact, neither the comprehensive Pneumotox website (www.pneumotox.com) nor a recent thorough review on drug-induced ILD[5] include denosumab as a causative agent of ILD. Moreover, a PubMed search using the search terms ‘denosumab’ and ‘interstitial lung disease’ revealed no previous case reports on this matter published in the English literature (accessed on 29 April 2019).\n\nHowever, on the other hand, a study on ILD related to the administration of monoclonal antibodies which includes denosumab has been recently reported[6]. The aim of this analysis was to investigate the time-to-onset and onset pattern of drug-induced ILD after the administration of monoclonal antibodies through the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report (JADER) database. In conclusion, the results of the study showed that with the exception of denosumab (64.5 days) and adalimumab (126 days), the time-to-onset of drug-induced ILD for monoclonal antibody agents ranged from 1 to 2 months after the initial administration. Nevertheless, it is worth stating here that, as the authors of this report pointed out, there are several problems associated with spontaneous reporting databases, such as the JADER, that need to be taken into account. These problems include: (a) the size and characteristics of the target population are often unclear, which indicates that the usefulness of the obtained results cannot be definitively established; (b) due to bias in the process of obtaining and transferring information, it is difficult to evaluate the magnitude of the potential adverse event; (c) there are countless confounding prognostic factors and covariates, thereby making it hard to investigate which of these might have truly influenced the results; (d) there is no way to confirm the causal relationship, even if a suspected side effect is found; and (e) there is difficulty ascertaining the accuracy of the report.\n\nAs a result, careful attention needs to be paid to any interpretation of the results from the JADER database.\n\nIn addition, a search on VigiBase (www.vigiaccess.org) resulted in 62 hits for denosumab and ILD (accessed on 29 April 2019). VigiBase, the WHO global database of individual case safety reports, is the largest and most comprehensive database in the world, and is developed and maintained by the Uppsala Monitoring Centre on behalf of the WHO. It consists of reports of adverse reactions to medicines and vaccines received from member countries since 1968. VigiBase is updated with incoming case reports on a continuous basis. Although data from VigiBase can be published, VigiBase should not be regarded as a publication itself.\n\nWhile the evidence from this single report is circumstantial, the history of drug exposure, absence of another more probable cause (e.g. infection, radiation-induced lung injury, or progression of an underlying disease), and the favourable clinical and radiological outcome upon denosumab withdrawal along with corticosteroid therapy are all consistent with a likely causal relationship. Alveolar macrophages express RANK and following its binding to RANKL, extracellular matrix degradation can be induced[4]. We hypothesize that denosumab, through blocking the RANKL-RANK binding, could potentially reduce extracellular matrix degradation by macrophages and lead in this way to ILD. Plausible risk factors for developing denosumab-induced ILD in our patient could have been old age[5] and the possible presence of an idiosyncratic susceptibility. Why took it the patient nearly 2 years to develop ILD after starting denosumab treatment is a matter of discussion.\n\nCONCLUSION\nAlthough the findings from this isolated case do not prove causality, we suggest that until further data to support or refute the association are available, patient exposure to denosumab should be queried when a diagnosis of ILD is being considered.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Chest high-resolution CT images in a patient with interstitial lung disease while on denosumab: axial (A), coronal (B) and sagittal (C) reconstructions show mosaic attenuation and scattered ground-glass opacities as well as mild reticulation, ill-defined lobular micronodules, and minimal architectural distortion. Note that there is no honeycombing or traction bronchiectasis\n==== Refs\nREFERENCES\n1 Cummings SR San Martin J McClung MR Denosumab for prevention of fractures in postmenopausal women with osteoporosis N Engl J Med 2009 361 756 765 19671655 \n2 Lewiecki EM New and emerging concepts in the use of denosumab for the treatment of osteoporosis Ther Adv Musculoskel Dis 2018 10 209 223 \n3 Liu W Zhang X Receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin system in bone and other tissues Mol Med Rep 2015 11 3212 3218 25572286 \n4 Boorsma C Draijer C Cool R The RANKL-OPG balance in pulmonary fibrosis Eur Respir J 2015 46 PA3809 \n5 Skeoch S Weatherley N Swift AJ Drug-induced interstitial lung disease: a systematic review J Clin Med 2018 7 356 \n6 Komada F Nakayama Y Takara K Analysis of time-to-onset and onset-pattern of interstitial lung disease after the administration of monoclonal antibody agents Yakugaku Zasshi 2018 138 12 1587 1594 30504674\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(7)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Interstitial lung disease; denosumab; osteoporosis",
"medline_ta": "Eur J Case Rep Intern Med",
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"nlm_unique_id": "101648453",
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"pages": "001131",
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"title": "Interstitial Lung Disease in a Patient Treated with Denosumab.",
"title_normalized": "interstitial lung disease in a patient treated with denosumab"
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{
"abstract": "Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that reduces levels of low-density lipoprotein-cholesterol (LDL-C) in the plasma by inhibition of cholesterol synthesis in hepatic cells, which leads to up-regulation of hepatic LDL receptors. Bempedoic acid is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. In this case study, we describe a patient with HeFH who had a prior excellent response to statin but unable to take the same, and a less than expected response to PCSK9i, in whom initiation of bempedoic acid led to a substantial reduction of LDL-C. Our findings suggest that patients who are quite responsive to statins may also be quite responsive to bempedoic acid, a medication that works in the same biochemical pathway as HMG-CoA reductase inhibitors. Additionally, this medication may be particularly effective at lowering LDL-C among individuals not on background statin therapy.",
"affiliations": "Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6655 Travis Street, Suite 320, Houston, TX 77030, USA.;Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6655 Travis Street, Suite 320, Houston, TX 77030, USA; Houston Methodist Weight Management Center, Houston, TX, USA.;Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6655 Travis Street, Suite 320, Houston, TX 77030, USA.;Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6655 Travis Street, Suite 320, Houston, TX 77030, USA; Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.;Department of Medicine, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, 6655 Travis Street, Suite 320, Houston, TX 77030, USA; Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA. Electronic address: [email protected].",
"authors": "Agha|Ali M|AM|;Jones|Peter H|PH|;Ballantyne|Christie M|CM|;Virani|Salim S|SS|;Nambi|Vijay|V|",
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"title": "Greater than expected reduction in low-density lipoprotein-cholesterol (LDL-C) with bempedoic acid in a patient with heterozygous familial hypercholesterolemia (HeFH).",
"title_normalized": "greater than expected reduction in low density lipoprotein cholesterol ldl c with bempedoic acid in a patient with heterozygous familial hypercholesterolemia hefh"
} | [
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{
"abstract": "Valproic acid (VPA) is approved by the Food and Drug Administration (FDA) for the treatment of manic or mixed episodes associated with bipolar disorder. VPA is also used off-label to treat other conditions in psychiatry such as impulse control disorders, major depression, and posttraumatic stress disorder (PTSD). Although VPA is mostly well-tolerated, common adverse effects include gastrointestinal symptoms (nausea, vomiting, diarrhea), neurological symptoms (sedation, ataxia, tremor), weight gain, and alopecia. Less common adverse effects include VPA-induced parkinsonism and cognitive impairment. We describe a patient who developed parkinsonism and cognitive impairment eight years after starting divalproex sodium for bipolar disorder, type I. Over time, the patient's parkinsonian symptoms progressed, and the motor symptoms were partially responsive to carbidopa/levodopa. Her mild cognitive impairment was, for the most part, stable on donepezil. Rapid discontinuation of divalproex sodium resolved the parkinsonian symptoms as well as the cognitive impairment. A brief review of the literature regarding VPA-induced parkinsonism and cognitive impairment in adults is included. Given the reversible nature and potential severity of VPA-induced parkinsonism, improved recognition in psychiatric populations is critical, particularly after extended VPA exposure. To the best of our knowledge there are no reports describing the onset of VPA-induced parkinsonism in psychiatric patients more than eight years after starting VPA.",
"affiliations": null,
"authors": "Hassamal|Sameer|S|;Waller|Susan|S|;Reese|Kimberly|K|;Testa|Claudia|C|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-2163",
"issue": "27(3)",
"journal": "Turk psikiyatri dergisi = Turkish journal of psychiatry",
"keywords": null,
"medline_ta": "Turk Psikiyatri Derg",
"mesh_terms": "D000368:Aged; D018692:Antimanic Agents; D001714:Bipolar Disorder; D003072:Cognition Disorders; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D020734:Parkinsonian Disorders; D014635:Valproic Acid",
"nlm_unique_id": "9425936",
"other_id": null,
"pages": "213-217",
"pmc": null,
"pmid": "27711942",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible Valproic Acid-Induced Parkinsonism and Cognitive Impairment in an Elderly Patient With Bipolar Disorder I.",
"title_normalized": "reversible valproic acid induced parkinsonism and cognitive impairment in an elderly patient with bipolar disorder i"
} | [
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}
],
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},
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},
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},
{
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},
{
"reactionmeddrapt": "Dementia",
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"reactionoutcome": "1"
},
{
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},
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},
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],
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}
},
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"literaturereference": "HASSAMAL S, WALLER S, REESE K, TESTA C.. REVERSIBLE VALPROIC ACID-INDUCED PARKINSONISM AND COGNITIVE IMPAIRMENT IN AN ELDERLY PATIENT WITH BIPOLAR DISORDER I. TURK J PSY. 2016;1-5",
"literaturereference_normalized": "reversible valproic acid induced parkinsonism and cognitive impairment in an elderly patient with bipolar disorder i",
"qualification": "1",
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},
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},
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}
] |
{
"abstract": "Tumor necrosis factor-alpha inhibitors have become an established therapeutic regimen for patients\nwith rheumatoid arthritis. Regarding their harmful potential they are classified as category B medications. Animal\nreproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled\nstudies in pregnant women. Disease-modifying antirheumatic drugs (DMARDs) are often used in combination with\nbiological therapy and treatment with methotrexate has shown good results. This antimetabolite is classified as a\ncategory X drug and its teratogenic effect is well known. The incidence of inflammatory rheumatic diseases is significantly higher in women. There are many reports on pregnant patients treated with biological therapy, oft en in combination\nwith DMARDs. The effects of such a therapy on reproductive health is a theme of debate, with controversial\nviews on the matter. We present a patient with rheumatoid arthritis whose pregnancy was discovered at 31 weeks of\ngestation. During that period she had been treated with methotrexate and infliximab, with no adverse effects.",
"affiliations": null,
"authors": "Bakula|Marija|M|;Cerovec|Mislav|M|;Rukavina|Krešimir|K|;Čikeš|Nada|N|;Anić|Branimir|B|",
"chemical_list": "D018501:Antirheumatic Agents; D000069285:Infliximab; D008727:Methotrexate",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0374-1338",
"issue": "63(1)",
"journal": "Reumatizam",
"keywords": null,
"medline_ta": "Reumatizam",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D000069285:Infliximab; D008727:Methotrexate; D011247:Pregnancy",
"nlm_unique_id": "0216650",
"other_id": null,
"pages": "6-9",
"pmc": null,
"pmid": "29616536",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnant patient with rheumatoid arthritis treated with methotrexate and infliximab.",
"title_normalized": "pregnant patient with rheumatoid arthritis treated with methotrexate and infliximab"
} | [
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"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Contraindicated product administered",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Normal newborn",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rheumatoid arthritis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BAKULA M, CEROVEC M, RUKAVINA K, CIKES N, ANIC B.. PREGNANT PATIENT WITH RHEUMATOID ARTHRITIS TREATED WITH METHOTREXATE AND INFLIXIMAB.. REUMATIZAM. 2016?63 (1):6-9",
"literaturereference_normalized": "pregnant patient with rheumatoid arthritis treated with methotrexate and infliximab",
"qualification": "3",
"reportercountry": "HR"
},
"primarysourcecountry": "HR",
"receiptdate": "20190620",
"receivedate": "20181108",
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},
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"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
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"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Hemodialysis is the extracorporeal treatment of choice for various life-threatening intoxications, with the exception of highly protein-bound substances, which are preferably removed by charcoal hemoperfusion. This technique, however, is limited by its availability and its significant side effects. We present a potentially lifethreatening diphenhydramine (DPH) overdose in a stuporous female patient in which high cut-off hemodialysis was used. Timely detoxification resulted in rapid gain of consciousness, allowing the patient to state the existence and location of another poison victim.",
"affiliations": null,
"authors": "Baroke|Eva|E|;Schmidt|Julius J|JJ|;Strunk|Ann-Kathrin|AK|;Wiesner|Olaf|O|;Kühn-Velten|W Nikolaus|WN|;Kielstein|Jan T|JT|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D006993:Hypnotics and Sedatives; D004155:Diphenhydramine; D010830:Physostigmine",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN108441",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "84(2)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D001714:Bipolar Disorder; D002800:Cholinesterase Inhibitors; D004155:Diphenhydramine; D062787:Drug Overdose; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D010830:Physostigmine; D006435:Renal Dialysis; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "104-7",
"pmc": null,
"pmid": "25600858",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Saving two lives with one dialysis treatment.",
"title_normalized": "saving two lives with one dialysis treatment"
} | [
{
"companynumb": "US-JNJFOC-20150802876",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "999999",
"drugbatchnumb": null,
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DIPHENHYDRAMINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "DIPHENHYDRAMINE HYDROCHLORIDE."
}
],
"patientagegroup": null,
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"patientonsetageunit": "801",
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"patientweight": "54",
"reaction": [
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Stupor",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BAROKE E, SCHMIDT J, STRUNK A, WIESNER O, KUHN-VELTEN W, KIELSTEIN J. SAVING TWO LIVES WITH ONE DIALYSIS TREATMENT. CLINICAL NEPHROLOGY 2015;84 (8):104-7. BAROKE E, SCHMIDT JJ, STRUNK AK, WIESNER O, KUHN-VELTEN WN, KIELSTEIN JT. SAVING TWO LIVES WITH ONE DIALYSIS TREATMENT: SUCCESSFUL TREATMENT OF LIFE THREATENING DIPHENHYDRAMINE INTOXICATION BY INTERMITTENT HEMODIALYSIS USING A HIGH CUT-OFF MEMBRANE. NIEREN- UND HOCHDRUCKKRANKHEITEN AUG-2016;45 (8):312-315.",
"literaturereference_normalized": "saving two lives with one dialysis treatment",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20161028",
"receivedate": "20150808",
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},
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"safetyreportversion": 3,
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20170206"
}
] |
{
"abstract": "This article reviews common and clinically important neuropsychiatric aspects of epilepsy. Comorbidities are common, underdiagnosed, and powerfully impact clinical outcomes. Biological, psychological, and social factors contribute to the associations between epilepsy and neuropsychiatric disorders. Epidemiologic studies point to a bidirectional relationships between epilepsy and neuropsychiatric disorders. People with epilepsy are more likely to develop certain neuropsychiatric disorders, and those with these disorders are more likely to develop epilepsy. This relationship suggests the possibility of shared underlying pathophysiologies. We review the neuropsychiatric impact of antiseizure medications and therapeutic options for treatment. Diagnosis and treatment involve close collaboration among a multidisciplinary team.",
"affiliations": "Department of Neurology, Comprehensive Epilepsy Center, Yale University School of Medicine, 15 York Street, New Haven, CT 06510, USA; Epilepsy Center of Excellence, VA Connecticut Healthcare System, West Haven, CT, USA. Electronic address: [email protected].;Department of Neurology, Comprehensive Epilepsy Center, Yale University School of Medicine, 15 York Street, New Haven, CT 06510, USA.;Brown University, Rhode Island Hospital, Potter 3, 593 Eddy Street, Providence, RI 02903, USA.",
"authors": "Tolchin|Benjamin|B|;Hirsch|Lawrence J|LJ|;LaFrance|William Curt|WC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.psc.2020.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-953X",
"issue": "43(2)",
"journal": "The Psychiatric clinics of North America",
"keywords": "Anxiety and epilepsy; Autism and epilepsy; Cognitive impairment and epilepsy; Depression and epilepsy; Psychogenic nonepileptic seizures; Psychosis and epilepsy",
"medline_ta": "Psychiatr Clin North Am",
"mesh_terms": "D001007:Anxiety; D060825:Cognitive Dysfunction; D015897:Comorbidity; D003863:Depression; D004827:Epilepsy; D006801:Humans; D011618:Psychotic Disorders; D011788:Quality of Life",
"nlm_unique_id": "7708110",
"other_id": null,
"pages": "275-290",
"pmc": null,
"pmid": "32439022",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": null,
"title": "Neuropsychiatric Aspects of Epilepsy.",
"title_normalized": "neuropsychiatric aspects of epilepsy"
} | [
{
"companynumb": "US-OTSUKA-2020_017934",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
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"drugauthorizationnumb": "021436",
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"drugdosagetext": "UNK",
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"drugindication": "Product used for unknown indication",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "ARIPIPRAZOLE"
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Tolchin B, Hirsch LJ, LaFrance WCJ. Neuropsychiatric Aspects of Epilepsy. PSYCHIATRIC CLINICS OF NORTH AMERICA. 2020;43(2):275-90",
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},
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},
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"safetyreportversion": 1,
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},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "OBJECTIVE\nAtypical anti-psychotic drugs (APDs) are widely used in psychotic disorders refractory to conventional neuroleptic agents.\n\n\nRESULTS\nThree cases of new-onset diabetes are reported in Caucasian men who were on clozapine (one) or olanzapine (two) for 3-6 months. They had a distinct presentation: weight loss, ketosis (one ketoacidosis), severe hyperglycaemia requiring insulin therapy, and relative insulin deficiency as reflected by glucagon stimulatory tests. In all cases, insulin was stopped within 1 month after the APD was discontinued.\n\n\nCONCLUSIONS\nNovel APDs not only induce diabetes as a result of weight gain in predisposed patients, but can also lead to a reversible state of insulin deficiency, and sometimes ketoacidosis.",
"affiliations": "Service de Nutrition-Diabétologie, Hôpital Haut-Lévêque, Pessac, France.",
"authors": "Rigalleau|V|V|;Gatta|B|B|;Bonnaud|S|S|;Masson|M|M|;Bourgeois|M L|ML|;Vergnot|V|V|;Gin|H|H|",
"chemical_list": "D014150:Antipsychotic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D001569:Benzodiazepines; D010890:Pirenzepine; D003024:Clozapine; D000077152:Olanzapine; D005905:Glyburide",
"country": "England",
"delete": false,
"doi": "10.1046/j.1464-5491.2000.00296.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-3071",
"issue": "17(6)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
"keywords": null,
"medline_ta": "Diabet Med",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003024:Clozapine; D003866:Depressive Disorder; D003920:Diabetes Mellitus; D005905:Glyburide; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010890:Pirenzepine; D011618:Psychotic Disorders; D012559:Schizophrenia",
"nlm_unique_id": "8500858",
"other_id": null,
"pages": "484-6",
"pmc": null,
"pmid": "10975220",
"pubdate": "2000-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diabetes as a result of atypical anti-psychotic drugs--a report of three cases.",
"title_normalized": "diabetes as a result of atypical anti psychotic drugs a report of three cases"
} | [
{
"companynumb": "FR-MACLEODS PHARMACEUTICALS US LTD-MAC2022034439",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "Psychotic disorder",
"drugintervaldosagedefinition": null,
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}
],
"patientagegroup": null,
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"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Diabetes mellitus",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Ketoacidosis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Rigalleau V, Gatta B, Bonnaud S, Masson M, Bourgeois ML, Vergnot V et.al. Diabetes as a result of atypical anti-psychotic drugs-a report of three cases. Diabetic Medicine. 2000;17(6):484-6",
"literaturereference_normalized": "diabetes as a result of atypical anti psychotic drugs a report of three cases",
"qualification": "1",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20220221",
"receivedate": "20220221",
"receiver": {
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},
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"safetyreportid": 20495662,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
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"seriousnessdeath": 2,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
},
{
"companynumb": "FR-MACLEODS PHARMACEUTICALS US LTD-MAC2022034437",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "10 MILLIGRAM, QD",
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"drugindication": "Depression",
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"medicinalproduct": "OLANZAPINE"
},
{
"actiondrug": "1",
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},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "20 MILLIGRAM, QD, INCREASED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstartdate": "199904",
"drugstartdateformat": "610",
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"drugstructuredosageunit": "003",
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"medicinalproduct": "OLANZAPINE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Diabetes mellitus",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Rigalleau V, Gatta B, Bonnaud S, Masson M, Bourgeois ML, Vergnot V, et al. Diabetes as a result of atypical anti-psychotic drugs-a report of three cases. Diabetic Medicine. 2000;17(6):484-6",
"literaturereference_normalized": "diabetes as a result of atypical anti psychotic drugs a report of three cases",
"qualification": "1",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20220221",
"receivedate": "20220221",
"receiver": {
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},
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"safetyreportversion": 1,
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220424"
}
] |
{
"abstract": "Recently, novel therapeutic regimens, such as FOLFIRINOX, have been demonstrated to show promising anti-cancer activity and to be superior to single-agent gemcitabine for unresectable pancreatic cancer patients with good performance status. In this study, we report 2 cases of pancreatic cancer treated with FOLFIRINOX and G-CSF prophylaxis at the standard therapeutic dose, after treatment with gemcitabine and S-1 chemotherapy failed. It has been reported that grade 3-4 neutropenia frequently occurs in patients treated with the FOLFIRINOX regimen. Furthermore, granulocyte colony-stimulating factor(G-CSF) has not been recommended for helping with neutropenia in pancreatic cancer patients treated with FOLFIRINOX: however, prophylactic use of G-CSF is recommended for cancer patients who are at high risk of neutropenic events. On the other hand, modified FOLFIRINOX(no bolus 5-FU)has demonstrated an improved safety profile with maintained efficacy, and further randomized studies to compare the overall survivals of the modified FOLFIRINOX versus FOLFIRINOX regimen and G-CSF prophylaxis are hence needed in the future.",
"affiliations": "Division of Modern Medical Technology, Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center.",
"authors": "Kiba|Takayoshi|T|;Okada|Yuko|Y|;Kajiume|Sayoko|S|;Yamaguchi|Atsushi|A|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008297:Male; D009503:Neutropenia; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "629-32",
"pmc": null,
"pmid": "25981661",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Two cases of pancreatic cancer treated with FOLFIRINOX regimen and G-CSF prophylaxis at the standard therapeutic dose.",
"title_normalized": "two cases of pancreatic cancer treated with folfirinox regimen and g csf prophylaxis at the standard therapeutic dose"
} | [
{
"companynumb": "JP-ACCORD-031835",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "FOLFIRINOX.?STARTED 1ST COURSE WITH 85MG/M2.?THEN DOSE REDUCED TO 65MG/M2 IN 2ND COURSE.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "1",
"activesubstance": {
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{
"abstract": "PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors.\n\n\n\nPatients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m2 (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m2 and LV 200 mg/m2 on days 1 and 8, every 3 weeks.\n\n\n\nA total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m2 dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m2. The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level.\n\n\n\nThe MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m2, which will be the recommended dose for future studies.\n\n\n\nThe trial was retrospectively registered ( NCT02884128 ) with date of registration: August 12, 2016.",
"affiliations": "National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan, 704, Taiwan.;Division of Hematology and Oncology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.;Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.;Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.;PharmaEngine, Inc, Taipei, Taiwan.;PharmaEngine, Inc, Taipei, Taiwan.;National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan, 704, Taiwan. [email protected].",
"authors": "Chiang|Nai-Jung|NJ|;Chao|Tsu-Yi|TY|;Hsieh|Ruey-Kuen|RK|;Wang|Cheng-Hsu|CH|;Wang|Yi-Wen|YW|;Yeh|C Grace|CG|;Chen|Li-Tzong|LT|",
"chemical_list": "D004338:Drug Combinations; D008081:Liposomes; D013395:Sucrose; C584112:irinotecan sucrosofate; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-016-2933-6",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 293310.1186/s12885-016-2933-6Research ArticleA phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors Chiang Nai-Jung [email protected] 12Chao Tsu-Yi [email protected] 3Hsieh Ruey-Kuen [email protected] 4Wang Cheng-Hsu [email protected] 5Wang Yi-Wen [email protected] 6Yeh C. Grace [email protected] 6Chen Li-Tzong [email protected]@nhri.org.tw 1271 National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan, 704 Taiwan 2 Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 3 Division of Hematology and Oncology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan 4 Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan 5 Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan 6 PharmaEngine, Inc, Taipei, Taiwan 7 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 21 11 2016 21 11 2016 2016 16 9072 3 2016 28 10 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors.\n\nMethods\nPatients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m2 (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m2 and LV 200 mg/m2 on days 1 and 8, every 3 weeks.\n\nResults\nA total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m2 dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m2. The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level.\n\nConclusions\nThe MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m2, which will be the recommended dose for future studies.\n\nTrial registration\nThe trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12885-016-2933-6) contains supplementary material, which is available to authorized users.\n\nKeywords\nLiposomal irinotecan5-fluorouracilDose-limiting toxicityMaximum tolerated doseissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nPEP02 (also known as MM-398, nal-IRI) is an encapsulated nanoliposomal formulation of irinotecan hydrochloride (CPT-11) [1]. Irinotecan is a water-soluble semi-synthetic analogue of the natural alkaloid, camptothecin. It prevents DNA from unwinding and replication by inhibition of topoisomerase-I, and has already been approved for use worldwide. However, at higher dosage, irinotecan causes severe diarrhea and myelosuppression, which limits its therapeutic index. The therapeutic benefits of encapsulating anti-cancer drugs such as daunorubicin, doxorubicin and cytarabine in liposomes have been documented [2]. An appropriately designed liposome formulation may reduce the toxicity of cytotoxic agents to healthy tissues while maintaining its anti-tumor potency, which in turn improves treatment efficacy.\n\nIn our previous study, the maximum tolerated dose (MTD) of PEP02 monotherapy was found to be 120 mg/m2 at 3-week interval with favorable pharmacokinetic (PK) parameters of the active metabolite, SN-38 [3]. The acceptable toxicity profile explains the beneficial effects of PEP02 in combination with other cytotoxic agents. Irinotecan in combination with 5-fluorouracil (5-FU) and leucovorin (LV) is the first-line or second-line therapy for locally advanced and metastatic colorectal cancer [4]. A synergistic effect was observed upon the sequential administration of irinotecan and 5-FU [5, 6]. On the basis of these results, the combination of PEP02 with 5-FU and LV is considered a reasonable approach to enhance their therapeutic efficacy. This Phase I dose escalation study aimed to investigate the MTD, dose-limiting toxicity (DLT) and recommended dose of PEP02 in combination with 5-FU and LV.\n\nIrinotecan is converted by carboxylesterases to its potent metabolite, SN-38, which is detoxified in part by converting to inactive SN-38 glucuronide (SN-38G) through UDP-glucuronosyl transferase 1A isoforms (UGT1A) [7]. The activity of UGT1A is related to gene polymorphism of UGT1A family members. Individuals with genetic mutations of UGT1A exhibit reduced glucuronidation of SN-38 and an elevated risk of neutropenia and diarrhea compared with patients with wild-type alleles [8]. The correlation of UGT1A polymorphisms and toxicities is discussed.\n\nMethods\nPatient eligibility\nThis trial was a multi-center, open-label, Phase I, dose escalation study of PEP02 (PharmaEngine, Inc., Taipei, Taiwan) in combination with 5-FU and LV in patients with advanced solid tumors. The inclusion criteria were as follows: (1) histologically or cytologically confirmed advanced solid tumor refractory to standard systemic chemotherapy; (2) aged between 20 and 70 years; (3) Eastern Cooperative Oncology Group performance score (ECOG PS) of 0 or 1; (4) life expectancy ≥ 2 months; (5) adequate bone marrow, hepatic and renal functions: white blood cells ≥ 3,000/mm3, absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 10 g/dL, serum total bilirubin within normal range, AST and ALT ≤ 3× upper limit of normal range, serum creatinine ≤ 1.5 mg/dL and blood urea nitrogen ≤ 25 mg/dL; (6) no prior treatment for at least 4 weeks before study initiation, including major surgery, chemotherapy, any investigational products or radiotherapy (6 weeks for nitrosoureas and mitomycin C); (7) recovered from all treatment-related toxicities or resolved to no greater than grade 1 before enrollment; and (8) written informed consent.\n\nThe exclusion criteria were as follows: (1) known or suspicious primary or secondary brain tumors; (2) HBsAg-positive or anti-HCV antibody-positive with splenomegaly (defined as spleen size > 11 cm measured in longest diameter by CT scan); (3) uncontrolled active infection or other concomitant serious disease; (4) pregnancy or breast-feeding; (5) previous exposure to irinotecan; (6) history of allergic reactions to compounds of similar chemical or biologic composition as PEP02, 5-FU, or LV. This trial was approved by the independent ethics committee of each participating institute and the Department of Health, Executive Yuan, Taiwan, and was performed in accordance with International Conference on Harmonization Good Clinical Practice guidelines and Good Clinical Laboratory Practice.\n\nTreatment and dose escalation schedule\nThe study had a traditional 3 + 3 design with three-patient cohorts for each dose level. Dose escalation was only performed after the successful completion of at least 1 full 3-week cycle by each patient in the dosing cohort. If none of the first three patients experienced DLT, dose escalation was carried out for the next cohort of patients. If one of three patients developed DLT, the cohort was expanded to six patients. If two or more patients experienced any DLT, no more patients were to be entered at the current dose level and the lower dose level was to be declared the MTD. The MTD was the highest dose level with no more than 1 DLT among the accruals. A minimum of six patients were required to be tested at the dose level defined as the MTD. The starting dose of PEP02 was 60 mg/m2 with dose expressing as the irinotecan hydrochloride trihydrate salt, which was escalated by increments of 20 mg/m2 between dose levels. Each patient was assigned to a dose level, and no intra-patient dose escalation was allowed. 5-FU and LV were administered at a fixed dose of 2000 and 200 mg/m2, respectively. PEP02 was administered by intravenous infusion over 90 min on Day 1, followed by 24-h intravenous infusion of 5-FU and LV on days 1 and 8 every 3 weeks. Pre-medication included dexamethasone and a serotonin-antagonist. Prophylactic anti-cholinergic agent was not administered unless acute cholinergic reaction was observed in prior cycles of treatment. Anti-diarrhea agents were started according to the guideline of American Society of Clinical Oncology. Treatment was continued to a maximum of 6 cycles or until disease progression, unacceptable toxicity, treatment delay > 2 weeks, or patient’s refusal or death.\n\nDose modification on day 1 of subsequent cycles was only applied to PEP02, while the dosage of 5-FU/LV remained unchanged. All dose modifications were to be based on the worst proceeding toxicity. For patients who experienced ≥ grade 3 hematologic or non-hematologic toxicities, the dose of PEP02 was reduced by one dose level. In addition, the dose of 5-FU on day 8 of each cycle could be adjusted according to the laboratory data before the dosing. If the absolute neutrophil count (ANC) is between 1,000 and 1,499/μL, platelet count is between 50,000 and 99,999/μL, or diarrhea of grade 2 severity is observed, the dose of 5-FU could be decreased by 25%. 5-FU was withheld when ANC < 999/μL, platelet count < 50,000/μL or grade 3 diarrhea was observed. The conditions for the administration of the next cycle of treatment were ANC ≥ 1,500/μL, platelet counts ≥ 100,000/μL, serum creatinine ≤ 1.5 mg/dL, and full resolution of gastrointestinal toxicities.\n\nDefinition of dose-limiting toxicity (DLT)\nToxicities were assessed according to the National Cancer Institute’s CTCAE version 3.0 (CTCAE, v3). DLT was defined as occurrence of 1 or more of the following events attributable to the study drugs during the first cycle: (1) grade III or IV non-hematological toxicity, except grade III nausea, vomiting, or anorexia; (2) grade IV hematologic toxicity lasting for ≥3 days; (3) grade III hematologic toxicity associated with complications (e.g. neutropenic fever or bleeding); (4) dose delay of more than 2 weeks owing to drug-related toxicity. In addition, hematological assessment was performed daily whenever grade IV hematological toxicity occurred.\n\nPatient evaluation\nPretreatment evaluations included medical history, physical examination, performance status, complete blood count, hepatic and renal functions and serology of HBsAg and anti-HCV antibody. Patients were evaluated weekly with complete blood count and biochemistry analysis. Radiologic studies to assess response were performed at baseline and then every 2 cycles of therapy according to the guidelines of Responses Evaluation Criteria in Solid Tumors criteria version 1.0. All complete and partial responses required confirmation by two consecutive observations at least 4 weeks apart.\n\nPharmacokinetic sampling and analyzing\nDuring the first cycle of treatment, blood samples were collected before treatment, during the infusion at 30 and 60 min, at the end of infusion, at1, 3, 9, 24, 48, 72 and 168 h after the end of infusion, and before the second cycle. Plasma levels of irinotecan and SN-38 were measured by validated LC/MS/MS analytical methods. The peak plasma concentration (Cmax), time at which Cmax occurred (Tmax), elimination half-life (t1/2), area under the plasma concentration-time curve from zero to time t (AUC0→t), AUC through infinite time (AUC0→∞), and clearance (CL) were calculated. Pharmacokinetic parameters of individual data set were analyzed by a non-compartmental model by using WinNonlin™ (Centara, St. Louis, MO).\n\nPharmacogenetic studies\nAdditional 5 mL blood sample was collected into a PAXgene vacutainer tube and DNA was extracted using a DNA purification kit. Fragment analysis was used for the detection of short tandem repeat polymorphism. The TaqMan-Allelic discrimination method or direct sequencing was used for the detection of single nucleotide polymorphisms, including UGT1A1*28 and UGT1A1*6.\n\nStatistical analysis\nThe statistical analysis was descriptive and any inferential statistics was exploratory in nature. Summary statistics were provided for all efficacy, pharmacokinetic, pharmacogenetic, safety and baseline/demographic variables. For categorical variables, frequency tables including percentages were presented. For continuous variables, descriptive statistics such as number of available observations, mean with standard deviation (STD), minimum, and maximum were tabulated.\n\nResults\nPatient characteristics, dose escalation, DLT and MTD\nBetween March 2006 and August 2008, a total of 16 patients (seven men and nine women) were enrolled. The demographics and baseline characteristics of all patients are summarized in Table 1. The median age was 49 years (range: 30–67 years). The most common primary tumors were pancreatic, stomach, and breast carcinomas. Other tumor types included keratinizing squamous cell carcinoma, cervical cancer and nasopharyngeal carcinoma. A total of 66 cycles of treatment were initiated, with an average of 4.1 cycles per patient (range: 1–6 cycles). There were seven patients (43.8%) completed all 6 cycles of treatment.Table 1 Patient characteristics\n\nCharacteristic\tPatients, n (%)\t\nPatients enrolled\t16\t\nAge (yrs)\t\n Median\t49\t\n Range\t30–67\t\nSex\t\n Male\t7 (44)\t\n Female\t9 (56)\t\nECOG performance status\t\n 0\t3 (19)\t\n 1\t13 (81)\t\nTumor type\t\n Breast cancer\t4 (25)\t\n Pancreatic cancer\t5 (31)\t\n gastric cancer\t4 (25)\t\n Other\t3 (19)\t\nPrevious treatment\t\n Surgery\t14 (88)\t\n Radiotherapy\t9 (56)\t\n Chemotherapy\t16 (100)\t\n\nAbbreviation: ECOG Eastern Cooperative Oncology Group\n\n\n\n\nThe dose escalation schedule is outlined in Table 2. These patients were assigned to four dose levels, with three, six, five and two patients in dose level I, II, III, and IV, respectively. At first, none of the first three patients experienced DLT at dose level I, II, and III; therefore, the dose level was further escalated to 120 mg/m2. Because both of the initial two patients at 120 mg/m2 level experienced DLT during the first cycle of treatment (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea), three additional patients were recruited at the prior dose level, 100 mg/m2. However, both of the two newly accrued patients at 100 mg/m2 level experienced DLTs (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), resulting in 2 episodes of DLT among the five patients at this dose level. Therefore, the tested dose level was further de-escalated to 80 mg/m2. Since none of the patients experienced any DLT, 80 mg/m2 of PEP02 by 90-min intravenous infusion was determined as the MTD in combination with weekly infusion of 5-FU/LV on days 1 and 8 of a 21-day cycle.Table 2 Dose escalation scheme\n\nDose Level\tPEP02 (mg/m2)\tNo. patients\tNo. patients with DLT\t\nI\t60\t3\t0\t\nII\t80\t3 + 3\t0 + 0\t\nIII\t100\t3 + 2\t0 + 2\t\nIV\t120\t2\t2\t\n\nAbbreviation: DLT dose-limiting toxicity\n\n\n\n\nToxicity\nAll 16 patients were assessed for toxicity. Table 3 summarizes the therapy-induced toxicity during treatment. There were three (18.4%) patients had grade III or above adverse events (AEs), and 13 and 0.2% of AEs led to dosing delay/reduction and permanent discontinuation of treatment, respectively. No treatment-related death was reported in the study.Table 3 Treatment-emergent AEs with maximum CTC grade by dose level (incidence ≥ 20%)\n\n\tTotal (N = 16)\t60 mg/m2\n\n\nN = 3\t80 mg/m2\n\n\nN = 6\t100 mg/m2\n\n\nN = 5\t120 mg/m2\n\n\nN = 2\t\nAE\tAll grade\tGrade 3–4\t\nAnemia\t7 (43.8%)\t0\t0\t2 (40%)\t0\t\nLeukopenia\t6 (37.5%)\t0\t0\t2 (40%)\t1 (50%)\t\nNeutropenia\t6 (37.5%)\t1 (33.3%)\t1 (16.7%)\t2 (40%)\t1 (50%)\t\nAbdominal pain\t7 (43.8%)\t0\t0\t1 (20%)\t1 (50%)\t\nDiarrhea\t12 (75.0%)\t0\t1 (16.7%)\t2 (40%)\t2 (100%)\t\nNausea\t13 (81.3%)\t0\t1 (16.7%)\t0\t0\t\nVomiting\t12 (75.0%)\t0\t1 (16.7%)\t0\t0\t\nFatigue\t8 (50.0%)\t0\t0\t1 (20%)\t0\t\nInfection\t6 (37.5%)\t0\t0\t2 (40%)\t1 (50%)\t\nAnorexia\t4 (25.0%)\t0\t0\t1 (20%)\t0\t\nHypoalbuminemia\t4 (25.0%)\t0\t1 (16.7%)\t0\t0\t\nHypokalemia\t8 (50.0%)\t1 (33.3%)\t2 (33.3%)\t2 (40%)\t1 (50%)\t\nHyponatremia\t4 (25.0%)\t0\t0\t1 (20%)\t1 (50%)\t\nCough\t5 (31.3%)\t1 (33.3%)\t0\t0\t0\t\n\nAbbreviation: AE adverse event\n\n\n\n\nThe most common treatment-related AEs included nausea (81.3% in incidence), followed by diarrhea (75.0%), vomiting (68.8%), fatigue (43.8%), mucositis (mucosa inflammation, 43.8%), leucopenia (37.5%), neutropenia (37.5%), weight loss (37.5%), anemia (31.3%), and alopecia (31.3%). Acute cholinergic reaction was rarely observed. Compared with the entire safety population, patients who received 80 mg/m2, the MTD dose of PEP02 experienced less treatment-related AEs (51.1% versus 57.6%), as well as grade III or above AEs (10.6% versus 18.4%).\n\nPharmacokinetics and exploratory pharmacogenetic studies\nThe PK of PEP02 is shown in Table 4, Fig. 1a and b. CPT-11 and SN-38 were characterized for PEP02 single dose PK at dose levels of 60, 80, 100, and 120 mg/m2 by 90-min intravenous infusion. Changes in the plasma concentration of CPT-11 showed almost the same pattern at all levels. All concentration curves of plasma CPT-11 peaked quickly and reached the maximum around 1 h after the end of PEP02 infusion and gradually dropped in a mono-exponential pattern until the last sampling point, which was similar to that observed for PEP02 monotherapy in a previous study [3]. At the MTD of PEP02, the Cmax of SN-38 was lower (7.98 ± 4.39 ng/ml) than that of the conventional formulation of irinotecan at 125 mg/m2 (26.3 ± 11.9 ng/ml), whereas the AUC of SN-38 was higher than that of irinotecan (AUC0 → t: 343.36 ± 133.24 ng/ml*h vs. 229 ± 108 ng/mL*h). The t1/2 of SN-38 at the MTD of PEP02 was 57.54 ± 17.81 h, which was relatively longer than that of the conventional formulation (10.4 ± 3.1 h). No statistically significant difference was observed in the mean values of all pharmacokinetic parameters of SN-38 among the 4 dose levels.Table 4 Pharmacokinetic parameters of PEP02 at each dose level\n\n\tDose of PEP02\n(mg/m2)\t\nC\nmax\n\nCPT-11\n(μg/mL)\nSN-38\n(ng/mL)\t\nT\nmax\n\n(hr)\tAUC0→169.5\n\nCPT-11\n(hr-μg/mL)\nSN-38\n(hr-ng/mL)\tAUC0→∞\n\nCPT-11\n(hr-μg/mL)\nSN-38\n(hr-ng/mL)\t\nV\nss\n\n(L/m2)\tCl\n(mL/hr/m2)\t\nt\n1/2\n\n(hr)\t\nTotal CPT-11\t60, N = 3\t28.9 ± 15.8\t2.4 ± 0.7\t1047 ± 1210\t1047 ± 1210\t2.80 ± 1.59\t136 ± 116\t21.1 ± 11.7\t\n80, N = 6\t29.2 ± 5.2\t2.1 ± 0.7\t1096 ± 834\t1151 ± 880\t3.39 ± 0.74\t124 ± 106\t33.3 ± 15.1\t\n100, N = 5\t44.1 ± 7.7\t4.0 ± 3.8\t2237 ± 1090\t2289 ± 1119\t2.86 ± 0.75\t58 ± 37\t43.17 ± 4.8\t\n120, N = 2\t47.9 ± 16.2\t2.3 ± 0.9\t1254 ± 553\t1254 ± 553\t3.95 ± 0.83\t106 ± 47\t54.4 ± 17.4\t\nSN-38\t60, N = 3\t7.02 ± 5.64\t13.1 ± 11.7\t364 ± 222\t1370 ± 1122\tNA\tNA\t183.8 ± 172.3\t\n80, N = 6\t7.98 ± 4.39\t13.3 ± 18.3\t343 ± 133\t505 ± 165\tNA\tNA\t57.5 ± 17.8\t\n100, N = 5\t7.39 ± 1.68\t12.2 ± 12.3\t539 ± 368\t840 ± 433\tNA\tNA\t73.4 ± 18.3\t\n120, N = 2\t7.26 ± 3.90\t37.8 ± 17.2\t353 ± 164\t305\tNA\tNA\t30.8\t\n\tIrinotecana\n\t26.3 ± 11.9\tNA\t229 ± 108\tNA\tNA\tNA\t10.4 ± 3.1\t\nMean ± STD; C\nmax, peak concentration in plasma; T\nmax, time to achieve peak plasma concentration; AUC0→169.5 and AUC0→∞, area under the plasma concentration-time curve from time zero to 169.5 h and infinity, respectively; Vss, volume of distribution at steady state; t\n1/2, plasma terminal elimination half-life; Cl, total clearance of drug from plasma; NA, not available\n\n\naIrinotecan 125 mg/m2, package inset of Campto®\n\n\n\nFig. 1 Plasma concentration-time profiles of a CPT-11 and b SN-38 at different PEP02 doses\n\n\n\n\nThe majority of subjects showed wild type alleles for UGT1A1*28 (TA6TA6: 88%) and UGT1A1*6 (GG: 69%). No subject harbored homozygous mutation in UGT1A1*28 or UGT1A1*6 allele. Two and five patients had heterozygous UGT1A1*28 and UGT1A1*6, respectively. Of which, one patient with heterozygous UGT1A1*28 and UGT1A1*6 experienced grade IV neutropenia and grade III diarrhea, and had the largest dose-normalized AUC of SN-38. Four out of the 5 subjects with heterozygous UGT1A1*6 possessed relatively higher dose-normalized AUC of SN-38 comparing to other subjects; of which 3 patients experienced grade III toxicities.\n\nAntitumor activity\nOne patient at dose level III, who suffered from DLT did not complete at least one post-treatment tumor assessment. Among the 15 efficacy evaluable patients, two (13.3%) had confirmed partial response (PR) and nine (60%) had stable disease (SD), leading to the overall disease control rate (DCR) of 73.3%. At the MTD of 80 mg/m2, 1 PR and 4 SD were observed among six patients. The tumor response rate and the disease control rate were 16.7 and 83.3%, respectively. PR was observed in one gastric cancer patient (at the 80 mg/m2 dose level) and one breast cancer patient (at the 100 mg/m2 dose level).\n\nDiscussion\nThe current study evaluated the safety profile and preliminary efficacy of PEP02 in combination with 5-FU and LV, in patients with refractory advanced malignancy. Gastrointestinal toxicities and myelosuppression were the major DLTs, which were comparable to those of free irinotecan and PEP02 monotherapy [3, 9]. The MTD (80 mg/m2) of PEP02, in combination with infusion of 5-FU and LV on days 1 and 8 of every-3-week schedule is recommended for the future studies. In a previous study, the MTD of PEP02 monotherapy with a 3-week interval was 120 mg/m2 [3]. The favorable toxicity profiles of PEP02 made it a better agent to combine with other cytotoxic agents. 5-FU/LV in combination with irinotecan was the first line treatment of colorectal cancer, which explains our interest in the evaluation of PEP02 in combination with 5-FU/LV. The dose of weekly 5-FU in this study was fixed as 2000 mg/m2, which mimicked the AIO regimen commonly used in Europe and Asia [10, 11]. The percentage of grade III or above AEs or all treatment-related AEs in the MTD group was lower than that in the overall safety population. For hematologic laboratory parameters, nadir was observed between days 13 and 16 after PEP02 administration; however blood biochemistry was mostly unaffected. These tolerable and manageable hematological and non-hematological toxicities indicated that this combination therapy is feasible for further application.\n\nPEP02 affected the PK characteristics of irinotecan. Compared to the data of 125 mg/m2 free-form irinotecan, 80 mg/m2 of PEP02 showed lower Cmax (8.0 ± 4.4 ng/mL vs. 26.3 ± 11.9 ng/mL), longer terminal t1/2 (57.5 ± 17.8 h vs. 10.4 ± 3.1 h) and higher AUC (343 ± 133 ng/mL*hr vs. 229 ± 108 ng/mL*hr) of SN-38 [12, 13]. These favorable PK parameters indicated that PEP02 could decrease the influx of SN-38 from the central compartment to the peripheral, leading to less treatment-related toxicities, even in combination with 5-FU/LV. The PK data showed the dose-dependent linear distribution of CPT-11 when study doses were increased from 60 to 120 mg/m2, but no statistically significant difference was observed in the mean values of pharmacokinetic parameters of CPT-11 and SN-38, including dose-normalized Cmax, AUC parameters, t1/2, CL, and Vss, possibly owning to narrow dose increments, small sample size and high inter-individual variability.\n\nThe UGT1A1 gene encoded a varied spectrum of active enzymes that are responsible for drug metabolism, including UGT. The UGT1A1*28 allele is characterized by the presence of a 7th dinucleotide repeat in the TATA box of the promoter region, compared to the UGT1A1*1 allele with 6 repeats. This increased number of repeats results in the reduction in the expression of UGT, leading to decreased SN-38 detoxification and prolonged exposure time of SN-38 in the intestines. Thus, patients with homozygous or heterozygous UGT1A1*28 and treated with irinotecan commonly developed dose limiting neutropenia and late diarrhea [14]. Similar to UGT1A1*28 polymorphism, the UGT1A1*6 allele also can decrease the activity of the enzyme in the heterozygous or homozygous genotype. It has been reported that patients with both UGT1A1*28 and UGT1A1*6 heterozygosity were at high risk to develop irinotecan-related toxicities [15, 16]. In our study, owning to the small sample size, a clear correlation cannot be obtained between polymorphism of UGT1A family genes and pharmacokinetic parameters or toxicity of PEP02. However, one subject with heterozygous mutation in both UGT1A1*6 and UGT1A1*28 had the highest dose-normalized AUC of SN-38 and experienced grade IV neutropenia and grade III diarrhea. To draw any firm conclusions, a PK/PD study according to polymorphism of UGT1A family genes should be performed [17].\n\nWith the limitation of being a very small sample size study of 15 efficacy evaluable population, two subjects had confirmed PR and nine subjects had SD as their best-ever responses during this study period. The tumor response rate and disease control rate were 13 and 73%, respectively. In a Phase I trial, clinical efficacy cannot be defined accurately because of heterogeneous tumor types and different dose levels. Of the evaluable patients, PR was noted in a heavily treated breast cancer patient and a gastric cancer patient, and four out of five patients with pancreatic cancer had SD, implying that this combination regimen is worthy of further investigation. Indeed, PEP02 either alone or in combination with 5-FU/LV was investigated in a phase II PEP0208 study [18] and a phase III NAPOLI-1 study [19] in metastatic pancreatic cancer patients who progressed after gemcitabine-containing regimen. The NAPOLI-1 study formed the basis for the regulatory approvals of PEP02 (Irinotecan liposome injection) by the Taiwan FDA and US FDA in October 2015.\n\nConclusions\nThis is the first trial to apply PEP02 in combination with 5-FU and LV in patients with solid tumors, and major treatment-related DLTs were myelosuppression and diarrhea. PEP02 had a lower Cmax, longer t1/2 and increased AUC0→t of SN-38 compared to irinotecan; similar results were observed in another study on PEP02 infusion alone. The dose of 80 mg/m2 of PEP02 in combination with D1 and D8 infusion of 5-FU/LV with every-3-week schedule is recommended for future studies.\n\nAdditional file\n\nAdditional file 1: Table S1. Tumor type, dose level, DLT, best response and single nucleotide polymorphisms of UGT1A1*28 and UGT1A1*6. (DOCX 18 kb)\n\n\n\n\nAbbreviations\n5-FU5-fluorouracil\n\nAEsAdverse events\n\nANCAbsolute neutrophil count\n\nAUC0→∞AUC through infinite time\n\nAUC0→tPlasma concentration-time curve from zero to time t\n\nCLClearance\n\nCmaxPeak plasma concentration\n\nCPT-11Irinotecan hydrochloride\n\nCTComputed tomography\n\nDLTDose-limiting toxicity\n\nECOGEastern Cooperative Oncology Group\n\nFDAThe Food and Drug Administration\n\nLVLeucovorin\n\nMTDMaximum tolerated dose\n\nPGPharmacogenetics\n\nPKPharmacokinetics\n\nPRPartial response\n\nPSPerformance score\n\nSDStable disease\n\nSN-38GSN-38 glucuronide\n\nSTDStandard deviation\n\nt1/2Elimination half-life\n\nTmaxTime at which Cmax occurred\n\nUGT1AUDP-glucuronosyl transferase 1A isoforms\n\nVssVolume of distribution at steady state\n\nWe thank the patients and their families who participated in this phase I study, and also thank the medical and nursing staff of the investigational sites for the care and support of the patients in this study.\n\nFunding\nThis study was supported by PharmaEngine, Inc., Taipei, Taiwan.\n\nAvailability of data and materials\nThe study is an industry-sponsored study. The sponsor, PharmaEngine Inc, Taipei, Taiwan, prefers to keep the raw dataset in-house. However, all the information supporting the conclusions of this article is included within the text and tables of the article and summarized in Additional file 1: Table S1.\n\nAuthors’ contributions\nNJC and LTC wrote the manuscript. TYC, RKH, CHW and LTC enrolled the patients. NJC, YWW, CGY and LTC collected and analyzed data. YWW, CGY and LTC conceived of the study, participated in its design and coordination. All authors contributed to and approved the final version of the manuscript.\n\nCompeting interests\nNJC, TYC, RKH, JYC, and CHW report no conflicts of interests. YWW and CGY are full-time employees of PharmaEngine. LTC has received an honorarium from PharmaEngine for an advisory board.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe protocol and all recruiting materials and consent foam had been approved by the Joint Institutional Review Board (JIRB), covering all the participating hospitals in the study including Tri-Service General Hospital, Mackay Memorial Hospital, Linkou Chang Gung Memorial Hospital, National Cheng Kung University Hospital, and Kaohsiung Medical University This study had been performed in accordance with International Conference on Harmonization Good Clinical Practice guidelines, Good Clinical Laboratory Practice, and the Declaration of Helsinki. All participants from each institutions provided written informed consent.\n==== Refs\nReferences\n1. Drummond DC Noble CO Guo Z Hong K Park JW Kirpotin DB Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy Cancer Res 2006 66 6 3271 3277 10.1158/0008-5472.CAN-05-4007 16540680 \n2. Tsai CS Park JW Chen LT Nanovector-based therapies in advanced pancreatic cancer J Gastrointest Oncol 2011 2 3 185 194 22811849 \n3. Chang TC, Shiah HS, Yang CH, Yeh KH, Cheng AL, Shen BN, Wang YW, Yeh CG, Chiang NJ, Chang JY et al. Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients. Cancer Chemother Pharmacol. 2015;75(3):579–86.\n4. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905–14.\n5. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041–7.\n6. Kambe M Kikuchi H Gamo M Yoshioka T Ohashi Y Kanamaru R Phase I study of irinotecan by 24-h intravenous infusion in combination with 5-fluorouracil in metastatic colorectal cancer Int J Clin Oncol 2012 17 2 150 154 10.1007/s10147-011-0272-9 21786211 \n7. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998;101(4):847–54.\n8. Hoskins JM McLeod HL UGT1A and irinotecan toxicity: keeping it in the family J Clin Oncol 2009 27 15 2419 2421 10.1200/JCO.2008.20.9478 19364959 \n9. Fuchs CS Moore MR Harker G Villa L Rinaldi D Hecht JR Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer J Clin Oncol 2003 21 5 807 814 10.1200/JCO.2003.08.058 12610178 \n10. Kohne CH, Wils J, Lorenz M, Schoffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R et al. Randomized phase III study of high-dose fluorouracil given as a weekly 24-h infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003;21(20):3721–8.\n11. Chen LT, Liu TW, Wu CW, Chung TR, Shiah HS, Jan CM, Liu JM, Whang-Peng J, Chang JY. A phase I study of weekly docetaxel, 24-h infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer. Oncology. 2002;63(3):239–47.\n12. Rivory LP Haaz MC Canal P Lokiec F Armand JP Robert J Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials Clin Cancer Res 1997 3 8 1261 1266 9815808 \n13. Rothenberg ML, Kuhn JG, Burris 3rd HA, Nelson J, Eckardt JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI et al. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol. 1993;11(11):2194–204.\n14. Palomaki GE Bradley LA Douglas MP Kolor K Dotson WD Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review Genet Med 2009 11 1 21 34 10.1097/GIM.0b013e31818efd77 19125129 \n15. Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, Kaniwa N, Sawada J, Hamaguchi T, Yamamoto N et al. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1 6 and 28. Pharmacogenet Genomics. 2007;17(7):497–504.\n16. Shimoyama S Pharmacogenetics of irinotecan: An ethnicity-based prediction of irinotecan adverse events World J Gastrointest Surg 2010 2 1 14 21 10.4240/wjgs.v2.i1.14 21160829 \n17. Saif MW. MM-398 achieves primary endpoint of overall survival in phase III study in patients with gemcitabine refractory metastatic pancreatic cancer. JOP. 2014;15(3):278–9. doi: 210.6092/1590-8577/2507.\n18. Ko AH, Tempero MA, Shan Y, Su W, Lin Y, Dito E, Ong A, Yeh CG, Chen L. A multinational phase II study of liposome irinotecan (PEP02) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013;109:920–5.\n19. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, et al. NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–57.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "16(1)",
"journal": "BMC cancer",
"keywords": "5-fluorouracil; Dose-limiting toxicity; Liposomal irinotecan; Maximum tolerated dose",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D004334:Drug Administration Schedule; D004338:Drug Combinations; D016903:Drug Monitoring; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms; D000071184:Pharmacogenomic Variants; D013395:Sucrose; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "907",
"pmc": null,
"pmid": "27871319",
"pubdate": "2016-11-21",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study",
"references": "9815808;23880820;19364959;8229134;16540680;9466980;24865544;12963704;21786211;11006366;12381903;26615328;22811849;21160829;17558305;10744089;25577133;19125129;12610178",
"title": "A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors.",
"title_normalized": "a phase i dose escalation study of pep02 irinotecan liposome injection in combination with 5 fluorouracil and leucovorin in advanced solid tumors"
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{
"abstract": "OBJECTIVE\nThis paper describes a project to assess the feasibility of a brief healthy lifestyle health education group (HE) program and its effects on patient outcomes.\n\n\nMETHODS\nForty adult inpatients were enrolled in the HE program, which featured a one-group, pretest or posttest design deployed in an adult psychiatric unit. Outcomes comprised (1) feasibility and acceptability of the program and (2) changes in patient knowledge and weight.\n\n\nRESULTS\nThe HE program demonstrates not only feasibility, but also improvement in patient outcomes related to maintaining a healthy lifestyle.\n\n\nCONCLUSIONS\nRequisite changes in practice are necessary for the success of the HE program deployed in a typical, inpatient psychiatric unit.",
"affiliations": "Cedar Hills Hospital and Western Psychological and Counseling Services, Portland, Oregon.;School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania.;School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania.;School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania.",
"authors": "Foresman|Jennifer|J|;Mitchell|Ann|A|;Ren|Dianxu|D|;Lee|Heeyoung|H|http://orcid.org/0000-0001-6568-8123",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ppc.12328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-5990",
"issue": "55(3)",
"journal": "Perspectives in psychiatric care",
"keywords": "health behavior; healthy lifestyle; inpatients; mental disorders",
"medline_ta": "Perspect Psychiatr Care",
"mesh_terms": "D000328:Adult; D005260:Female; D015438:Health Behavior; D007722:Health Knowledge, Attitudes, Practice; D000070497:Healthy Lifestyle; D006801:Humans; D007297:Inpatients; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D010353:Patient Education as Topic; D010414:Pennsylvania; D015397:Program Evaluation; D011446:Prospective Studies",
"nlm_unique_id": "0401133",
"other_id": null,
"pages": "424-429",
"pmc": null,
"pmid": "30430594",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Implementing a brief healthy-lifestyle group program on a psychiatric inpatient unit.",
"title_normalized": "implementing a brief healthy lifestyle group program on a psychiatric inpatient unit"
} | [
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"medicinalproduct": "ABILIFY"
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"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "24.1",
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}
],
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},
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"literaturereference": "Foresman J, Mitchell A, Ren D, Lee H. Implementing a brief healthy-lifestyle group program on a psychiatric inpatient unit. PERSPECTIVES IN PSYCHIATRIC CARE. 2019;55(3):424-429",
"literaturereference_normalized": "implementing a brief healthy lifestyle group program on a psychiatric inpatient unit",
"qualification": "3",
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},
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"receiptdate": "20211004",
"receivedate": "20211004",
"receiver": {
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},
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},
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{
"abstract": "OBJECTIVE\nTo describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab.\n\n\nMETHODS\nRetrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 μg/L) were administered variable-dose tocilizumab.\n\n\nRESULTS\nAt between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days.\n\n\nCONCLUSIONS\nTocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.",
"affiliations": "Department of Immunology and Allergy, Campbelltown Hospital, Sydney, NSW, Australia.;Department of Respiratory Medicine, Concord Hospital, Sydney, NSW, Australia.;Clinical Haematology Unit, Monash Health, Melbourne, VIC, Australia.;Department of Medicine, Campbelltown Hospital, Sydney, NSW, Australia.;Department of Medicine, Concord Hospital, Sydney, NSW, Australia.;Intensive Care Unit, Campbelltown Hospital, Sydney, NSW, Australia.;Department of Respiratory Medicine, Campbelltown Hospital, Sydney, NSW, Australia.;Department of Microbiology and Infectious Diseases, Concord Hospital, Sydney, NSW, Australia.;School of Medicine, Western Sydney University, Sydney, NSW, Australia.;Intensive Care Unit, Concord Hospital, Sydney, NSW, Australia.;Department of Respiratory Medicine, Campbelltown Hospital, Sydney, NSW, Australia.;Intensive Care Unit, Monash Health, Melbourne, VIC, Australia.;Department of Respiratory Medicine, Concord Hospital, Sydney, NSW, Australia.;Department of Microbiology and Infectious Diseases, Concord Hospital, Sydney, NSW, Australia.;Monash Infectious Diseases, Monash University, Melbourne, VIC, Australia.;Intensive Care Unit, Concord Hospital, Sydney, NSW, Australia.;Intensive Care Unit, Monash Health, Melbourne, VIC, Australia.;Department of Respiratory Medicine, Campbelltown Hospital, Sydney, NSW, Australia.;Intensive Care Unit, Concord Hospital, Sydney, NSW, Australia.;Intensive Care Unit, Concord Hospital, Sydney, NSW, Australia.;Monash Infectious Diseases, Monash University, Melbourne, VIC, Australia.;Department of Immunology and Allergy, Campbelltown Hospital, Sydney, NSW, Australia.;Department of Respiratory Medicine, Concord Hospital, Sydney, NSW, Australia.;Department of Immunology and Allergy, Campbelltown Hospital, Sydney, NSW, Australia.",
"authors": "West|Timothy A|TA|https://orcid.org/0000-0002-5469-5501;Malik|Sameer|S|;Nalpantidis|Anastasios|A|;Tran|Tuan|T|;Cannon|Christine|C|;Bhonagiri|Deepak|D|;Chan|Kevin|K|;Cheong|Elaine|E|;Wan Sai Cheong|Jenny|J|;Cheung|Winston|W|;Choudhury|Faisal|F|;Ernest|David|D|;Farah|Claude S|CS|;Fernando|Shelanah|S|;Kanapathipillai|Rupa|R|;Kol|Mark|M|;Murfin|Brendan|B|;Naqvi|Haider|H|;Shah|Asim|A|;Wagh|Atul|A|;Ojaimi|Samar|S|;Frankum|Bradley|B|;Riminton|Sean|S|;Keat|Karuna|K|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13913",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "23(8)",
"journal": "International journal of rheumatic diseases",
"keywords": "acute respiratory distress syndrome; coronavirus; immunomodulation; interleukin‐6; pneumonia; tocilizumab; viral",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000368:Aged; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D000076662:Host Microbial Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009517:New South Wales; D058873:Pandemics; D011024:Pneumonia, Viral; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014739:Victoria",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "1030-1039",
"pmc": null,
"pmid": "32881350",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": "31440860;32448770;32300051;32405160;22797452;30992265;22136372;32192578;10793162;30995492;32517645;32171076;19325482;32303591;27381687;32125452;30233566;32105632;32362270",
"title": "Tocilizumab for severe COVID-19 pneumonia: Case series of 5 Australian patients.",
"title_normalized": "tocilizumab for severe covid 19 pneumonia case series of 5 australian patients"
} | [
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}
],
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{
"reactionmeddrapt": "Encephalopathy",
"reactionmeddraversionpt": "23.1",
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}
],
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},
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"literaturereference": "WEST, T.. TOCILIZUMAB FOR SEVERE COVID?19 PNEUMONIA: CASE SERIES OF 5 AUSTRALIAN PATIENTS. INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES. 2020?23 (8):1030?1039",
"literaturereference_normalized": "tocilizumab for severe covid 19 pneumonia case series of 5 australian patients",
"qualification": "3",
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},
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},
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"safetyreportversion": 1,
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},
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"seriousnesscongenitalanomali": null,
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}
] |
{
"abstract": "A 70-year-old male with a history of atrial fibrillation who is being anticoagulated with dabigatran etexilate presents to the emergency room with melena. He reports taking his most recent dose of dabigatran more than 2 hours ago. On examination, he is hypotensive and tachycardic, and he continues to have melanotic stools. Laboratory testing reveals a calculated creatinine clearance of 15 mL/min, a prothrombin time of 16.5 seconds (reference range: 11.8-15.2 seconds), an international normalized ratio of 1.2 (reference range: 0.9-1.2), and an activated partial thromboplastin time of 50 seconds (reference range: 22.2-33.0 seconds). You are asked by the emergency medicine physician whether hemodialysis should be considered to decrease the patient's plasma dabigatran level.",
"affiliations": "Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA; and.;Division of Hematology, Department of Medicine, University of Washington, Seattle, WA.",
"authors": "Kim|Benjamin|B|;Garcia|David A|DA|",
"chemical_list": "D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1182/asheducation-2014.1.514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1520-4383",
"issue": "2014(1)",
"journal": "Hematology. American Society of Hematology. Education Program",
"keywords": null,
"medline_ta": "Hematology Am Soc Hematol Educ Program",
"mesh_terms": "D000368:Aged; D001562:Benzimidazoles; D000069604:Dabigatran; D006470:Hemorrhage; D006801:Humans; D008297:Male; D064887:Observational Studies as Topic; D006435:Renal Dialysis; D015091:beta-Alanine",
"nlm_unique_id": "100890099",
"other_id": null,
"pages": "514-7",
"pmc": null,
"pmid": "25696903",
"pubdate": "2014-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "What is the role of hemodialysis for dabigatran-associated major bleeding?",
"title_normalized": "what is the role of hemodialysis for dabigatran associated major bleeding"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-10159GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "022512",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ATRIAL FIBRILLATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PRADAXA"
}
],
"patientagegroup": null,
"patientonsetage": "70",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Creatinine renal clearance decreased",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Melaena",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KIM B,GARCIA D. WHAT IS THE ROLE OF HEMODIALYSIS FOR DABIGATRAN-ASSOCIATED MAJOR BLEEDING?. HEMATOLOGY AM SOC HEMATOL EDUC PROGRAM 2014;2014:1:514-517.",
"literaturereference_normalized": "what is the role of hemodialysis for dabigatran associated major bleeding",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20150226",
"receivedate": "20150226",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10872239,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20150721"
}
] |
{
"abstract": "BACKGROUND\nHematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.\n\n\nMETHODS\nHerein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.\n\n\nCONCLUSIONS\nThis case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.",
"affiliations": "Division of Hematology and Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.;Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.;Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.;Center for Hematologic Malignancies, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.;Department of Cell, Developmental, and Cancer Biology, Portland, OR, USA.;Center for Hematologic Malignancies, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. [email protected].",
"authors": "Leonard|Jessica T|JT|;Raess|Philipp W|PW|;Dunlap|Jennifer|J|;Hayes-Lattin|Brandon|B|;Tyner|Jeffrey W|JW|;Traer|Elie|E|http://orcid.org/0000-0001-8844-2345",
"chemical_list": "D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53; C560077:trametinib; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human",
"country": "England",
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"doi": "10.1186/s13045-016-0258-1",
"fulltext": "\n==== Front\nJ Hematol OncolJ Hematol OncolJournal of Hematology & Oncology1756-8722BioMed Central London 25810.1186/s13045-016-0258-1Case ReportFunctional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent Leonard Jessica T. [email protected] Raess Philipp W. [email protected] Dunlap Jennifer [email protected] Hayes-Lattin Brandon [email protected] Tyner Jeffrey W. [email protected] http://orcid.org/0000-0001-8844-2345Traer Elie [email protected] Division of Hematology and Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239 USA Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239 USA Center for Hematologic Malignancies, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239 USA Department of Cell, Developmental, and Cancer Biology, Portland, OR USA Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239 USA 31 3 2016 31 3 2016 2016 9 3120 1 2016 14 3 2016 © Leonard et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.\n\nCase Presentation\nHerein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient’s leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient’s blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.\n\nConclusions\nThis case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s13045-016-0258-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nAcute myeloid leukemiaNRASTrametinibGerm cell neoplasmHigh-throughput nucleotide sequencinghttp://dx.doi.org/10.13039/100005189Leukemia and Lymphoma SocietyLLS SCORTyner Jeffrey W. issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nMediastinal germ cell tumors (GCT) are capable of malignant transformation into tumors of endodermal, mesodermal, and ectodermal origin. With regard to hematologic malignancies, GCT are most frequently associated with acute myeloid leukemia (often with megakaryoblastic differentiation); but myelodysplastic syndromes, malignant histiocytosis, myeloproliferative neoplasms, and acute lymphoblastic leukemia have all been described [1–7]. Identification of shared cytogenetic abnormalities in the GCT and hematologic malignancy (most commonly isochromosome 12p) indicate a clonal relationship and common precursor [8].\n\nThe prognosis for GCT with a concurrent hematologic malignancy is poor, as the disease is usually refractory to conventional chemotherapy and patients are unable to attain a clinical remission [9]. For those that do attain a remission, relapse without consolidative allogeneic stem cell transplant is inevitable, and successful outcomes are limited to two cases in which patients underwent allogeneic hematopoietic stem cell transplant early in the first complete remission [1, 10]. Given these dismal outcomes, novel therapeutic approaches are needed.\n\nHere, we report the case of a young man with metasynchronous presentation of a GCT and acute myeloid leukemia (AML). Following failure of conventional cytotoxic chemotherapy, a functional in vitro assay was used to identify a targeted therapeutic agent with activity against the leukemic blasts: trametinib, an inhibitor of mitogen-activated protein kinase kinase (MEK). This in vitro sensitivity correlated with the identification of a somatic NRAS missense mutation, which also predicts sensitivity to MEK inhibition. The patient was treated with trametinib for 6 months, during which time his leukemia remained stable. This case highlights the utility of combining mutational profiling with functional in vitro testing of the leukemic clone to identify effective personalized therapies for rare malignancies.\n\nCase presentation\nA 23-year-old male presented with fevers, hemoptysis, and an 18-cm anterior mediastinal mass (Fig. 1a). A computed tomography-guided core biopsy of the mass contained mostly necrotic tissue with rare atypical cells that were partially positive for alpha-fetoprotein (AFP), glypican, and pancytokeratin by immunohistochemistry. Serum AFP was elevated at >60,000 ng/mL, leading to a presumptive diagnosis of a mediastinal germ cell tumor. The patient was treated with four cycles of VIP (vinblastine, ifosfamide, etoposide) with concomitant decrease in serum AFP to 300 ng/mL. Prior to resection of the residual mediastinal mass (4 months after the original diagnosis), a complete blood count (CBC) demonstrated elevation of the WBC to 55 k/μL with 28 % circulating myeloid blasts. His lactate dehydrogenase (LDH) was markedly elevated at 17,481 U/L, although his AFP decreased to 211 ng/mL. A bone marrow biopsy demonstrated acute erythroid leukemia with 70–80 % markedly left-shifted erythroid precursors with dysplastic and megaloblastoid changes and myeloid blasts accounting for more than 20 % of non-erythroid cell population (Fig. 1b). Cytogenetics showed a complex clone (Fig. 2d). Targeted massively parallel sequencing analysis also identified TP53 p.G245S and NRAS p.G12C point mutations at 87 and 86 % allele frequency, respectively (see Additional file 1 and Additional file 2: Table S1 for details). As the patient’s mediastinal mass had not yet been resected, a regimen that would treat both his AML and his residual germ cell tumor (containing platinum-based therapy) was desired. For this reason, he was treated with HAEP (high-dose cytarabine, etoposide, and cisplatin), previously reported as an effective salvage therapy for AML [11]. Following induction, the patient achieved morphologic complete remission (CR) of his AML; however, low-level residual disease was identified by cytogenetics (3 of 20 cells with the prior abnormal clone) and massively parallel sequencing analysis (1 % TP53 and 2 % NRAS mutant allele frequencies).Fig. 1 A 23-year-old male with a metasynchronous mediastinal germ cell tumor and acute myeloid leukemia. a Computed tomography demonstrated an 18-cm anterior mediastinal mass. b Bone marrow aspirate smear examination (4 months after germ cell tumor diagnosis) demonstrated acute erythroid leukemia 70–80 % markedly dysplastic and left-shifted erythroid precursors with myeloid blasts (inset) accounting for more than 20 % of non-erythroid cellularity. c Post-treatment resection of the mediastinal germ cell tumor demonstrated predominantly mature teratoma with focus of rhabdomyosarcoma (pictured) with desmin positivity (inset). d Separate focus of angiosarcoma was also identified in the mediastinal germ cell tumor (pictured), supported by CD31 positivity (inset)\n\nFig. 2 Trametinib inhibits leukemic blast viability in vitro and in vivo and also during cytogenetic and molecular clonal evolution. a Trametinib inhibits leukemic blast viability in vitro in a dose-dependent manner. b siRNA-mediated knock-down of NRAS decreases in vitro blast viability (horizontal red bar = 95 % percentile. c Trametinib therapy correlates with partial remission of leukemic blasts. Blast counts (black line) decreased when on trametinib therapy (red shaded boxes) following AML relapse after standard induction therapy. Note the non-linear time scale. d Karyotyping demonstrates clonal evolution before and during trametinib therapy. e Targeted massively parallel sequencing demonstrates persistent NRAS and TP53 missense point mutations before and during trametinib therapy; WT1 mutations were identified at the time of germ cell tumor relapse. Identical NRAS and TP53 mutations were identified by targeted sequencing analysis of the patient’s mediastinal germ cell tumor\n\n\n\nHe was treated with a single cycle of HAEP consolidation therapy, after which he underwent resection of the mediastinal mass. Histopathologic examination demonstrated mature teratoma with foci of rhabdomyosarcoma and angiosarcoma (Fig. 1c, d). Targeted Sanger-based DNA sequencing analysis identified the same TP53 and NRAS point mutations present in the acute erythroid leukemia, confirming a shared clonal origin.\n\nSix weeks after resection of the mediastinal mass, a restaging bone marrow biopsy demonstrated relapsed disease with a morphologically abnormal erythroid series, 5–10 % myeloid blasts, and persistent TP53 and NRAS mutations at 87 and 86 % allele frequency (Fig. 2e). Cytogenetics identified the original abnormal clone and the emergence of two additional clones (Fig. 2d). Since the patient was not fit for re-induction chemotherapy due to recent surgery, his leukemic cells were isolated and tested against a panel of small molecule kinase inhibitors to identify in vitro drug sensitivity. Trametinib was identified as one of the most potent in vitro inhibitors of leukemic cell viability (Fig. 2a). In vitro small inhibitory RNA (siRNA) studies further identified that silencing of NRAS had a profound inhibitory effect on blast viability (Fig. 2b), consistent with his known activating NRAS mutation (for full list of silenced genes please see Additional file 3: Table S2). The patient began treatment with single-agent trametinib therapy obtained on a compassionate use basis and had an immediate reduction in his peripheral blasts after a week of therapy (Fig. 2c).\n\nA bone marrow biopsy after 1 month of trametinib revealed a slight reduction in the blast count (4–5 %) but persistent erythroid dysplasia. Although the AML remained stable, multiple cytogenetically complex clones were identified and the TP53 and NRAS mutant allele frequency increased to 96 and 97 %, respectively (Fig. 2e). After 3 months of trametinib monotherapy, the patient developed pneumonia and Staphylococcus aureus bacteremia. A bone marrow biopsy at that time demonstrated 8 % blasts and erythroid dysplasia. Trametinib was held twice due to infections, and during these intervals, there was an increase in peripheral blasts, which resolved following resumption of trametinib (Fig. 2c). A bone marrow biopsy after 5 months of trametinib therapy demonstrated stability of his AML with 6 % blasts and erythroid dysplasia. Karyotyping and repeat sequencing analysis demonstrated continued clonal evolution, with multiple cytogenetically complex subclones (Fig. 2d). There was a persistent high-level NRAS and TP53 mutant allele frequency but two additional WT1 point mutations were also identified at allele frequencies of 20 and 15 %, further indicating clonal evolution (Fig. 2e). Repeat testing confirmed that the leukemic clone remained sensitive to trametinib in vitro (data not shown). However, imaging studies performed in preparation for allogeneic stem cell transplantation demonstrated a 3-cm pulmonary nodule and serum AFP also rose to 12 ng/dL, consistent with relapse of metastatic GCT. Given his poor prognosis, the patient opted for palliative care and died a month later with frank relapse of his AML after trametinib discontinuation.\n\nDiscussion\nAlthough exceedingly rare, at least 60 cases of concurrent mediastinal GCT and hematologic malignancy have been reported in the literature. A common clonal origin was long suspected given the temporal relationship between the two malignancies, and recent work has convincingly demonstrated conserved isochromosome 12p rearrangements as well as somatic point mutations [12]. We provide further evidence of the clonal relationship between GCT and acute erythroid leukemia based on shared NRAS and TP53 mutations. Furthermore, we demonstrate that targeted sequencing in combination with functional screening can identify active drugs for these rare diseases.\n\nMassively parallel sequencing has identified a number of recurrent mutations in AML. However, the heterogeneity of mutations [13] precludes a uniform approach to treatment. Furthermore, the functional relevance of identified mutations is not always known for each AML patient. In light of this, our group has developed a tripartite approach to identifying therapeutic targets through (1) small molecule inhibitor screens, (2) siRNA knock-down, and (3) targeted massively parallel sequencing. In the presented case, an activating NRAS mutation and a TP53 mutation were identified by sequencing. Parallel siRNA and small molecule screens demonstrated the functional importance of the activated NRAS/Raf/MEK/ERK pathway in vitro. MEK inhibitors such as trametinib have shown activity in RAS-mutated AML; however, the overall response rate is only 28 %, indicating that a RAS mutation by itself is not sufficient to predict which patients will respond to therapy [14]. While trametinib monotherapy did not lead to CR in this patient, it did reduce peripheral blast counts and provided 6 months of disease control, allowing time to potentially coordinate a stem cell transplant. This response is consistent with pre-clinical models of RAS-activated AML in which trametinib inhibited leukemic proliferation but did not eradicate disease [15].\n\nDisease control by trametinib also highlighted another interesting aspect of this case. Progressive clonal evolution was identified both through increasing cytogenetic complexity with development of at least four subclones. Targeted massively parallel sequencing analysis also demonstrated clonal evolution, with the development of two point mutations in WT1. We hypothesize that the p53 mutation contributed to the complex clonal evolution and disease progression, as loss of p53 function is known to impair DNA repair and genomic stability [16].\n\nThe use of next-generation sequencing to identify potentially targetable mutations is an emerging area of interest, particularly for rare or refractory malignancies. A small clinical series using sunitinib to treat refractory GCT identified amplification of the RET gene in one exceptional responder [17]. Other potential approaches to treating rare malignancies include basket trials, in which patients with a specified mutations are treated with targeted therapy irrespective of their underlying malignancy, or umbrella trials, in which patients with a defined cancers type are subclassified by genotype, and then treated based on their molecular classification [18]. Our approach blends genotype with functional in vitro drug screen as an additional predictor of targeted drug response to identify potential therapeutic targets.\n\nConclusions\nIn conclusion, we report a case of metasynchronous mediastinal GCT and AML in a young male patient with identical TP53 and NRAS mutations in both malignancies. In vitro functional assays were used to confirm the importance of the NRAS mutation to leukemic blast proliferation and the ability of trametinib to inhibit growth. Trametinib therapy led to sustained disease control in vivo over 6 months following failure of conventional cytotoxic chemotherapy. This case highlights the power of in vitro functional assays to identify novel targeted agents to treat rare and aggressive malignancies and supports the exploratory use of small molecule kinase inhibitors in the treatment of AML, particularly in rare presentations of AML where therapeutic options are limited and outcomes are poor.\n\nConsents\nWritten informed consent was obtained from the patient to participate in a trial which would allow collection and sequencing of his leukemic blasts for sequencing and testing against a panel of small molecule inhibitors. In addition, he consented to sequencing of his normal tissue and his germ cell tumor. The patient is deceased and had no next of kin or legal guardian, so consent for publication of this case report and any accompanying images was not obtained. This lack of support contributed to his inability to proceed to allogeneic stem cell transplant.\n\nAdditional files\nAdditional file 1: Supplemental information on the methods of the next-generation sequencing panel at OHSU used for analysis. (DOC 29.5 kb)\n\nAdditional file 2: Table S1. Table of genes tested by the next-generation sequencing panel. (PPTX 58.1 kb)\n\nAdditional file 3: Table S2. Table of genes targeted by siRNA panel in Fig. 2. (PPTX 47.3 kb)\n\n\n\nAbbreviations\nAFPalpha-fetoprotein\n\nAMLacute myeloid leukemia\n\nCBCcomplete blood count\n\nCRcomplete remission\n\nGCTgerm cell tumor\n\nLDHlactate dehydrogenase\n\nsiRNAsmall inhibitory RNA\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nJL, PWR, JD, and ET wrote the manuscript. JT developed the in vitro assays. PWR, JD, and MT interpreted the genetic tests and pathology. ET, JL, and BHL provided clinical care. All authors critically revised the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe appreciate critical revision of the manuscript by Megan L. Troxell, M.D. This work was supported in part by the Leukemia and Lymphoma Society SCOR grant (Specialized Center of Research).\n==== Refs\nReferences\n1. Christodoulou J Myelodysplastic syndrome (RARS) with +i(12p) abnormality in a patient 10 months after diagnosis and successful treatment of a mediastinal germ cell tumor (MGCT) Ann Hematol 2004 83 6 386 9 10.1007/s00277-003-0787-x 14615911 \n2. Berruti A Acute myeloblastic leukemia associated with mediastinal nonseminomatous germ cell tumors Report on two cases. Tumori 1995 81 4 299 301 8540131 \n3. Sole F Refractory anemia with excess of blasts and isochromosome 12p in a patient with primary mediastinal germ-cell tumor Cancer Genet Cytogenet 1994 77 2 111 3 10.1016/0165-4608(94)90224-0 7954319 \n4. Chariot P Systemic mastocytosis following mediastinal germ cell tumor: an association confirmed Hum Pathol 1993 24 1 111 2 10.1016/0046-8177(93)90071-N 8380274 \n5. Koo CH True histiocytic malignancy associated with a malignant teratoma in a patient with 46XY gonadal dysgenesis Am J Surg Pathol 1992 16 2 175 83 10.1097/00000478-199202000-00011 1346359 \n6. Downie PA Establishment of a leukemia cell line with i(12p) from a patient with a mediastinal germ cell tumor and acute lymphoblastic leukemia Cancer Res 1994 54 18 4999 5004 8069867 \n7. Larsen M Acute lymphoblastic leukemia. Possible origin from a mediastinal germ cell tumor Cancer 1984 53 3 441 4 10.1002/1097-0142(19840201)53:3<441::AID-CNCR2820530312>3.0.CO;2-S 6318949 \n8. Ladanyi M Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors J Natl Cancer Inst 1990 82 3 221 7 10.1093/jnci/82.3.221 2153216 \n9. Nichols CR Hematologic neoplasia associated with primary mediastinal germ-cell tumors N Engl J Med 1990 322 20 1425 9 10.1056/NEJM199005173222004 2158625 \n10. Hiramatsu H Successful treatment of a patient with Klinefelter’s syndrome complicated by mediastinal germ cell tumor and AML(M7) Bone Marrow Transplant 2008 41 10 907 8 10.1038/sj.bmt.1705991 18223696 \n11. Lee YG Effective salvage therapy for high-risk relapsed or refractory acute myeloid leukaemia with cisplatin in combination with high-dose cytarabine and etoposide Eur J Haematol 2014 92 6 478 84 10.1111/ejh.12274 24460733 \n12. Oshrine BR Acquired isochromosome 12p, somatic TP53 and PTEN mutations, and a germline ATM variant in an adolescent male with concurrent acute megakaryoblastic leukemia and mediastinal germ cell tumor Cancer Genet 2014 207 4 153 9 10.1016/j.cancergen.2014.03.009 24831771 \n13. Estey E Levine RL Lowenberg B Current challenges in clinical development of “targeted therapies”: the case of acute myeloid leukemia Blood 2015 125 16 2461 6 10.1182/blood-2015-01-561373 25762181 \n14. Borthakur G Phase I/II trial of the MEK1/2 inhibitor trametinib (GSK1120212) in relapsed/refractory myeloid malignancies: evidence of activity in patients with RAS mutation-positive disease 2012 Atlanta, GA ASH \n15. Burgess MR Preclinical efficacy of MEK inhibition in Nras-mutant AML Blood 2014 124 26 3947 55 10.1182/blood-2014-05-574582 25361812 \n16. Hanel W Moll UM Links between mutant p53 and genomic instability J Cell Biochem 2012 113 2 433 9 10.1002/jcb.23400 22006292 \n17. Subbiah V Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent(R)) a VEGFR2/PDGFRbeta/c-kit/ FLT3/RET/CSF1R inhibitor in a phase II trial J Hematol Oncol 2014 7 52 10.1186/s13045-014-0052-x 25085632 \n18. Billingham L Malottki K Steven N Research methods to change clinical practice for patients with rare cancers Lancet Oncol 2016 17 2 e70 80 10.1016/S1470-2045(15)00396-4 26868356\n\n",
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"abstract": "A 26-year-old woman with no prior medical history presented post-partum with altered mental status. She had no complications during pregnancy and had a spontaneous vaginal delivery at term one week prior. On post-partum day five, she began complaining of headaches, initially responsive to ibuprofen but eventually worsened with no relief. On the evening of admission, her boyfriend noted strange behavior and movements consistent with a tonic-clonic seizure. On the way to the hospital, she had two more similar seizures witnessed by emergency medical serevices (EMS). EMS reported her blood pressures in route to be 200/100s. She was given 5 mg of magnesium by EMS due to concern for postpartum eclampsia. Upon arrival at the emergency room, she was somnolent but arousable although unable to answer any questions. She was mildly tachycardic at 106 beats per minute and had a temperature of 38.2°C. Her blood pressure was elevated at 165/95 mm Hg. On exam, dried blood was noted on her lips and her tongue was swollen. On auscultation, she was tachycardic with clear lung sounds. Her abdomen was soft and non-tender and there was no vaginal bleeding or other discharge. Laboratory values revealed a sodium of 142, potassium of 3.3, chloride of 110, bicarbonate of 16, creatinine of 1.1, magnesium of 3.9, and white blood cell count of 12.3 x103/mm3 with 88% neutrophils and no bands. A toxicology panel was negative for opiates, benzodiazepines, or other illicit drugs. Urine was remarkable for large blood, 448 red blood cells, protein, moderate leukocyte esterase, and 73 white blood cells. Chest x-ray and CT scan of the head were both normal. She was admitted to the medical intensive care unit for close monitoring, neurological checks, and continued magnesium administration. By hospital day two, her mental status had improved significantly.",
"affiliations": "Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.;Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana.",
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"nlm_unique_id": "7505618",
"other_id": null,
"pages": "151",
"pmc": null,
"pmid": "27159471",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "\"BABY, BABY I'VE GOT HEADACHE\".",
"title_normalized": "baby baby i ve got headache"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP016326",
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"occurcountry": "US",
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"reaction": [
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "KAIKSOW FA, BHATNAGAR D. ^BABY, BABY I^VE GOT HEADACHE^. J LA STATE MED SOC. 2015;167(3):151",
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},
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"transmissiondate": "20170429"
}
] |
{
"abstract": "We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.",
"affiliations": "Department of Hematology, Endocrinology and Metabolism Niigata University Faculty of Medicine, Japan.",
"authors": "Fuse|Kyoko|K|;Matsuyama|Yuichi|Y|;Moriyama|Masato|M|;Miyakoshi|Shukuko|S|;Shibasaki|Yasuhiko|Y|;Takizawa|Jun|J|;Furukawa|Tatsuo|T|;Fuse|Ichiro|I|;Matsumura|Hiro|H|;Uchida|Shigeharu|S|;Takahashi|Yoshifumi|Y|;Kamimura|Kenya|K|;Abe|Hiroyuki|H|;Suda|Takeshi|T|;Aoyagi|Yutaka|Y|;Sone|Hirohito|H|;Masuko|Masayoshi|M|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.2332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D005260:Female; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D016867:Immunocompromised Host; D015473:Leukemia, Promyelocytic, Acute; D065227:Transfusion Reaction; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "657-61",
"pmc": null,
"pmid": "25786459",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late onset post-transfusion hepatitis E developing during chemotherapy for acute promyelocytic leukemia.",
"title_normalized": "late onset post transfusion hepatitis e developing during chemotherapy for acute promyelocytic leukemia"
} | [
{
"companynumb": "JP-PFIZER INC-2015114681",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "CYTARABINE"
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{
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},
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"drugcharacterization": "1",
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"drugdosagetext": "12 MG/M2, UNK",
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"medicinalproduct": "IDARUBICIN HCL"
}
],
"patientagegroup": null,
"patientonsetage": "27",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatitis E",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2012"
}
},
"primarysource": {
"literaturereference": "KYOKO FUSE ET AL. LATE ONSET POST-TRANSFUSION HEPATITIS E DEVELOPING DURING CHEMOTHERAPY FOR ACUTE PROMYELOCYTIC LEUKEMIA. INTERNAL MEDICINE. 2015;54:657-661",
"literaturereference_normalized": "late onset post transfusion hepatitis e developing during chemotherapy for acute promyelocytic leukemia",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20150406",
"receivedate": "20150406",
"receiver": {
"receiverorganization": "FDA",
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},
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"safetyreportid": 10991428,
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Steroid therapy is the first-line treatment for autoimmune pancreatitis but relapses are frequent. The aims were to assess the efficacy and the safety of immunomodulator treatments for relapsing autoimmune pancreatitis and rituximab in particular and to identify relapsing risk factors.\n\n\n\nPatients followed for autoimmune pancreatitis from 2000 to 2016 were included. Data were retrospectively analysed regarding autoimmune pancreatitis treatment.\n\n\n\nIn total, 162 patients with autoimmune pancreatitis type 1 (n = 92) and type 2 (n = 70) were included (median follow-up: 3 years (0.5-14). Relapse occurred in 46.5% of patients with autoimmune pancreatitis type 1 (vs 19.3% in autoimmune pancreatitis 2; p < 0.001). Risk factors of relapse were cholangitis, initial use of steroids, other organ involvement and chronic pancreatitis in autoimmune pancreatitis type 1 and initial use of steroids, tobacco consumption and chronic pancreatitis for autoimmune pancreatitis type 2. Overall, 21 patients were treated with immunomodulators (azathioprine, n = 19, or methotrexate, n = 2) for relapses. The efficiency rate was 67%. A total of 17 patients were treated with rituximab, with two perfusions at 15 days apart. The efficacy was 94% (16/17), significantly better than immunomodulator drugs (p = 0.03), with a median follow-up of 20 months (11-44). Only two patients needed two supplementary perfusions.\n\n\n\nIn relapsing autoimmune pancreatitis, rituximab is more efficient than immunomodulator drugs and shows better tolerance.",
"affiliations": "Pancreatology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.;Radiology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.;Pancreatology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.;Pancreatology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.;Pancreatology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.;Pancreatology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.;Pancreatology department, Beaujon Hospital, France and Paris-Diderot University, Clichy, France.",
"authors": "Soliman|Heithem|H|0000-0003-1644-7272;Vullierme|Marie-Pierre|MP|;Maire|Frédérique|F|;Hentic|Olivia|O|;Ruszniewski|Philippe|P|;Lévy|Philippe|P|;Rebours|Vinciane|V|",
"chemical_list": "D007155:Immunologic Factors; D013256:Steroids; D000069283:Rituximab; D001379:Azathioprine; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1177/2050640619862459",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2050-6406",
"issue": "7(8)",
"journal": "United European gastroenterology journal",
"keywords": "Autoimmune pancreatitis; IgG4 related disease; azathioprine; cholangitis; rituximab",
"medline_ta": "United European Gastroenterol J",
"mesh_terms": "D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases; D000081012:Autoimmune Pancreatitis; D001379:Azathioprine; D002761:Cholangitis; D005260:Female; D006801:Humans; D000077733:Immunoglobulin G4-Related Disease; D007155:Immunologic Factors; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D050500:Pancreatitis, Chronic; D010477:Perfusion; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D012449:Safety; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "101606807",
"other_id": null,
"pages": "1073-1083",
"pmc": null,
"pmid": "31662864",
"pubdate": "2019-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "22210556;30312787;23232048;26971690;28448071;20736934;19837455;27543430;24815737;15517359;18222442;23136242;21412117;23698232;22218969;19345283;20353791;20639082;28915275;19398440;22936672;13746542;28027896;17525092",
"title": "Risk factors and treatment of relapses in autoimmune pancreatitis: Rituximab is safe and effective.",
"title_normalized": "risk factors and treatment of relapses in autoimmune pancreatitis rituximab is safe and effective"
} | [
{
"companynumb": "FR-CELLTRION INC.-2020FR018693",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "4",
"drugadministrationroute": "041",
"drugauthorizationnumb": "761088",
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"drugcharacterization": "1",
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"drugdosageform": "Concentrate for solution for infusion",
"drugdosagetext": "1000 MG, EVERY 15 DAYS; RECEIVED 2 INFUSIONS; ADDITIONAL INFO: ADDITIONAL INFO: OFF LABEL USE",
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"drugindication": "Autoimmune pancreatitis",
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"drugdosagetext": "40 MILLIGRAM DAILY; RECEIVED TWO COURSES; ADDITIONAL INFO: ADDITIONAL INFO: ACTION TAKEN: THERAPY TA",
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"drugindication": "Autoimmune pancreatitis",
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},
{
"actiondrug": "5",
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},
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "100 MG",
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"medicinalproduct": "METHYLPREDNISOLONE"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Autoimmune pancreatitis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Soliman H, Vullierme M-P, Maire F, Hentic O, Ruszniewski P, Levy P, et al.. Risk factors and treatment of relapses in autoimmune pancreatitis: Rituximab is safe and effective. United-European-Gastroenterol-J. 2019;7(8):1073-1083",
"literaturereference_normalized": "risk factors and treatment of relapses in autoimmune pancreatitis rituximab is safe and effective",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20220112",
"receivedate": "20220112",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220423"
},
{
"companynumb": "FR-CELLTRION INC.-2022FR000144",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "4",
"drugadministrationroute": "041",
"drugauthorizationnumb": "761088",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Concentrate for solution for infusion",
"drugdosagetext": "1000 MILLIGRAM, EVERY 15 DAYS (RECEIVED 2 INFUSIONS)",
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"drugindication": "Autoimmune pancreatitis",
"drugintervaldosagedefinition": null,
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{
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{
"abstract": "OBJECTIVE\nThere are little data regarding safety and effectiveness of neoadjuvant chemotherapy (NACT) in patients who are considered unfit for receiving 3 weekly paclitaxel and carboplatin. The aim of this study was to study the toxicity and response rates of weekly paclitaxel and carboplatin as NACT in such cohort of patients.\n\n\nMETHODS\nStudy population included advanced ovarian cancer patients who were unlikely to tolerate 3 weekly paclitaxel and carboplatin and hence received weekly paclitaxel (80 mg/m2) and carboplatin AUC-2 as NACT. The data regarding the baseline characteristics, chemotherapy tolerance, completion rates, toxicity (CTCAE version 4.02), and radiological response rates are presented. SPSS version 16 was used for analysis. Descriptive statistics is presented.\n\n\nRESULTS\nEleven patients received this schedule. Nine patients completed nine cycles of NACT. Except one, all patients completed NACT with an average relative dose intensity of >0.8. There was no chemotherapy-related mortality. Grade 3-4 life-threatening complications were seen in two patients. The post NACT response rate was 100%.\n\n\nCONCLUSIONS\nWeekly paclitaxel and carboplatin chemotherapy is safe and efficacious in patients who are unsuitable for 3 weekly paclitaxel and carboplatin chemotherapy schedules.",
"affiliations": "Department of Surgical Oncology, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Radiation Oncology, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Cancer Imaging, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Oncopathology and Translational Medicine, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Division of Clinical Research and Biostatistics, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Radiation Oncology, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Surgical Oncology, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.;Department of Clinical Hematology and Medical Oncology, Malabar Cancer Center, Malabar Cancer Center, Moozhikkara, Kodiyeri, Thalassery, Kannur, Kerala, India.",
"authors": "Dessai|S B|SB|;Chakraborty|S|S|;Babu|Tvs|T|;Nayanar|S|S|;Bhattacharjee|A|A|;Jones|J|J|;Balasubramanian|S|S|;Patil|V M|VM|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel",
"country": "India",
"delete": false,
"doi": "10.4103/0019-509X.197742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-509X",
"issue": "53(2)",
"journal": "Indian journal of cancer",
"keywords": null,
"medline_ta": "Indian J Cancer",
"mesh_terms": "D000970:Antineoplastic Agents; D016190:Carboplatin; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms; D017239:Paclitaxel",
"nlm_unique_id": "0112040",
"other_id": null,
"pages": "280-283",
"pmc": null,
"pmid": "28071627",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tolerance of weekly paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin.",
"title_normalized": "tolerance of weekly paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin"
} | [
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{
"abstract": "We report the first Italian case of Mycobacterium chimaera disseminated infection in a patient with a history of cardiac surgery. The patient was initially diagnosed with sarcoidosis and started on immunosuppressive therapy. Ten months later she developed a vertebral osteomyelitis: M. chimaera was isolated from bone specimen. A review of the literature shows that M. chimaera infection occurs specifically in this population of patients, due to contamination of heater-cooler units used during cardiosurgery. Devices responsible for the transmission were produced by Sorin Group Deutschland. Mycobacterium chimaera infection should be included in the differential diagnosis for patients undergoing cardiac surgery.",
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"authors": "Chiesi|Sheila|S|;Piacentini|Daniela|D|;Salerno|Nicola Duccio|ND|;Luise|Dora|D|;Peracchi|Marta|M|;Concia|Ercole|E|;Cazzadori|Angelo|A|;Piovan|Enrico|E|;Lanzafame|Massimiliano|M|",
"chemical_list": "D000069349:Linezolid; D011241:Prednisone; D012293:Rifampin",
"country": "Italy",
"delete": false,
"doi": null,
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"issn_linking": "1124-9390",
"issue": "25(3)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000151:Acinetobacter Infections; D000368:Aged; D016470:Bacteremia; D003951:Diagnostic Errors; D004359:Drug Therapy, Combination; D004866:Equipment Contamination; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006361:Heating; D006801:Humans; D000069349:Linezolid; D008159:Lumbar Vertebrae; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D010019:Osteomyelitis; D011183:Postoperative Complications; D011241:Prednisone; D012293:Rifampin; D012507:Sarcoidosis; D013166:Spondylitis; D054854:Vertebroplasty; D014871:Water Microbiology",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "267-269",
"pmc": null,
"pmid": "28956545",
"pubdate": "2017-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Disseminated Mycobacterium chimaera infection after open heart surgery in an Italian woman: a case report and a review of the literature.",
"title_normalized": "disseminated mycobacterium chimaera infection after open heart surgery in an italian woman a case report and a review of the literature"
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{
"abstract": "OBJECTIVE\nTo evaluate the incidence of optic neuritis (ON) in patients using anti-tumor necrosis factor (TNF) alpha therapy.\n\n\nMETHODS\nRetrospective, population-based cohort study.\n\n\nMETHODS\nWe identified new users of anti-TNF therapy (etanercept, infliximab, or adalimumab) or nonbiologic disease-modifying antirheumatic drugs (DMARDs) during 2000-2007 from the following data sources: Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and National Medicaid/Medicare. Within this cohort, we used validated algorithms to identify ON cases occurring after onset of new drug exposure. We then calculated and compared ON incidence rates between exposure groups.\n\n\nRESULTS\nWe identified 61 227 eligible inflammatory disease patients with either new anti-TNF or new nonbiologic DMARD use. Among this cohort, we found 3 ON cases among anti-TNF new users, occurring a median of 123 days (range, 37-221 days) after anti-TNF start. The crude incidence rate of ON across all disease indications among anti-TNF new users was 10.4 (95% CI 3.3-32.2) cases per 100 000 person-years. In a sensitivity analysis considering current or past anti-TNF or DMARD use, we identified a total of 6 ON cases: 3 among anti-TNF users and 3 among DMARD users. Crude ON rates were similar among anti-TNF and DMARD groups: 4.5 (95% CI 1.4-13.8) and 5.4 (95% CI 1.7-16.6) per 100 000 person-years, respectively.\n\n\nCONCLUSIONS\nOptic neuritis is rare among those who initiate anti-TNF therapy and occurs with similar frequency among those with nonbiologic DMARD exposure.",
"affiliations": "Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA. [email protected]",
"authors": "Winthrop|Kevin L|KL|;Chen|Lang|L|;Fraunfelder|Frederick W|FW|;Ku|Jennifer H|JH|;Varley|Cara D|CD|;Suhler|Eric|E|;Hills|William L|WL|;Gattey|Devin|D|;Baddley|John W|JW|;Liu|Liyan|L|;Grijalva|Carlos G|CG|;Delzell|Elizabeth|E|;Beukelman|Timothy|T|;Patkar|Nivedita M|NM|;Xie|Fenglong|F|;Herrinton|Lisa J|LJ|;Fraunfelder|Fritz T|FT|;Saag|Kenneth G|KG|;Lewis|James D|JD|;Solomon|Daniel H|DH|;Curtis|Jeffrey R|JR|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "155(1)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000465:Algorithms; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015331:Cohort Studies; D016208:Databases, Factual; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D015994:Incidence; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D009902:Optic Neuritis; D018124:Receptors, Tumor Necrosis Factor; D012189:Retrospective Studies; D018570:Risk Assessment; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "183-189.e1",
"pmc": null,
"pmid": "22967869",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": "17136752;10449104;16705109;17530704;15234126;16142860;21919113;14585769;18499716;17456525;7854520;11592357;21285425;21693740",
"title": "Initiation of anti-TNF therapy and the risk of optic neuritis: from the safety assessment of biologic ThERapy (SABER) Study.",
"title_normalized": "initiation of anti tnf therapy and the risk of optic neuritis from the safety assessment of biologic therapy saber study"
} | [
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"literaturereference": "WINTHROP KL, CHEN L, FRAUNFELDER FW, KU JH, VARLEY CD, SUHLER E, ET AL. INITIATION OF ANTI-TNF THERAPY AND THE RISK OF OPTIC NEURITIS: FROM THE SAFETY ASSESSMENT OF BIOLOGIC THERAPY (SABER) STUDY. AMERICAN JOURNAL OF OPHTHAMOLOGY 2013;155 (1):183-189.",
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}
],
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"literaturereference": "WINTHROP KL, CHEN L, FRAUNFELDER FW, KU JH, VARLEY CD, SUHLER E, ET AL. INITIATION OF ANTI-TNF THERAPY AND THE RISK OF OPTIC NEURITIS: FROM THE SAFETY ASSESSMENT OF BIOLOGIC THERAPY (SABER) STUDY. AMERICAN JOURNAL OF OPHTHAMOLOGY 2013;155 (1):183-189.",
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] |
{
"abstract": "Genitourinary tuberculosis (TB) is a rare but well-described form of extrapulmonary TB. We present a case of a 35-year-old man from Ethiopia with scrotal swelling and fever who was found to have epididymo-orchitis due to Mycobacterium tuberculosis. The patient presented to the hospital multiple times before undergoing operative debridement with fine needle aspiration and tissue biopsy to confirm the diagnosis. He improved with antituberculous therapy. Patients with TB risk factors presenting with epididymitis that is refractory to empiric antibiotic therapy warrant consideration of TB epididymitis. Our case demonstrates the high index of suspicion required to establish a diagnosis of genitourinary TB.",
"affiliations": "Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Department of Urology, HealthPartners, St. Paul, Minnesota.;Division of Infectious Diseases, HealthPartners, St. Paul, Minnesota.;Travel and Tropical Medicine Center, HealthPartners, Minneapolis, Minnesota.;Travel and Tropical Medicine Center, HealthPartners, Minneapolis, Minnesota.",
"authors": "Hane|Jessica|J|;Duffey|Branden|B|;Kaiser|Robyn|R|;Walker|Patricia F|PF|;Alpern|Jonathan D|JD|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.19-0162",
"fulltext": null,
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"issn_linking": "0002-9637",
"issue": "101(5)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D004822:Epididymis; D005002:Ethiopia; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis; D009920:Orchitis; D014389:Tuberculosis, Male Genital",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1070-1072",
"pmc": null,
"pmid": "31482781",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18061028;29565838;28087922;27621353;11373214;29590543;16006701;18765130;19793000;23540084",
"title": "Case Report: Epididymo-Orchitis due to Mycobacterium tuberculosis.",
"title_normalized": "case report epididymo orchitis due to mycobacterium tuberculosis"
} | [
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}
],
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}
],
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}
},
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"literaturereference": "HANE J, DUFFEY B, KAISER R, WALKER PF, ALPERN JD. CASE REPORT: EPIDIDYMO-ORCHITIS DUE TO MYCOBACTERIUM TUBERCULOSIS. AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE. 2019?101(5):51070-1072. DOI: 10.4269/AJTMH.19-0162",
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},
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}
],
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},
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},
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"receiptdate": "20191220",
"receivedate": "20191220",
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},
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"sendertype": "2"
},
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"seriousnessdisabling": null,
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
},
{
"companynumb": "NVSC2019US065301",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
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"drugdosagetext": "UNK",
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"drugindication": "ORCHITIS",
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},
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},
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"medicinalproduct": "CIPROFLOXACIN."
}
],
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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},
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},
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},
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}
] |
{
"abstract": "OBJECTIVE\nTo determine the effectiveness and the incidence of severe adverse events in a cohort of Costa Rican patients with Rheumatoid Arthritis (RA) treated with intravenous (IV) tocilizumab (TCZ).\n\n\nMETHODS\nA retrospective analysis was carried out in 45 patients that were unresponsive to disease-modifying antirheumatic drugs (DMARDs). The study included patients who received IV TCZ every 4 weeks (4mg/kg) along with methotrexate or leflunomide. Effectiveness was measured through the incidence of clinical remission according to a disease activity score - erythrocyte sedimentation rate (DAS28-ESR) less than 2.6. Safety was assessed by the incidence rate of serious adverse events. An univariate and multivariate logistic regression analysis was performed to assess the association of potential variables with the probability of achieving remission during the first 3 months of TCZ therapy.\n\n\nRESULTS\nDuring the 3rd month of TCZ therapy, a total of 22 patients (48.9%; 95% Confidence Interval (CI) 34.3-63.5%) achieved remission. The cumulative incidence of patients with remission at month 12 was 75.0% (n=34) (95% CI: 62.3-87.6%). A total of 18 patients (40%; 95% CI: 25.7-54.3%) were switched to a 8mg/kg dose due to the absence of remission. The incidence rate of serious adverse events was .98 per 100 patients/year, all of them due to infectious diseases with no fatal events reported. Only basal DAS28-ESR was associated with the probability of achieving remission at month 3.\n\n\nCONCLUSIONS\nIV TCZ (4mg/kg) is an effective and safe treatment for RA patients in a clinical setting in Costa Rica.",
"affiliations": "Servicio de Reumatología, Hospital San Juan de Dios, San José, Costa Rica. Electronic address: [email protected].;Servicio de Reumatología, Hospital San Juan de Dios, San José, Costa Rica.;Departamento de Farmacología, Universidad de Costa Rica, San José, Costa Rica.",
"authors": "Cordero-Alfaro|Mauricio|M|;León-Céspedes|Carlos|C|;Ramos-Esquivel|Allan|A|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.reuma.2019.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5743",
"issue": "17(6)",
"journal": "Reumatologia clinica",
"keywords": "Anticuerpo monoclonal humanizado; Artritis reumatoide; Disease-modifying antirheumatic drugs; Efectividad; Effectiveness; Fármacos modificadores de la enfermedad reumática; Humanised monoclonal antibody; Optimisation; Optimización; Rheumatoid arthritis; Safety; Seguridad; Tocilizumab",
"medline_ta": "Reumatol Clin (Engl Ed)",
"mesh_terms": null,
"nlm_unique_id": "101717526",
"other_id": null,
"pages": "329-334",
"pmc": null,
"pmid": "32057667",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis.",
"title_normalized": "effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of costa rican patients with rheumatoid arthritis"
} | [
{
"companynumb": "CR-ROCHE-2553807",
"fulfillexpeditecriteria": "1",
"occurcountry": "CR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
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},
{
"actiondrug": "5",
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"activesubstancename": "TOCILIZUMAB"
},
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"drugadministrationroute": "042",
"drugauthorizationnumb": "125276",
"drugbatchnumb": "UNKNOWN,UNKNOWN",
"drugcharacterization": "1",
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"drugindication": "RHEUMATOID ARTHRITIS",
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"medicinalproduct": "TOCILIZUMAB."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
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"drugbatchnumb": "UNKNOWN",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LEFLUNOMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "125276",
"drugbatchnumb": "UNKNOWN,UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "IN 18 PATIENTS, DOSE INCREASED.",
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"drugstructuredosagenumb": "8",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TOCILIZUMAB."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fournier^s gangrene",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Urinary tract infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CORDERO?ALFARO M, LEON?CESPEDES C AND RAMOS?ESQUIVEL A. EFFECTIVENESS OF INTRAVENOUS TOCILIZUMAB IN ROUTINE CLINICAL PRACTICE IN A COHORT OF COSTA RICAN PATIENTS WITH RHEUMATOID ARTHRITIS. REUMATOLOGIA CLINICA 2021 JUN?17 (6):329?34.",
"literaturereference_normalized": "effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of costa rican patients with rheumatoid arthritis",
"qualification": "3",
"reportercountry": "CR"
},
"primarysourcecountry": "CR",
"receiptdate": "20210608",
"receivedate": "20200806",
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"receivertype": "6"
},
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"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210717"
}
] |
{
"abstract": "A 44-year-old woman with a 26-year history of Crohn's disease (CD) presented with intermittent fever, vomiting, and watery diarrhea. Her medication included an elemental diet, mesalazine, and infliximab. Liver profile and viral hepatitis markers were normal. Computed tomography scans showed a hepatic tumor by chance. Serum tumor markers disclosed elevated protein induced by vitamin K absence-II. With a diagnosis of hepatocellular carcinoma (HCC), she underwent a hepatic resection of the tumor, revealing well-to-moderately differentiated HCC. The nontumor region of the liver disclosed the absence of cirrhosis or other diseases. Here, the development of HCC in CD without underlying liver diseases is discussed with a review of the literature.",
"affiliations": "Department of Endoscopy, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of General and Digestive Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of General and Digestive Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Pathology, University of the Ryukyus Hospital, Nishihara, JPN.;Department of Pathology, University of the Ryukyus Hospital, Nishihara, JPN.;Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of General and Digestive Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.;Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN.",
"authors": "Hokama|Akira|A|;Arakaki|Shingo|S|;Ishino|Shinichiro|S|;Nakagawa|Yutaka|Y|;Tabata|Souhei|S|;Agarie|Daiki|D|;Kuwae|Satoshi|S|;Zukeyama|Ryuta|R|;Maeshiro|Tatsuji|T|;Tsuruta|Yuma|Y|;Matsuzaki|Akiko|A|;Wada|Naoki|N|;Takatsuki|Mitsuhisa|M|;Fujita|Jiro|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16570",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16570\nGastroenterology\nOncology\nHepatocellular Carcinoma in a Patient With Crohn’s Disease\nMuacevic Alexander\nAdler John R\nHokama Akira 1\nArakaki Shingo 2\nIshino Shinichiro 3\nNakagawa Yutaka 3\nTabata Souhei 2\nAgarie Daiki 2\nKuwae Satoshi 2\nZukeyama Ryuta 2\nMaeshiro Tatsuji 2\nTsuruta Yuma 4\nMatsuzaki Akiko 4\nWada Naoki 5\nTakatsuki Mitsuhisa 3\nFujita Jiro 2\n1 Department of Endoscopy, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN\n2 Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN\n3 Department of General and Digestive Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN\n4 Department of Pathology, University of the Ryukyus Hospital, Nishihara, JPN\n5 Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JPN\nAkira Hokama [email protected]\n22 7 2021\n7 2021\n13 7 e1657022 7 2021\nCopyright © 2021, Hokama et al.\n2021\nHokama et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/60880-hepatocellular-carcinoma-in-a-patient-with-crohns-disease\nA 44-year-old woman with a 26-year history of Crohn’s disease (CD) presented with intermittent fever, vomiting, and watery diarrhea. Her medication included an elemental diet, mesalazine, and infliximab. Liver profile and viral hepatitis markers were normal. Computed tomography scans showed a hepatic tumor by chance. Serum tumor markers disclosed elevated protein induced by vitamin K absence-II. With a diagnosis of hepatocellular carcinoma (HCC), she underwent a hepatic resection of the tumor, revealing well-to-moderately differentiated HCC. The nontumor region of the liver disclosed the absence of cirrhosis or other diseases. Here, the development of HCC in CD without underlying liver diseases is discussed with a review of the literature.\n\nhepatocellular carcinoma\ninfliximab\npathology\ncomputed tomography\ncrohn’s disease (cd)\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nThe development of hepatocellular carcinoma (HCC) is mostly associated with underlying liver diseases, such as cirrhosis and chronic hepatitis. Crohn’s disease (CD) is often complicated with various hepatobiliary disorders, including cholelithiasis and abnormal liver function [1]. Recently, several cases of HCC have been reported among CD patients without cirrhosis, and immunosuppressive treatments for CD have been focused on as potential carcinogenic factors. Here, we present the case of a patient with CD who developed HCC in the absence of underlying liver diseases and discuss the background of carcinogenesis.\n\nCase presentation\n\nA 44-year-old woman with a 26-year history of CD presented with intermittent fever, vomiting, and watery diarrhea. Her medical history was significant for a colonic resection at the age of 40 and a proctocolectomy with end ileostomy at the age of 41. Her medication included an elemental diet, mesalazine 3 g daily, and infliximab (IFX) 10 mg/kg every eight weeks. She denied smoking and alcohol use. Physical examination revealed stable vital signs and a body mass index of 17.9 kg/m2. The abdomen was soft and nontender. Laboratory tests showed white blood cells of 5,700/μL, hemoglobin of 10.1 g/dL, platelets of 32.5 × 104/μL, and C-reactive protein of 0.85 mg/dL (reference range: <0.23 mg/dL). Liver profile and viral hepatitis markers were normal: bilirubin 0.4 mg/dL (reference range: 0.4-1.5 mg/dL), aspartate aminotransferase 20 U/L (reference range: 13-30 U/L), alanine aminotransferase 35 U/L (reference range: 7-23 U/L), alkaline phosphatase 158 U/L (reference range: 106-322 U/L), lactate dehydrogenase 120 U/L (reference range: 124-222 U/L), and gamma-glutamyl transferase 11 U/L (reference range: 9-32 U/L). Computed tomography (CT) scans were performed to evaluate the symptoms, which showed a hepatic tumor incidentally. A CT scan showed a heterogeneously enhancing hepatic tumor at the arterial phase (Figure 1).\n\nFigure 1 Abdominal CT.\n\nCT scan showing a heterogeneously enhancing hepatic tumor (arrow) at the arterial phase.\n\nCT: computed tomography\n\nGadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging showed the hyperintense tumor on T2-weighted imaging (Figure 2).\n\nFigure 2 Abdominal MRI.\n\nGadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI showed the 28-mm-sized hepatic tumor (arrow) on T2-weighted imaging.\n\nMRI: magnetic resonance imaging\n\nSerum tumor markers showed α-fetoprotein of 7 ng/mL (reference range: <9 ng/mL) and elevated protein induced by vitamin K absence-II of 1,411 mAU/mL (reference range: <40 mAU/mL). HCC was suspected based on laboratory and imaging studies. She underwent a hepatic resection of the tumor with an uncomplicated postoperative course. Pathological examination of the tumor showed well-to-moderately differentiated HCC without evidence of microvascular invasion (Figure 3). The non-neoplastic liver showed no evidence of chronic hepatitis, liver cirrhosis, or other metabolic disorders (Figure 4).\n\nFigure 3 Histopathological figure.\n\nHistopathological findings of the tumor showed well-to-moderately differentiated HCC without evidence of microvascular invasion (hematoxylin and eosin staining, magnification: ×200).\n\nHCC: hepatocellular carcinoma\n\nFigure 4 Histopathological figure.\n\nThe nontumor region of the liver disclosed the absence of cirrhosis or other diseases (magnification: ×200).\n\nIFX was discontinued because of the potential effects in post-cancer surgery and vedolizumab was initiated. The patient has been free from recurrence for two years.\n\nDiscussion\n\nMost HCC cases develop in the presence of cirrhosis or hepatitis. This case presents important clinical issues that HCC can occur in patients with CD, even without underlying liver diseases for HCC. The occurrence of HCC among patients with CD is extremely rare, with only 15 cases, including our case, published as case reports in the literature [2-15].\n\nTable 1 summarizes the clinicopathological features of HCC in CD patients. The average age of the diagnosis of HCC among these CD patients was 40.6 years, which was younger than that of usual HCC (50 years) [16]. The average period between the onset of CD and the diagnosis of HCC was 19.3 years. Several hepatic diseases have been reported in association with CD, which include cholelithiasis, primary sclerosing cholangitis (PSC), steatosis, and drug-induced abnormal liver function [1]. A total of eight (53.3%) cases, including the present case, had no underlying liver diseases; whereas two cases had PSC, four cases had focal hepatic glycogenosis (FHG), and one case had chronic liver inflammation. It is well known that both PSC and FHG have significant neoplastic potentials.\n\nTable 1 Clinicopathological features of HCC in patients with CD.\n\nCD: Crohn’s disease; AFP: alfa-fetoprotein; PIVKA-II: protein induced by vitamin K absence-II; HCC: hepatocellular carcinoma; AZA: azathioprine; PSL: prednisolone; NA: not available; DOD: died of disease; 5-ASA: 5-aminosalicylic acid; FHG: focal hepatocyte glycogenosis; LT: liver transplantation; PSC: primary sclerosing cholangitis; TACE: transcatheter arterial chemoembolization; ADA: adalimumab\n\nCase No.\tGender\tAge: onset of CD/discovery of HCC\tTherapy for CD\tSerum AFP/PIVKA II (ng/mL, mAU/mL)\tPathology of HCC\tPathology of non-neoplastic liver\tTherapy and outcome\tReference No.\t\n1\tF\t29/43\tAZA, PSL\tNA/NA\tNA\tNo cirrhosis\tDOD with carcinomatosis\t[2]\t\n2\tF\t9/22\t5-ASA, AZA\t55,000/NA\tTrabecular\tNo cirrhosis positive FHG\tRecurrence 6 months after surgery\t[3]\t\n3\tM\t13/33\t5-ASA, AZA\tNA/NA\tNA\tNo cirrhosis\tLung metastasis\t[4]\t\n4\tF\t63/63\t5-ASA\tNA/1,100\tNA\tPSC\tNo recurrence 15 months after LT\t[5]\t\n5\tF\t14/28\tAZA, IFX\t26.9/NA\tTrabecular, pleomorphic\tNo cirrhosis positive FHG\tSurgery\t[6]\t\n6\tM\t17/33\tAZA\tNormal range/NA\tNA\tPSC\tDOD with carcinomatosis\t[7]\t\n7\tM\t19/37\t5-ASA, AZA, PSL\t15/NA\tTrabecular to sinusoidal, pleomorphic\tNA\tDOD 3 months after onset\t[8]\t\n8\tM\t16/52\t5-ASA\t13.9/16,300\tTrabecular\tChronic liver inflammation\tRecurrence after TACE\t[9]\t\n9\tM\t13/25\tAZA, IFX, PSL\t78/NA\tPleomorphic\tNo cirrhosis positive FHG\tNo recurrence 1 year after surgery\t[10]\t\n10\tM\t29/37\t5-ASA, AZA, PSL\t7.7/757\tPseudoglandular\tNo cirrhosis positive FHG\tNo recurrence 2 years after surgery\t[11]\t\n11\tM\t9/34\tAZA, IFX\t3307/NA\tTrabecular\tNo cirrhosis\tCarcinomatosis; died 5 months after\t[12]\t\n12\tM\t20/58\t5-ASA, AZA\t10.3/NA\tModerately differentiated\tNo cirrhosis\tRecurrence 4 years after surgery\t[13]\t\n13\tM\t20/40\tIFX, ADA\tNA/NA\tModerately differentiated\tNo cirrhosis\tRecurrence 5 years after surgery\t[14]\t\n14\tF\t31/61\t5-ASA, AZA, IFX\tNA/NA\tWell-differentiated\tNo fibrosis\tNo recurrence 11 months after surgery\t[15]\t\n15\tF\t18/44\t5-ASA, IFX\t7/1,411\tModerately differentiated\tNo cirrhosis\tNo recurrence 2 years after surgery\tPresent case\t\n\nConsidering the association with the treatments for CD, 11 (73.3%) cases were treated with AZA, and six (40%) cases were administered IFX. Although AZA has an increased risk of neoplasms including lymphoma and skin cancer, the association with HCC is unknown. The effects of IFX on the development of HCC have not been clarified. Several epidemiology investigations revealed no association between IFX and cancer risks [17,18]. Therefore, IFX may be an innocent bystander in HCC among patients with CD [12]. Although acute liver injury caused by immunosuppressants and biologics has been well studied in the treatment for CD [19], long-term hepatotoxicity and hepatocarcinogenesis should be further monitored carefully. In addition, a recent Swedish/Danish population-based cohort study (1969-2017) revealed 28 deaths from HCC among 47,399 patients with CD and corresponding hazard ratios (HRs) of 1.96 (95% confidence interval: 1.31-2.93) [20]. Although this data lacked information on smoking, alcohol consumption, and underlying hepatic diseases, specific surveillance strategies for HCC was needed because of high HRs.\n\nConclusions\n\nIn summary, we present a case of HCC in a patient with CD who was treated with IFX in the absence of underlying liver diseases. Although the precise pathophysiology of the development of HCC in CD has not been clarified and potential links should be further investigated, the liver should be surveyed closely by imaging studies in addition to routine blood tests in the era of immunosuppressive treatments with AZA or biologics.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Hepatic manifestations of inflammatory bowel diseases Liver Int Restellini S Chazouillères O Frossard JL 475 489 37 2017 27712010\n2 Primary liver cell cancer occurring in association with Crohn's disease treated with prednisolone and azathioprine Hepatogastroenterology Lee FL Murray SM Prior J Shreeve DR 188 30 1983 https://pubmed.ncbi.nlm.nih.gov/6315555/ 6315555\n3 Hepatocellular carcinoma and focal hepatic glycogenosis after prolonged azathioprine therapy Hum Pathol Cattan S Wendum D Chazouilleres O Schmitz J Gendre JP 874 876 31 2000 10923928\n4 Unusual development of hepatocellular carcinoma in a patient with Crohn's disease Dig Dis Sci Borum ML 2199 2200 46 2001 11680596\n5 Living related donor liver transplantation for primary sclerosing cholangitis with hepatocellular carcinoma and Crohn's disease: a case report Transplant Proc Oya H Sato Y Yamamoto S Takeishi T Kobayashi T Hatakeyama K 2297 2298 36 2004 15561226\n6 Hepatocellular carcinoma occurring in a patient with Crohn's disease treated with both azathioprine and infliximab Dig Dis Sci Chen SC Cummings OW Hartley MP Filomena CA Cho WK 952 955 51 2006 16670938\n7 Hepatocellular carcinoma complicating primary sclerosing cholangitis in Crohn's disease. A case report Minerva Gastroenterol Dietol Demarchi B Bresso F Novero D 279 283 53 2007 https://pubmed.ncbi.nlm.nih.gov/17912190/ 17912190\n8 Development of hepatocellular carcinoma in a patient with Crohn's disease treated with azathioprine Dig Dis Sci Samarasena J Borgaonkar M 2748 2750 52 2007 17404860\n9 Hepatocellular carcinoma and Crohn's disease: a case report and review Intern Med Miura H Kawaguchi T Takazoe M Kitamura S Yamada H 815 819 48 2009 19443977\n10 Hepatocellular carcinoma occurring in a young Crohn's disease patient Pathol Int Murakami A Tanaka Y Ueda M 492 496 59 2009 19563414\n11 Hepatocellular carcinoma occurring in a Crohn's disease patient World J Gastroenterol Ishida M Naka S Shiomi H 3215 3218 16 2010 20593510\n12 Metastatic hepatocellular carcinoma in a patient with Crohn's disease treated with azathioprine and infliximab: a case report and literature review Case Rep Gastrointest Med Fortinsky KJ Alali A Jeejeebhoy K Fischer S Sherman M Fung S 340836 2014 2014 25587469\n13 Recurrent hepatocellular carcinoma in patient with Crohn's disease: incidental or expected outcome of azathioprine? Case Rep Gastrointest Med Botros Y Mathews M Patel H Shah N Baddoura W de la Torre A 939136 2015 2015 26788381\n14 Hepatocellular carcinoma regression after cessation of immunosuppressive therapy J Clin Oncol Kumar A Le DT 0 2 34 2016\n15 Resected hepatocellular carcinoma in a patient with Crohn's disease on azathioprine Case Rep Gastroenterol Heron V Fortinsky KJ Spiegle G Hilzenrat N Szilagyi A 50 56 10 2016 27403102\n16 From diagnosis to treatment of hepatocellular carcinoma: an epidemic problem for both developed and developing world World J Gastroenterol Dimitroulis D Damaskos C Valsami S 5282 5294 23 2017 28839428\n17 Cancer in Crohn's disease patients treated with infliximab: a long-term multicenter matched pair study Inflamm Bowel Dis Biancone L Petruzziello C Orlando A 758 766 17 2011 20684009\n18 Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data Pharmacoepidemiol Drug Saf Askling J Fahrbach K Nordstrom B Ross S Schmid CH Symmons D 119 130 20 2011 21254282\n19 Hepatic complications induced by immunosuppressants and biologics in inflammatory bowel disease World J Hepatol Tran-Minh ML Sousa P Maillet M Allez M Gornet JM 613 626 9 2017 28539989\n20 Hepatobiliary cancer risk in patients with inflammatory bowel disease: a Scandinavian population-based cohort study Cancer Epidemiol Biomarkers Prev Erichsen R Olén O Sachs MC 886 894 30 2021 33627380\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(7)",
"journal": "Cureus",
"keywords": "computed tomography; crohn’s disease (cd); hepatocellular carcinoma; infliximab; pathology",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
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"pages": "e16570",
"pmc": null,
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"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "10923928;28839428;28539989;19443977;15561226;26788381;19563414;25245441;25587469;27403102;21254282;17912190;20684009;6315555;11680596;33627380;16670938;27712010;17404860;20593510",
"title": "Hepatocellular Carcinoma in a Patient With Crohn's Disease.",
"title_normalized": "hepatocellular carcinoma in a patient with crohn s disease"
} | [
{
"companynumb": "JP-CELLTRION INC.-2021JP012072",
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"drugindication": "CROHN^S DISEASE",
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"reaction": [
{
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"reactionoutcome": "6"
},
{
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},
{
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},
{
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},
{
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},
{
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"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HOKAMA A, ARAKAKI S, ISHINO S, NAKAGAWA Y, TABATA S, AGARIE D, ET AL.. HEPATOCELLULAR CARCINOMA IN A PATIENT WITH CROHN^S DISEASE. CUREUS. 2021?13(7):E16570:1?6",
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},
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},
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}
] |
{
"abstract": "Cerebral edema (CE) and non cardiogenic pulmonary edema (acute respiratory distress syndrome, ARDS) are life-threatening complications of diabetic ketoacidosis (DKA). In contrast to CE complicating DKA, which is primarily reported in pediatric patients, ARDS is rarely described in this age group. Here, the authors present a child with DKA who developed both cerebral edema and ARDS during the course of her management. It is feasible that severe acidosis, hypotension, azotemia, hypoalbuminemia and the superimposed aggressive intravenous fluid administration were important risk factors for the development of cerebral edema and ARDS in the index patient. The report highlights the importance of early diagnosis and aggressive therapy in the management of ARDS, and summarizes the published literature on this rarely reported complication of pediatric DKA.",
"affiliations": "Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, Uttar Pradesh, India.;Division of Endocrinology and Diabetes, Medanta the Medicity, Gurgaon, Haryana, India.;Department of Anesthesiology, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Department of Anesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, Uttar Pradesh, India.;Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, Uttar Pradesh, India. [email protected].",
"authors": "Sudhanshu|Siddhnath|S|;Jevalikar|Ganesh|G|;Das|Pravin K|PK|;Singh|Pramod K|PK|;Bhatia|Eesh|E|;Bhatia|Vijayalakshmi|V|",
"chemical_list": "D004234:Diuretics, Osmotic; D008353:Mannitol",
"country": "India",
"delete": false,
"doi": "10.1007/s12098-015-1961-6",
"fulltext": null,
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"issn_linking": "0019-5456",
"issue": "83(5)",
"journal": "Indian journal of pediatrics",
"keywords": "ARDS; Cerebral edema; DKA; Mannitol; Pediatric",
"medline_ta": "Indian J Pediatr",
"mesh_terms": "D000293:Adolescent; D001929:Brain Edema; D016883:Diabetic Ketoacidosis; D004234:Diuretics, Osmotic; D042241:Early Diagnosis; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D008168:Lung; D008353:Mannitol; D009460:Neurologic Examination; D011859:Radiography; D006435:Renal Dialysis; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0417442",
"other_id": null,
"pages": "463-5",
"pmc": null,
"pmid": "26666907",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22391852;11786509;9877465;9448236;3105098;17452217;3117997;6821490;3133457;8612448;15329157",
"title": "Acute Respiratory Distress Syndrome: A Rare Complication in Pediatric Diabetic Ketoacidosis.",
"title_normalized": "acute respiratory distress syndrome a rare complication in pediatric diabetic ketoacidosis"
} | [
{
"companynumb": "IN-B. BRAUN MEDICAL INC.-1065650",
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"activesubstancename": "INSULIN NOS"
},
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{
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"activesubstancename": "SODIUM CHLORIDE"
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{
"abstract": "Myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G-associated optic neuritis (ON) is a newly recognized antibody-mediated demyelinating disease of the central nervous system, resulting in acute visual loss and pain with eye movement. The effects of pregnancy on disease pathogenesis remain incompletely understood. Herein, we present a novel association between a frozen embryo transfer (FET) and the first manifestation of MOG-ON in a previously healthy patient with unexplained infertility. The patient presented with acute bilateral visual loss 3 weeks after a single FET and was found to test positive for MOG antibodies with an otherwise unremarkable workup. The patient's vision returned to baseline with high-dose intravenous methylprednisolone and therapeutic plasma exchange. This is the first published case highlighting an association between MOG-ON and assisted reproductive technology (ART) in a patient without prior risk factors. Further studies are needed to clarify the effects of ART and pregnancy in general on disease pathogenesis.",
"affiliations": "Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.;Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.;Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.",
"authors": "Siegel|Dana Rebecca|DR|;Luu|Thanh-Ha|TH|;Skaznik-Wikiel|Malgorzata E|ME|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jhrs.jhrs_30_21",
"fulltext": "\n==== Front\nJ Hum Reprod Sci\nJ Hum Reprod Sci\nJHRS\nJournal of Human Reproductive Sciences\n0974-1208\n1998-4766\nWolters Kluwer - Medknow India\n\nJHRS-14-203\n10.4103/jhrs.jhrs_30_21\nCase Report\nPrimary Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G-associated Optic Neuritis Presenting after a Frozen Embryo Transfer\nSiegel Dana Rebecca\nLuu Thanh-Ha\nSkaznik-Wikiel Malgorzata E.\nDepartment of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA\nAddress for correspondence: Dr. Dana Rebecca Siegel, 12631 East 17th Ave, B198-6, Aurora, Colorado 80045, USA. E-mail: [email protected]\nApr-Jun 2021\n28 6 2021\n14 2 203205\n14 2 2021\n19 5 2021\n20 5 2021\nCopyright: © 2021 Journal of Human Reproductive Sciences\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nMyelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G-associated optic neuritis (ON) is a newly recognized antibody-mediated demyelinating disease of the central nervous system, resulting in acute visual loss and pain with eye movement. The effects of pregnancy on disease pathogenesis remain incompletely understood. Herein, we present a novel association between a frozen embryo transfer (FET) and the first manifestation of MOG-ON in a previously healthy patient with unexplained infertility. The patient presented with acute bilateral visual loss 3 weeks after a single FET and was found to test positive for MOG antibodies with an otherwise unremarkable workup. The patient's vision returned to baseline with high-dose intravenous methylprednisolone and therapeutic plasma exchange. This is the first published case highlighting an association between MOG-ON and assisted reproductive technology (ART) in a patient without prior risk factors. Further studies are needed to clarify the effects of ART and pregnancy in general on disease pathogenesis.\n\nKEYWORDS:\n\nAssisted reproductive technology\nautoimmune diseases\ncase report\nmyelin oligodendrocyte glycoprotein\noptic neuritis\n==== Body\nINTRODUCTION\n\nMyelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG)-associated optic neuritis (ON) is a rare and distinct antibody-mediated demyelinating disease of the central nervous system with autoantibodies directed against MOG that can result in severe vision loss.[1] While there have been several well-documented reports highlighting the association between multiple sclerosis (MS) and assisted reproductive technology (ART), there have been no reported cases of ART triggering MOG-ON.[234]\n\nMethods\n\nThe authors certify that they have obtained appropriate written informed consent from the patient described in the present case. Consent was obtained after the authors participated in the care of this patient.\n\nCASE REPORT\n\nA 39-year-old female with a history of unexplained primary infertility who was approximately 4 months after oocyte retrieval and 3 weeks after a single frozen embryo transfer (FET) presented to the hospital with acute bilateral vision loss, ophthalmalgia, and a positive serum pregnancy test.\n\nWhen the patient arrived, she exhibited light perception in the right eye and no light perception in the left eye, which was drastically decreased from her baseline of 20/20 bilaterally. The patient also had grade one optic disc swelling of the right eye and grade two optic disc swelling of the left eye with bilateral minimally reactive pupillary responses but without an afferent pupillary defect. There was a normal anterior segment of both eyes by slit lamp exam and optical coherence tomography (OCT) was consistent with borderline thinning. The patient's review of systems was unremarkable, and she denied any recent illness, vaccinations, trauma, or personal or family history of autoimmune or neurological disease.\n\nShe had previously undergone controlled ovarian hyperstimulation using 150 international units (IU) of Gonal-F® (follitropin alfa; Merck and Co., Darmstadt, Germany) and 150 IU of Menopur® (menotropin; Ferring Pharmaceuticals) for 10 days with 250 mcg of the GnRH antagonist Cetrotide® (cetrorelix acetate; Merck and Co., Darmstadt, Germany) initiated on day 5. A trigger shot of 1 mg Lupron® (leuprolide acetate; Abbott Laboratories, Chicago, IL) was then administered on day 10 with retrieval 35 hours afterward consisting of 11 oocytes and four resulting embryos. She then had an uncomplicated FET roughly 4 months after the retrieval with a peak estradiol level of 831 pg/mL. First, endometrial preparation was initiated using oral contraceptive pills for 12 weeks, followed by oral Estrace® 2 mg TID (estradiol; Novo Nordisk, Denmark) an estradiol patch 0.1 mg/24 h for 2 weeks and vaginal progesterone 100 mg TID (Endometrin®; Ferring Pharmaceuticals, Saint Prex, Switzerland).\n\nOn arrival, the patient's lumbar puncture was unremarkable; oligoclonal bands were absent and cerebrospinal fluid (CSF) cultures were negative. Further workup revealed T2 hyperintensity and thickening of the prechiasmatic left optic nerve and equivocal findings for the right intraorbital optic nerve [Figure 1]. Autoantibodies against aquaporin 4 were absent, while MOG antibodies were positive in a 1:40 titer. Additionally, patient had positive antibodies to JC virus and negative Sjogren's syndrome (anti SSB and anti SSA), antiphospholipid (anticardiolipin IgG, anti cardiolipin IgM, beta 2 glycoprotein IgG, and IgM antibodies), and treponema antibodies. Futhermore, QuantiFERON tuberculosis gold, hepatitis B, hepatitis C, and human immunodeficiency virus antibodies were negative.\n\nFigure 1 Focal thickening with increased T2 signal of the prechiasmatic left optic nerve in a patient with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated optic neuritis (see arrow)\n\nThe patient was started on 5 days of high-dose intravenous methylprednisolone 1000 mg/day as well as therapeutic plasma exchange. With treatment, the patient's vision progressively improved. However, on day 3 of the plasma exchange, the patient began to have vaginal bleeding with an abnormal beta-human chorionic gonadotropin trend. She was diagnosed with an ectopic pregnancy, which was managed medically with a single dose of 105 mg methotrexate (Pfizer; New York, NY).\n\nThe patient was discharged from the hospital on a 5 day course of an oral prednisone taper along with initiation of the disease modifying treatment (DMT) rituximab with plan for 1 g twice over 2 weeks repeated at 6 months with a repeat brain magnetic resonance imaging (MRI) 3 months after starting DMT to determine the exact duration.\n\nDISCUSSION\n\nThis is the first case report of MOG-ON associated with FET. Although definitive causation is difficult to ascertain in this limited report consisting of one patient, the timing of onset and association of ART and other neurological conditions suggest FET as a possible contributor to the inciting manifestation of MOG-ON in the present case.\n\nMOG-ON has emerged as a unique antibody-mediated demyelinating disease of the central nervous system. It has been proposed that MOG-specific effector T-cells may be triggered if the protein escapes into the CSF and periphery, resulting in a marked activation of the classical complement cascade.[1] In terms of MOG-ON effects on pregnancy, a single retrospective multicenter study of MOG-IgG-positive patients showed that, while roughly half of the patients with a documented pregnancy had an attack during pregnancy or postpartum, the attacks most commonly occurred in the postpartum period (57%). The cases that did occur during pregnancy were in patients with previously diagnosed recurrent disease.[5]\n\nPregnancy may be protective for certain autoimmune diseases such as MS. To elaborate, there is a shift from T helper 1 (Th1) dominance to T helper 2-type cytokines and associated humoral response postulated to improve Th1-dominant cell-mediated immune diseases.[67] While MS is predominantly a cell-mediated disease dominated by Th1 cytokines, CSF studies from patients with MOG-ON have shown a predominance of Th17 cell upregulation and cytokine production.[8] Interestingly, these Th17-related cytokines can recruit both humoral and cellular immunity with estradiol-enhancing cell-mediated immunity at low concentrations and augmenting humoral immunity at high concentrations.[6]\n\nA proposed mechanism of ART associated with MOG-ON points to several studies showing that ovulation induction may increase the levels of vascular endothelial growth factor, which is a protein associated with blood–brain barrier (BBB) breakdown.[29] Furthermore, the estrogenic fluctuations after the use of GnRH agonists or antagonists have been shown to have a direct effect on the proliferation of B and T-cells as well as on autoantibody production and immune cell migration across the BBB.[10] In addition, ovulation induction can significantly increase the number of MOG-IgG autoantibodies as well as B-cell survival factor B-cell-activating factor.[2] In the present case, the initial BBB breakdown as well as the increase in MOG-IgG production may have originally occurred during the ovarian stimulation phase of her ART. However, her long-term suppressive contraceptive therapy taken from the time of stimulation to implantation may have initially inhibited her autoimmune cells until she was initiated on oral and dermal estradiol and vaginal progesterone.\n\nThis case highlights a proposed association between ART and MOG-ON though more studies are needed to validate the findings. We aim to increase the recognition of this rare manifestation so that clinicians can promptly diagnose and treat as well as counsel patients on the theoretical risk of appearance and/or relapse when undergoing ART or when planning future pregnancies.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Chun BY Cestari DM Myelin oligodendrocyte glycoprotein-IgG-associated optic neuritis Curr Opin Ophthalmol 2018 29 508 13 30281030\n2 Correale J Farez MF Ysrraelit MC Increase in multiple sclerosis activity after assisted reproduction technology Ann Neurol 2012 72 682 94 23034952\n3 Hellwig K Schimrigk S Beste C Muller T Gold R Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis Eur Neurol 2009 61 65 8 19039223\n4 Laplaud DA Lefrère F Leray E Barrière P Wiertlewski S Increased risk of relapse in multiple sclerosis patients after ovarian stimulation for in vitro fertilization Gynecol Obstet Fertil 2007 35 1047 50 17916439\n5 Jarius S Ruprecht K Kleiter I Borisow N Asgari N Pitarokoili K MOG-IgG in NMO and related disorders: A multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome J Neuroinflammation 2016 13 280 27793206\n6 Straub RH The complex role of estrogens in inflammation Endocr Rev 2007 28 521 74 17640948\n7 Piccinni MP Scaletti C Maggi E Romagnani S Role of hormone-controlled Th1- and Th2-type cytokines in successful pregnancy J Neuroimmunol 2000 109 30 3 10969178\n8 Kaneko K Sato DK Nakashima I Ogawa R Akaishi T Takai Y CSF cytokine profile in MOG-IgG+neurological disease is similar to AQP4-IgG+NMOSD but distinct from MS: A cross-sectional study and potential therapeutic implications J Neurol Neurosurg Psychiatry 2018 89 927 36 29875186\n9 Latham KA Zamora A Drought H Subramanian S Matejuk A Offner H Estradiol treatment redirects the isotype of the autoantibody response and prevents the development of autoimmune arthritis J Immunol 2003 171 5820 7 14634091\n10 Giunti D Borsellino G Benelli R Marchese M Capello E Valle MT Phenotypic and functional analysis of T cells homing into the CSF of subjects with inflammatory diseases of the CNS J Leukoc Biol 2003 73 584 90 12714572\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1998-4766",
"issue": "14(2)",
"journal": "Journal of human reproductive sciences",
"keywords": "Assisted reproductive technology; autoimmune diseases; case report; myelin oligodendrocyte glycoprotein; optic neuritis",
"medline_ta": "J Hum Reprod Sci",
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"pages": "203-205",
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"pmid": "34316239",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10969178;19039223;30281030;23034952;14634091;29875186;17640948;12714572;27793206;17916439",
"title": "Primary Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G-associated Optic Neuritis Presenting after a Frozen Embryo Transfer.",
"title_normalized": "primary myelin oligodendrocyte glycoprotein immunoglobulin g associated optic neuritis presenting after a frozen embryo transfer"
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"literaturereference": "Siegel DR, Luu TH, Skaznik-Wikiel ME. Primary myelin oligodendrocyte glycoprotein-immunoglobulin G-associated optic neuritis presenting after a frozen embryo transfer. Journal of Human Reproductive Sciences. 2021;14(2):203-205",
"literaturereference_normalized": "primary myelin oligodendrocyte glycoprotein immunoglobulin g associated optic neuritis presenting after a frozen embryo transfer",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220214",
"receivedate": "20220214",
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},
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{
"abstract": "BACKGROUND\nChemoradiotherapy (CRT) is a standard treatment for anal canal cancer although many patients with anal canal cancer undergo surgery in Japan. The efficacy of CRT for anal canal cancer was evaluated retrospectively.\n\n\nMETHODS\nMedical charts of 13 patients with anal canal cancer treated by definitive CRT from October 2004 to May 2016 were reviewed. Twelve patients had squamous cell carcinoma and one had adeno-squamous carcinoma. PET/CT simulation was performed in nine patients. The median total dose was 59.4 Gy (range 57.6-63.4 Gy) with fractions of 1.8-2.0 Gy. Ten patients received chemotherapy with mitomycin C (10 mg/m2) and fluorouracil (5-FU) (800 mg/m2 over 4 days) in weeks 1 and 5, while two patients were treated with cisplatin (40 mg) and 5-FU (750 mg over 5 days) in weeks 1 and 5. One elderly patient received radiotherapy (RT) alone.\n\n\nRESULTS\nAll 13 patients were alive after a median follow-up period of 102 months (range 16-121 months). Local failure only occurred in the patient with adeno-squamous cell carcinoma, while there was no loco-regional recurrence or distant metastasis in the other 12 patients. The 5-year loco-regional control rate (LRC) and 5-year overall survival rate (OS) were 92% and 100%, respectively. Acute toxicities of ≥ grade 3 were observed in six patients (46%), mainly being dermatitis around the anal verge, and late toxicity of ≥ grade 3 occurred in one patient.\n\n\nCONCLUSIONS\nCRT for squamous cell carcinoma of the anal canal achieved good LRC and OS with acceptable toxicities.",
"affiliations": "Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. [email protected].;Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Radiology, Ujitakeda Hospital, Uji, Kyoto, Japan.;Department of Radiation Oncology, Yamato Takada Municipal Hospital, Yamato-takada, Nara, Japan.;Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Radiation Oncology, Kindai University of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Surgery, Kindai University of Medicine, Osaka-Sayama, Osaka, Japan.",
"authors": "Tachibana|Izumi|I|;Nishimura|Yasumasa|Y|;Inada|Masahiro|M|;Fukuda|Kohei|K|;Ishikawa|Kazuki|K|;Nishikawa|Tatsuyuki|T|;Yokokawa|Masaki|M|;Nakamatsu|Kiyoshi|K|;Kanamori|Shuichi|S|;Hida|Jin-Ichi|JI|",
"chemical_list": "D016685:Mitomycin; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-018-1316-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "23(6)",
"journal": "International journal of clinical oncology",
"keywords": "Anal canal cancer; Chemoradiotherapy; Intensity-modulated radiation therapy; Squamous cell carcinoma",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D000072078:Positron Emission Tomography Computed Tomography; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "1121-1126",
"pmc": null,
"pmid": "29992389",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "1324782;8874455;6326995;9164216;23150707;26277433;19856049;26686872;16165347;28099957;17085056;4830803;20457349;19181409;19117696;8823332;22401917",
"title": "Definitive chemoradiotherapy for anal canal cancer: single-center experience.",
"title_normalized": "definitive chemoradiotherapy for anal canal cancer single center experience"
} | [
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] |
{
"abstract": "This is a case report of a 73-year-old man with new-onset acute renal failure while being investigated for pulmonary infiltrates and mediastinal lymphadenopathies. Urine tests showed tubular range proteinuria with no microhaematuria. Immunology tests showed elevated serum IgG and hypocomplementaemia (classical pathway activation). Renal biopsy and clinical-pathological correlation were crucial in this case, reinforcing their important role in the final diagnosis of acute kidney injury.",
"affiliations": "Servicio de Nefrología. Complejo Hospitalario de Navarra. Pamplona, Navarra España. Electronic address: [email protected].;Servicio de Anatomía Patológica. Hospital Germans Trias i Pujol. Badalona, Barcelona España.;Servicio de Inmunología. Hospital Germans Trias i Pujol. Badalona, Barcelona España.;Servicio de Nefrología. Hospital Germans Trias i Pujol. Badalona, Barcelona España.;Servicio de Anatomía Patológica. Hospital Germans Trias i Pujol. Badalona, Barcelona España.;Servicio de Medicina Interna. Hospital de Calella. Calella, Barcelona España.;Servicio de Nefrología. Hospital Germans Trias i Pujol. Badalona, Barcelona España.",
"authors": "Fernández Lorente|Loreto|L|;Álvarez|Dolores López|DL|;López|Virginia García|VG|;Kollros|Vesna Abujder|VA|;Ariza|Aurelio|A|;Gálvez|Alejandro|A|;Bonet|Josep|J|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007074:Immunoglobulin G",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0211-6995",
"issue": "35(2)",
"journal": "Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia",
"keywords": "Enfermedad relacionada con IgG4; IgG4 related disease; Immunology; Inmunología; Insuficiencia renal rápidamente; Rapidly progressive renal failure; progresiva",
"medline_ta": "Nefrologia",
"mesh_terms": "D058186:Acute Kidney Injury; D000305:Adrenal Cortex Hormones; D000368:Aged; D001327:Autoimmune Diseases; D001706:Biopsy; D002100:Cachexia; D006801:Humans; D007074:Immunoglobulin G; D008171:Lung Diseases; D000072281:Lymphadenopathy; D008297:Male; D008482:Mediastinum; D010265:Paraproteinemias; D010950:Plasma Cells",
"nlm_unique_id": "8301215",
"other_id": null,
"pages": "218-23",
"pmc": null,
"pmid": "26300516",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "IgG4-related disease: description of a case with pulmonary lesions, mediastinal lymphadenopathies and rapidly progressive renal failure.",
"title_normalized": "igg4 related disease description of a case with pulmonary lesions mediastinal lymphadenopathies and rapidly progressive renal failure"
} | [
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"literaturereference": "LORENTE L, ALVAREZ D, LOPEZ V, KOLLROS V, ARIZA A, GALVEZ A, ET AL. IGG4-RELATED DISEASE: DESCRIPTION OF A CASE WITH PULMONARY LESIONS, MEDIASTINAL LYMPHADENOPATHIES AND RAPIDLY PROGRESSIVE RENAL FAILURE. NEFROLOGIA. 2015?35(2):218-223.",
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}
] |
{
"abstract": "OBJECTIVE\nTo investigate the frequency of occult hepatitis B, the clinical course of hepatitis B virus (HBV) reactivation and reverse seroconversion and associated risk factors in autologous hematopoietic stem cell transplantation (HSCT) recipients.\n\n\nMETHODS\nThis study was conducted in 90 patients undergoing autologous HSCT. Occult HBV infection was investigated by HBV-DNA analysis prior to transplantation, while HBV serology and liver function tests were screened prior to and serially after transplantation. HBV-related events including reverse seroconversion and reactivation were recorded in all patients.\n\n\nRESULTS\nNone of the patients had occult HBV prior to transplantation. Six (6.7%) patients were positive for HBV surface antigen (HBsAg) prior to transplantation and received lamivudine prophylaxis; they did not develop HBV reactivation after transplantation. Clinical HBV infection emerged in three patients after transplantation who had negative HBV-DNA prior to HSCT. Two of these three patients had HBV reactivation while one patient developed acute hepatitis B. Three patients had anti-HBc as the sole hepatitis B-related antibody prior to transplantation, two of whom developed hepatitis B reactivation while none of the patients with antibody to HBV surface antigen (anti-HBs) did so. The 14 anti-HBs- and/or anti-HBc-positive patients among the 90 HSCT recipients experienced either persistent (8 patients) or transient (6 patients) disappearance of anti-HBs and/or anti-HBc. HBsAg seroconversion and clinical hepatitis did not develop in these patients. Female gender and multiple myeloma emerged as risk factors for loss of antibody in regression analysis (P < 0.05).\n\n\nCONCLUSIONS\nAnti-HBc as the sole HBV marker seems to be a risk factor for reactivation after autologous HSCT. Lamivudine prophylaxis in HbsAg-positive patients continues to be effective.",
"affiliations": "Department of Hematology, Gazi University, Faculty of Medicine, Beşevler 06500, Ankara, Turkey.",
"authors": "Ceneli|Ozcan|O|;Ozkurt|Zübeyde Nur|ZN|;Acar|Kadir|K|;Rota|Seyyal|S|;Aki|Sahika Zeynep|SZ|;Yeğin|Zeynep-Arzu|ZA|;Yağci|Münci|M|;Ozenirler|Seren|S|;Sucak|Gülsan Türköz|GT|",
"chemical_list": "D004279:DNA, Viral; D006510:Hepatitis B Antibodies",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v16.i14.1765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "16(14)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002353:Carrier State; D004279:DNA, Viral; D005260:Female; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012307:Risk Factors; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "1765-71",
"pmc": null,
"pmid": "20380010",
"pubdate": "2010-04-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19075267;11835357;10458258;16399572;4056345;15940651;12533042;15655050;2326865;12198664;16966273;9753342;11895763;17112622;16206102;15753855;15486926;15885351;15932364;18832247;17382252;14996349;15763333;12962817;16685581;11313673;19508685;12043693;12663244;12081601;10654023;19144986;1525609;10846463;15004543;16461218;12952220;10642815;2308481;16421814",
"title": "Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients.",
"title_normalized": "hepatitis b related events in autologous hematopoietic stem cell transplantation recipients"
} | [
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"abstract": "Mitral valve stenosis (MS) associated with rheumatic disease no longer represents a major heart problem during the perinatal period in Japan. Here we present a case of acute heart failure due to MS after emergency cesarean section (CS). The patient was transferred due to the development of fetal distress at 36 weeks gestation and underwent an emergency CS under general anesthesia. She developed acute heart failure immediately postoperatively and was diagnosed with MS associated with pulmonary artery hypertension for the first time. She underwent percutaneous transvenous mitral commissurotomy and was discharged from our hospital in good condition.",
"affiliations": "Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan.;Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan.;Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan.;Department of Surgery, Osaka Medical College, Takatsuki, Japan.;Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan.;Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan.;Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan.",
"authors": "Shimoyama|Yuichiro|Y|;Sawai|Toshiyuki|T|;Umegaki|Osamu|O|;Agui|Tomoyuki|T|;Kadono|Noriko|N|;Nakahira|Junko|J|;Minami|Toshiaki|T|",
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"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJa Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 4910.1186/s40981-016-0049-2Letter to the EditorSudden onset of severe pulmonary edema after emergency cesarean section Shimoyama Yuichiro [email protected] 1Sawai Toshiyuki [email protected] 1Umegaki Osamu [email protected] 1Agui Tomoyuki [email protected] 2Kadono Noriko [email protected] 1Nakahira Junko [email protected] 1Minami Toshiaki [email protected] 11 Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686 Japan 2 Department of Surgery, Osaka Medical College, Takatsuki, Japan 22 9 2016 22 9 2016 2016 2 1 2314 6 2016 2 9 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Mitral valve stenosis (MS) associated with rheumatic disease no longer represents a major heart problem during the perinatal period in Japan. Here we present a case of acute heart failure due to MS after emergency cesarean section (CS). The patient was transferred due to the development of fetal distress at 36 weeks gestation and underwent an emergency CS under general anesthesia. She developed acute heart failure immediately postoperatively and was diagnosed with MS associated with pulmonary artery hypertension for the first time. She underwent percutaneous transvenous mitral commissurotomy and was discharged from our hospital in good condition.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nFindings\nA 37-year-old patient (150 cm, 52 kg) originally from the Philippines with no remarkable history was transferred to our hospital at 36 weeks and 3 days gestation after having diagnosed with abruptio placentae. Upon admission, she underwent an emergency cesarean section (CS) under general anesthesia due to the development of fetal distress. The patient was induced with 100 mg IV propofol, 100 μg fentanyl, and 50 mg rocuronium and then underwent tracheal intubation. Anesthesia (sevoflurane 1 % and remifentanil 3 μg/kg/min) was maintained. Her hemodynamics and respiratory condition were both within normal ranges throughout the intraoperative period. She delivered a female live-born baby, with 1- and 5-min APGAR scores of 1 and 6, respectively, and a birth weight of 2626 g. The time from hospital arrival to delivery was 13 min. The baby recovered stably in the neonatal ICU. The patient was extubated and transferred to the ICU; her central venous pressure was 3 mmHg, heart rate 122 beats/min, arterial blood pressure 127/62 mmHg, and oxygen saturation 100 % (8 L facemask). The patient was administered a total of 1400 mL of fluid (700 mL acetate Ringer’s solution, 700 mL hydroxyethyl starch) during the operation. Her postoperative chest X-ray was unremarkable. After 15 min (102 min after delivery), however, the patient complained of dyspnea and her oxygen saturation gradually decreased to 93 %. Despite oxygen therapy, oxygen saturation further decreased to 67 % (15 L reservoir mask) rapidly. We immediately re-intubated the patient to manage respiratory failure; frothy, blood-stained sputum was aspirated through the intubation tube. Physical examination revealed a diastolic murmur at the mitral focus and bilateral pulmonary rales. An ECG showed a sinus tachycardia (HR145 beats/min), and the radiograph of the chest showed the butterfly pattern of pulmonary edema (Fig. 1). Although only minor bleeding through the drains was noted, her blood pressure and circulation were unstable (shock index >1; HR85 beats/min, BP53/34 mmHg). After administration of dopamine (3–5 μg/kg/min), hemodynamics showed an improvement. At this time, the patient was started on intravenous furosemide (20–40 mg/day) and 100 mg/day potassium canrenoate for the treatment of heart failure. After her general condition stabilized, we performed transthoracic echocardiography (TTE). TTE showed mitral valve stenosis (MS) with mild mitral valve regurgitation (Fig. 2a), with a mitral valve area (MVA) of 0.99 cm2 as measured by the pressure half-time method (Fig. 2b). Right ventricular systolic pressure (RVSP) was estimated to be 118 mmHg (CVP 15 mmHg) from the tricuspid valve regurgitation velocity (5 m/s). The final diagnosis was decompensated heart failure caused by post-rheumatic MS after delivery. After diuretic therapy, her pulmonary edema due to acute cardiac failure resolved. She was extubated on the following day and eventually underwent percutaneous transvenous mitral commissurotomy (PTMC), due to the Wilkins score, which was lower than 8. After the second inflation of the Inoue balloon, MVA increased to 1.34 cm2 and RVSP decreased by 50 %. The patient was discharged a few days after PTMC in good condition.Fig. 1 Chest X-ray showing the butterfly pattern of pulmonary edema\n\n\nFig. 2 \na Parasternal long-axis view with color Doppler assessment showing severe mitral valve stenosis. b Mitral valve area was 0.99 cm2 as measured by the pressure half-time method\n\n\n\n\nPTMC using the Inoue balloon catheter has become an accepted treatment option for patients with severe symptomatic MS. PTMC provides palliation for pregnant women with MS, with a reported success rate of nearly 100 %. Successful balloon valvuloplasty increases the valve area to >1.5 cm2 without a substantial increase in mitral regurgitation [1]. A report showed that mean MVA before the procedure (range, 0.75 to 1.2 cm2) increased after the procedure to 1.7 to 2.2 cm2. These results are comparable to the results reported on non-pregnant patients with MS [2]. In the present case, MS was not diagnosed before the patient was transferred to our hospital, and the patient presented with no pathological events, such as congestive heart failure and arrhythmia. Moreover, there was no time to diagnose MS from the time of arrival to CS due to fetal distress. Consequently, appropriate medication or invasive MS intervention was not performed until the postpartum period.\n\nIn the present case, the patient was diagnosed with MS associated with pulmonary edema for the first time during the postpartum period. It can explain decompensation in a postpartum woman with critical MS as follows. The sudden increase in the pre-load immediately following delivery, due to autotransfusion from the uterus, may flood the central circulation, resulting in severe pulmonary edema. In addition, given that autotransfusion of blood continues for 24–72 h post-delivery, there is an extended risk of pulmonary edema for several days post-delivery [3]. Maternal mortality occurs most frequently during this time period [4]. However, MS onset was within 2 h after delivery. It might be too early to explain only with this theory. In the present case, we performed general anesthesia in the patient as she underwent rapid induction. General anesthesia is disadvantageous as it increases pulmonary arterial pressure and tachycardia during endotracheal intubation. In addition, the harmful effects of positive pressure ventilation on venous return may ultimately lead to heart failure [5]. Regional anesthesia has proven to be a safe technique in cardiac patients undergoing CS [3]. That said, we have no information regarding MS development with anesthesia induction, so it may be prudent to perform regional anesthesia for now.\n\nWe experienced and managed a patient who was diagnosed with MS associated with pulmonary edema for the first time after emergency CS. An adequate perioperative management by a multidisciplinary team comprising an anesthesiologist, cardiologist, critical care physician, and obstetrician may lead to a reduction in perinatal mortality and morbidity.\n\nAbbreviations\nMSMitral valve stenosis\n\nCSCesarean section\n\nPTMCPercutaneous transvenous mitral commissurotomy\n\nTTETransthoracic echocardiography\n\nRVSPright ventricular systolic pressure\n\nAcknowledgements\nNone\n\nFunding\nResearch fund of the Department of Anesthesiology, Osaka Medical College\n\nAvailability of data and materials\nNot applicable\n\nAuthors’ contributions\nYS collected data and drafted the manuscript; TS, OU, TA, NK, JN, and TM revised the manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\nNone\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable\n==== Refs\nReferences\n1. Fawzy ME Kinsara AJ Stefadouros M Hegazy H Kattan H Chaudhary A Long-term outcome of mitral balloon valvotomy in pregnant women J Heart Valve Dis 2001 10 153 7 11297200 \n2. Rahmitoola SH Durairaj A Mehra A Nuno I Current evaluation and management of patients with mitral stenosis Circulation 2002 106 1183 8 10.1161/01.CIR.0000029210.14716.01 12208789 \n3. Kannan M Vijayanand G Mitral stenosis and pregnancy: current concepts in anaesthetic practice Indian J Anaesth 2010 54 439 44 10.4103/0019-5049.71043 21189882 \n4. Higton AM Whale C Musk M Gabbay E Pulmonary hypertension in pregnancy: two cases and review of the literature Int Med J 2009 39 766 70 10.1111/j.1445-5994.2009.02051.x \n5. Blaise G Langleben D Hubert B Pulmonary arterial hypertension: pathophysiology and anesthetic approach Anesthesiology 2003 99 1415 32 10.1097/00000542-200312000-00027 14639158\n\n",
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{
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}
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},
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},
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},
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},
{
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{
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}
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},
{
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},
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}
],
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},
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},
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},
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}
] |
{
"abstract": "Epistaxis is a well-known problem that is mostly self-limited. In certain cases it requires packing or cauterization. Tranexamic acid has been tried and has shown promising results. Here we report a case of prolonged epistaxis in a patient on dual anti-platelet agent therapy.",
"affiliations": "NYU Langone Hospital-Brooklyn, Department of Emergency Medicine, Brooklyn, NY, United States; NYMC, Metropolitan Hospital Center, Department of Emergency Medicine, New York, NY, United States. Electronic address: [email protected].;NYU Langone Hospital-Brooklyn, Department of Emergency Medicine, Brooklyn, NY, United States.;NYU Langone Hospital-Brooklyn, Department of Clinical Pharmacy, Brooklyn, NY, United States.;NYMC, Metropolitan Hospital Center, Department of Emergency Medicine, New York, NY, United States.",
"authors": "Hassen|Getaw Worku|GW|;Clemons|Paula|P|;Kaplun|Michelle|M|;Kalantari|Hossein|H|",
"chemical_list": "D000933:Antifibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D014148:Tranexamic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2018.01.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "36(4)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000281:Administration, Intranasal; D000287:Administration, Topical; D000933:Antifibrinolytic Agents; D004636:Emergency Service, Hospital; D004844:Epistaxis; D006489:Hemostatic Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011312:Pressure; D012008:Recurrence; D014148:Tranexamic Acid",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "734.e1-734.e2",
"pmc": null,
"pmid": "29310981",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Is topical tranexamic acid a better alternative for selected cases of anterior epistaxis management in the ED?",
"title_normalized": "is topical tranexamic acid a better alternative for selected cases of anterior epistaxis management in the ed"
} | [
{
"companynumb": "US-BAYER-2018-096055",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "TICAGRELOR"
},
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"medicinalproduct": "TICAGRELOR."
},
{
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"activesubstance": {
"activesubstancename": "ASPIRIN"
},
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"medicinalproduct": "ACETYLSALICYLIC ACID({=100 MG)"
}
],
"patientagegroup": "5",
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Epistaxis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HASSEN GW, CLEMONS P, KAPLUN M, KALANTARI H. IS TOPICAL TRANEXAMIC ACID A BETTER ALTERNATIVE FOR SELECTED CASES OF ANTERIOR EPISTAXIS MANAGEMENT IN THE ED?. AMERICAN JOURNAL OF EMERGENCY MEDICINE. 2018?36:4:734.E1-734.E2",
"literaturereference_normalized": "is topical tranexamic acid a better alternative for selected cases of anterior epistaxis management in the ed",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180522",
"receivedate": "20180522",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14924883,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Here, we review the case of a 26 1/7 weeks' gestation premature female infant born to a mother who intentionally ingested a large quantity of Tylenol, aspirin, quetiapine, and prenatal vitamins. The neonate subsequently had markedly elevated levels of both Tylenol and aspirin when checked on the first day of life. While overall clinically stable, the neonate did demonstrate coagulopathy as evidenced by abnormal coagulation studies. Both poison control and a pediatric gastroenterologist/hepatologist were consulted. She successfully tolerated a course of N-acetylcysteine; her subsequent Tylenol level was markedly decreased and the neonate exhibited no further effects of toxicity. The salicylate level decreased on its own accord. To our knowledge, this is the first report of a neonate at 26 weeks' gestation that has been successfully managed for supratherapeutic concentrations of acetaminophen and acetylsalicylic acid secondary to maternal ingestion. While rare, this case may serve as a reference for the effectiveness of N-acetylcysteine in premature infants in such instances.",
"affiliations": "Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Medical Scientist Training Program, The Ohio State University College of Medicine, The Ohio State University, Columbus, Ohio.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colorado.;Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, Colorado.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio.",
"authors": "Pavlek|Leeann|L|;Kraft|Monica|M|;Simmons|Caitlyn|C|;Ryan|Mary|M|;Prusakov|Pavel|P|;Campbell|Amanda|A|;Brandehoff|Nicklaus|N|;Ng|Patrick C|PC|;Russell|Jason|J|;Ciciora|Steven L|SL|;Fathi|Omid|O|",
"chemical_list": "D000928:Antidepressive Agents; D000931:Antidotes; D000069348:Quetiapine Fumarate; D000082:Acetaminophen; D003553:Cystine; D017693:Sodium Bicarbonate; D001241:Aspirin; C030905:N-monoacetylcystine",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0038-1661405",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "36(2)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000082:Acetaminophen; D000928:Antidepressive Agents; D000931:Antidotes; D001241:Aspirin; D003553:Cystine; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D018811:Maternal Exposure; D011041:Poisoning; D011247:Pregnancy; D000069348:Quetiapine Fumarate; D017693:Sodium Bicarbonate; D013406:Suicide, Attempted",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "136-140",
"pmc": null,
"pmid": "29945281",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acetaminophen and Acetylsalicylic Acid Exposure in a Preterm Infant after Maternal Overdose.",
"title_normalized": "acetaminophen and acetylsalicylic acid exposure in a preterm infant after maternal overdose"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-199598",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "201190",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "QUETIAPINE."
},
{
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},
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"medicinalproduct": "ASPIRIN."
},
{
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"activesubstancename": "ACETAMINOPHEN"
},
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"medicinalproduct": "TYLENOL"
}
],
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{
"abstract": "Following a minor meniscal injury to his right knee, a previously fit and well 58-year-old man developed profound somatisation leading to paraplegia. The patient developed a deep-seated belief that any exercise or walking would cause irreparable damage to his knee. Over the course of 2 years his, mobility reduced from active mountaineering to walking a short distance, and finally to paraplegia. Medical investigations were normal and organic causes were ruled out. Conventional therapy was exhausted, a number of medications were trialled over 5 years, including selective serotonin reuptake inhibitors (SSRIs) and antipsychotics without success. Eventually, with a combination of cognitive behavioural therapy, physiotherapy and a novel experimental therapy where the patient rolled dice and acted according to the roll results, the patient was able to literally and metaphorically get back on his feet.",
"affiliations": "General Medicine, Norfolk and Norwich University Hospital NHS Trust, Norwich, UK [email protected].;Clinical Pharmacology, Guy's and St Thomas' Hospitals NHS Trust, London, UK.",
"authors": "Rogers|Miles Alexander William|MAW|;Au Yeung|Joshua|J|",
"chemical_list": "D014150:Antipsychotic Agents; D017367:Serotonin Uptake Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227285",
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"issn_linking": "1757-790X",
"issue": "14(10)",
"journal": "BMJ case reports",
"keywords": "cognitive behavioural psychotherapy; somatoform disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D014150:Antipsychotic Agents; D015928:Cognitive Behavioral Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010264:Paraplegia; D017367:Serotonin Uptake Inhibitors; D016138:Walking",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34645622",
"pubdate": "2021-10-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Curing somatisation-induced paraplegia with experimental dice-based affective modulation.",
"title_normalized": "curing somatisation induced paraplegia with experimental dice based affective modulation"
} | [
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{
"abstract": "Hemophagocytic syndrome (HPS) is a life-threatening hematological disorder in immunocompromised patients. Reactive HPS is observed in patients with systemic infection, neoplasia or auto-immune diseases. It is a rare hematological disorder after renal transplantation and must be suspected when fever and pancytopenia are seen in association with viral infections. HPS is usually associated with infection with the Cytomegalovirus and Epstein-Barr viruses. We report here a case of BK-virus-associated HPS.",
"affiliations": "Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.",
"authors": "Yaich|S|S|;Charfeddine|K|K|;Hsairi|D|D|;Zaghdane|S|S|;Kammoun|K|K|;Makni|S|S|;Boudawara|T|T|;Hachicha|J|J|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.132205",
"fulltext": null,
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"issn_linking": "1319-2442",
"issue": "25(3)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D001739:BK Virus; D001706:Biopsy; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D027601:Polyomavirus Infections; D006435:Renal Dialysis; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014412:Tumor Virus Infections",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "610-4",
"pmc": null,
"pmid": "24821160",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "BK virus-associated hemophagocytic syndrome in a renal transplant recipient.",
"title_normalized": "bk virus associated hemophagocytic syndrome in a renal transplant recipient"
} | [
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"abstract": "Inadvertent emergency anticoagulation in patients with acute type A aortic dissection (ATAAD) has been sparsely reported. There are case reports bringing this potential critical incident to attention, however, little is known about the number of undetected and unreported cases. We approach this issue based on a case report of inadvertent emergency anticoagulation in ATAAD and attempt to shed light on aspects that may have contributed to the critical incident: The challenge of distinguishing an ATAAD from an acute coronary syndrome (ACS) and the potential underestimation of incidents of ATAAD. We also discuss errors and biases in medical decision making, and provide suggestions that may help raise awareness of how ATAAD can be mimicking ACS in clinical practice.",
"affiliations": "Institute for Anesthesiology, Deutsches Herzzentrum Berlin, Berlin, Germany.;Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany.;Institute for Anesthesiology, Deutsches Herzzentrum Berlin, Berlin, Germany.;Department of Emergency Medicine, Campus Benjamin Franklin (CBF), Charité-Universitätsmedizin Berlin, Berlin, Germany.;Institute for Anesthesiology, Deutsches Herzzentrum Berlin, Berlin, Germany.;Institute for Anesthesiology, Deutsches Herzzentrum Berlin, Berlin, Germany.",
"authors": "Zschaler|Silke|S|;Schmidt|Gerard|G|;Kukucka|Marian|M|;Syrmas|Georg|G|;Zaschke|Lisa|L|;Kurz|Stephan Dominik|SD|",
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"country": "China (Republic : 1949- )",
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"issn_linking": "2223-3652",
"issue": "8(6)",
"journal": "Cardiovascular diagnosis and therapy",
"keywords": "Aneurysm; anticoagulants; aortic rupture; dissecting; emergency medical services; patient safety",
"medline_ta": "Cardiovasc Diagn Ther",
"mesh_terms": null,
"nlm_unique_id": "101601613",
"other_id": null,
"pages": "805-810",
"pmc": null,
"pmid": "30740328",
"pubdate": "2018-12",
"publication_types": "D016421:Editorial",
"references": "10685714;11041906;11241091;12206127;12377672;12915363;16032607;17145990;18924016;18941610;19219221;19683131;21555704;21769215;25662791;26587083;27334108;28499667;28815188;28916213;29033036;29302461;29339166;8350637",
"title": "How to prevent inadvertent emergency anticoagulation in acute type A aortic dissection: when in doubt, don't.",
"title_normalized": "how to prevent inadvertent emergency anticoagulation in acute type a aortic dissection when in doubt don t"
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"literaturereference": "ZSCHALER S, SCHMIDT G, KUKUCKA M, SYRMAS G, ZASCHKE L, KURZ SD. HOW TO PREVENT INADVERTENT EMERGENCY ANTICOAGULATION IN ACUTE TYPE A AORTIC DISSECTION: WHEN IN DOUBT, DON?T. CARDIOVASCULAR DIAGNOSIS AND THERAPY. 2018?8:6:805-810",
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"abstract": "Intractable headaches can be debilitating, often leading to significant distress, prolonged medical treatment, and unanticipated hospital admissions. There have been significant advances in the treatment of primary intractable headaches such as migraines, tension headaches, and cluster headaches beyond medical management. Treatments may now include interventional strategies such as trigger-point injections, peripheral nerve stimulators, or peripheral nerve and ganglion blocks. There are few studies, however, describing the use of interventional techniques for the management of intractable secondary headaches, including those attributed to injury or infection. A new regional anesthetic technique, the erector spinae plane (ESP) block, was initially used for neuropathic thoracic pain. ESP block has since been reported to provide acute and chronic pain relief of the shoulder, spine, abdomen, pelvis, thorax, and lower extremity. Additionally, there has been one case report to describe the use of the ESP block in the treatment of refractory tension headache. We report four cases of effective analgesia for intractable secondary headache resistant to medical management with high thoracic ESP blocks. In each case, the ESP block provided instant pain relief. We suggest that the findings of this case series indicate that the ESP block may be a useful intervention in patients with severe secondary headache or posterior cervical pain where conventional therapies have limited success, though more studies are necessary.",
"affiliations": "Department of Anesthesiology, Division of Regional Anesthesiology and Acute Pain Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA.;Department of Anesthesiology, Division of Regional Anesthesiology and Acute Pain Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA.;Department of Neurology, Division of Trauma, Concussion and Sports Neuromedicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.;Department of Anesthesiology, Division of Chronic Pain Management, McGovern Medical School, Houston, TX 77030, USA.;Department of Anesthesiology, Division of Regional Anesthesiology and Acute Pain Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA.;Department of Anesthesiology, Division of Regional Anesthesiology and Acute Pain Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA.;Department of Anesthesiology, Beth-Israel Deaconness Medical Center, Harvard Medical School, Boston, MA, USA.;Department of Anesthesiology, Division of Regional Anesthesiology and Acute Pain Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA.",
"authors": "Hernandez|Nadia|N|;Guvernator|Grace|G|;Ansoanuur|George|G|0000-0003-3823-4585;Ge|Michelle|M|;Tabansi|Precious|P|;Le|Thanh-Thuy|TT|;Obeidat|Salameh S|SS|;de Haan|Johanna|J|",
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"fulltext": "\n==== Front\nLocal Reg Anesth\nLocal Reg Anesth\nLRA\nlra\nLocal and Regional Anesthesia\n1178-7112 Dove \n\n249250\n10.2147/LRA.S249250\nCase Series\nRelief of Secondary Headaches with High Thoracic Erector Spinae Plane Block\nHernandez et alHernandez et alHernandez Nadia 1 Guvernator Grace 1 http://orcid.org/0000-0003-3823-4585Ansoanuur George 2 Ge Michelle 3 Tabansi Precious 1 Le Thanh-Thuy 1 Obeidat Salameh S 4 de Haan Johanna 1 1 Department of Anesthesiology, Division of Regional Anesthesiology and Acute Pain Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX\n77030, USA\n2 Department of Neurology, Division of Trauma, Concussion and Sports Neuromedicine, University of Florida College of Medicine, Gainesville, FL\n32610, USA\n3 Department of Anesthesiology, Division of Chronic Pain Management, McGovern Medical School, Houston, TX\n77030, USA\n4 Department of Anesthesiology, Beth-Israel Deaconness Medical Center, Harvard Medical School, Boston, MA, USA\nCorrespondence: Johanna de Haan Tel +1 713-500-6200 Email [email protected]\n22 6 2020 \n2020 \n13 49 55\n11 2 2020 23 5 2020 © 2020 Hernandez et al.2020Hernandez et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nIntractable headaches can be debilitating, often leading to significant distress, prolonged medical treatment, and unanticipated hospital admissions. There have been significant advances in the treatment of primary intractable headaches such as migraines, tension headaches, and cluster headaches beyond medical management. Treatments may now include interventional strategies such as trigger-point injections, peripheral nerve stimulators, or peripheral nerve and ganglion blocks. There are few studies, however, describing the use of interventional techniques for the management of intractable secondary headaches, including those attributed to injury or infection. A new regional anesthetic technique, the erector spinae plane (ESP) block, was initially used for neuropathic thoracic pain. ESP block has since been reported to provide acute and chronic pain relief of the shoulder, spine, abdomen, pelvis, thorax, and lower extremity. Additionally, there has been one case report to describe the use of the ESP block in the treatment of refractory tension headache. We report four cases of effective analgesia for intractable secondary headache resistant to medical management with high thoracic ESP blocks. In each case, the ESP block provided instant pain relief. We suggest that the findings of this case series indicate that the ESP block may be a useful intervention in patients with severe secondary headache or posterior cervical pain where conventional therapies have limited success, though more studies are necessary.\n\nKeywords\nerector spinae plane blockrefractory headachehead painneck painscalp paincraniotomy pain\n==== Body\nIntroduction\nRefractory headache is a term used to describe several headache subtypes that are defined as being resistant to treatment or are intractable.1 Common refractory headache subtypes include primary headaches such as migraine, tension, and cluster headache, as well as secondary headaches attributable to trauma, inflammation, and infection.2 Refractory secondary headaches can be debilitating, leading to unanticipated emergency room visits and hospital admissions. Pharmacologic treatment of secondary headache has several limitations due to drug interactions, contraindications, allergies, and intolerable side effects. Regional anesthesia has been shown to provide prompt, complete, and prolonged relief of refractory primary headaches and their associated autonomic symptoms.3,4 However, there is a paucity of evidence for the use of peripheral nerve blocks in the treatment of intractable secondary headache, except for greater occipital nerve block for postdural puncture headache (PDPH) and cervicogenic headache.5–8 Greater occipital (GON), lesser occipital (LON), and supraorbital nerve (SON) blocks, as well as stellate and sphenopalatine ganglion (SPG) blocks, have successfully treated secondary headaches, although this literature is limited to retrospective studies, small case series, and case reports.\n\nA recently described fascial plane block that has successfully terminated primary headaches is the erector spinae plane (ESP) block. The ESP block was first reported in 2016 by Forero et al as an ultrasound-guided fascial plane block used to treat chronic thoracic pain.9 Local anesthetic injected in the plane between the transverse process (TP) and the erector spinae muscles spreads in a craniocaudal direction, anesthetizing the dorsal and ventral rami of adjacent spinal nerves. Twenty milliliters (mL) injection of 0.5% ropivacaine over the fifth TP resulted in analgesia of intercostal nerves 3–9. Since then, the ESP block has been reported at many different spinal levels and has been used to provide acute post-surgical pain relief for cervical spine, thoracic spine, lumbar spine, shoulder, abdomen, pelvis, thorax, and lower extremity surgeries.10–16 A report by Ueshima et al noted relief of tension headache in two patients following the use of T4 ESP block.17 In this manuscript, we report four cases in which bilateral T4 ESP blocks provided significant relief of headaches secondary to various pathologies.\n\nMethods\nProcedural consent and pre-procedure pain scores were obtained using the numerical pain scale (NPS) by the acute pain service. Patients were transferred to the block room, connected to pulse oximetry, non-invasive blood pressure and continuous electrocardiographic monitors and positioned in left lateral decubitus. A high-frequency linear or low-frequency curvilinear transducer (SonoSite, Bothell, WA) was placed in a sagittal plane over the 4th TP. The TP, pleura and erector spinae muscles were identified on ultrasound, as in Figure 1. After skin sterilization, a 22-gauge blunt-tipped echogenic needle (BBraun, Bethlehem, PA) was advanced in-plane from caudal to cranial until the needle made contact with the T4 TP. Normal saline was used to confirm needle tip location in the plane between the erector spinae muscles and TP. Twenty mL of 0.25% bupivacaine with 2–4 mg of preservative-free dexamethasone was injected into the plane bilaterally, aspirating every 5 mL to ensure that the needle tip had not been placed intravascularly or intrapleural. Patients were monitored for 30–60 mins after the procedure. All patients provided written informed consent for publication of details regarding their case, including publication of images. The institutional research ethics committees at both our affiliated hospital, the Clinical Innovation and Research Institute of Memorial Hermann Hospital, and our university, the Center for the Protection of Human Subjects at UTHealth Houston, have reviewed and approved of this study.Figure 1 Patient ultrasound.\n\nAbbreviations: TM, trapezius muscle; RMM, rhomboid major muscle; ESM, erector spinae muscle; T4 TP, thoracic 4 transverse process.\n\n\n\nCase 1 – Meningitic Cervical Pain and Headache\nA 29-year-old female presented with signs and symptoms of acute meningitis, notably severe headache with nuchal pain and rigidity. Lumbar puncture was performed by the neurology service with a 3.5-inch 22-gauge needle at the L2-L3 spinal interspace and cerebrospinal fluid (CSF) was obtained. Opening pressure was 18 mm H2O, closing pressure 12 mm H2O, with a total of 12 mL of clear CSF drained. Results from the fluid analysis showed Herpes Simplex Virus 2 (HSV2) meningitis without encephalitis. The patient received a course of intravenous acyclovir and transitioned to an oral antiviral regimen, but was unable to be discharged due to severe uncontrolled headache and neck pain.\n\nThroughout the patient’s hospital course, her head and neck pain were poorly controlled on both oral and intravenous analgesic medications. She described her headache as throbbing and circumferential, with increased intensity in the left frontal region. Headache was associated with severe posterior neck pain radiating to the upper back. She rated her headache pain at a level of 10 out of 10 using a 10-point numerical pain scale (NPS). Initially, she was started on scheduled acetaminophen-codeine 600–60 mg every 6 hrs, naproxen 500 mg twice daily, and tramadol 100 mg every 6 hrs; this regimen provided minimal relief for her pain. Immediate-release oral morphine 15 mg every 12 hrs and pregabalin 50 mg every 8 hrs were added without any benefit.\n\nAcute Pain Management Service (APMS) was consulted because the primary service was unable to discharge the patient on hospital day seven due to uncontrolled pain. The patient initially endorsed severe headache and neck pain exacerbated by bright lights and sitting in an upright position with minimal relief from medications. Given that she had undergone LP 3 days prior to APMS evaluation, and the positional nature of the headache, a diagnosis of post-dural puncture headache (PDPH) was considered. However, she was not a candidate for an epidural blood patch (EBP) because of her meningitis. The patient was started on caffeine-acetaminophen 200–650 mg every 6 hrs, with oxycodone 5 mg by mouth every 4 hrs as needed for breakthrough pain.\n\nThe patient’s headache and cervical pain were not relieved with this regimen, so the decision was made to perform bilateral T4 ESP blocks as described above on hospital day number eight. There were no complications from the procedure. Thirty minutes after the block was completed, the patient reported that the neck pain had decreased from a level of 10 on the NPS to a 2, and that the headache decreased from a level of 7 on the NPS to 0. She was able to sit upright and perform a valsalva and rotate her neck without exacerbation of the headache or cervical pain, which she had previously been unable to do. She also reported that neck stiffness was alleviated. All opioids were discontinued and she was discharged home the following day. She was contacted approximately 1 month after discharge and reported that her headache never returned.\n\nCase 2 – Headache Following Craniotomy for Pineal Cyst Resection\nAn 18-year-old obese female with a body mass index of 33.4 and a history of irritable bowel syndrome (IBS) and severe gastroparesis presented to APMS during readmission for inability to tolerate oral intake following supracerebellar transtentorial resection of 10 cm pineal cyst. Patient’s incision is shown in Figure 2. She had been discharged home on postoperative day (POD) two and readmitted for severe headache, nausea, vomiting, and constipation on POD three. The headache was primarily localized to the frontal region with associated photophobia. Neurologic exam was nonfocal, and imaging of the head revealed expected postoperative changes. She was started on acetazolamide 500 mg BID, dexamethasone 10 mg intravenously followed by 4 mg every 6 hrs. LP was performed for assessment of opening pressure, which was found to be elevated at 29 cm of water pressure; profile of CSF obtained during the LP was not consistent with infection or aseptic meningitis. Pain was initially managed by the primary team with as-needed acetaminophen, acetaminophen-hydrocodone, ibuprofen, ketorolac, and fentanyl. APMS was consulted for narcotic-sparing pain control due to her severe gastroparesis, constipation, vomiting and IBS; she was started on a multimodal regimen of scheduled acetaminophen, gabapentin, ketorolac, and dronabinol, with tramadol 50 to 100 mg every 4 hrs as needed for breakthrough pain with the minimal improvement of pain score on NPS. Bilateral T4 ESP blocks were performed to augment the narcotic-sparing multimodal pain regimen. Within 10 mins following completion of the block, patient reported complete relief of headache. During follow-up evaluation the following day, the patient continued to rate her pain as a zero out of 10 on the VAS pain scale. During follow-up phone call 1 month after discharge, the patient reported that her headache recurred approximately 2 weeks following discharge, but never reached the level of her pain prior to the ESP block.Figure 2 Pineal cyst resection – craniotomy incision.\n\n\n\nCase 3 – Chronic Headache and Scalp Pain After Craniotomy\nA 70-year-old male with a past medical history of peripheral artery disease, four coronary artery stents, two prior arterial ischemic strokes with residual right-sided weakness, anterior communicating artery aneurysm with several failed endovascular coilings, intracerebral hemorrhage, and subsequent right craniotomy for open aneurysm clipping 4 years prior to admission presented with a severe headache. He endorsed chronic moderate headache, scalp, and facial pain that was being managed by both a neurologist and a chronic pain specialist on an outpatient basis. He had been prescribed several different medical regimens including antidepressants, muscle relaxants, anticonvulsants, and narcotics without adequate pain relief. He had also undergone several trigger-point injections which failed to provide pain control. He was admitted due to an increase in severity of headache with a new onset of nausea.\n\nUpon evaluation by APMS, his headache was throbbing in nature, primarily localized to the frontal and occipital regions. His scalp pain was sharp and radiated from the incisional scar on the right side of his head caudally along the right side of his face and neck; it fluctuated in severity from a five to 10 on a 10-point pain NPS. He was evaluated by the neurology service and placed on a scheduled regimen of acetaminophen 650 mg by mouth every 6 hrs, tramadol 50 mg PO every 8 hrs, as well as as-needed cyclobenzaprine 10 mg every 8 hrs, and one-time intravenous doses of methylprednisolone 1 mg, morphine 4 mg, and zofran 4 mg. Despite this regimen, he continued to have uncontrolled head and neck pain with nausea.\n\nDue to the failure of initial pain management, the neurology team consulted APMS for further assistance. At the time of consultation, the patient reported 10 out of 10 right-sided facial pain, neck pain and headache. Bilateral T4 ESP blocks were performed as previously described without complications. The patient reported improved pain from his headache within 15 mins of completion of the block. A follow-up evaluation was performed roughly 1 hr following the procedure, and the patient continued to report complete alleviation of his headache, along with scalp and neck pain.\n\nCase 4 – Acute on Chronic Headache Following Craniotomy\nA 58-year-old male who had undergone resection of a brainstem cavernous sinus arteriovenous malformation 3 months prior to admission, but had recurrent bouts of aseptic meningitis resulting in headache. This headache was responsive to steroids and oral hydrocodone-acetaminophen 10/325 mg every 4 to 6 hrs. It was believed that this was likely due to an allergic reaction to the synthetic dural patch used during closure, so he was readmitted for removal of the synthetic dural patch and replacement with native graft from his fascia lata. Immediately postoperatively he endorsed a pain score of 10 on the NPS; he characterized his headache as occipital and frontal in location, with an extension down the posterior aspect of his neck. His post-operative headache and incisional pain were unresponsive to intravenous and oral medications, including acetaminophen 1000 mg, hydromorphone 3 mg, fentanyl 350 mcg, and ketamine 50 mg, oxycodone 5 mg, gabapentin 300 mg, and methocarbamol 1000 mg. Due to his uncontrolled pain, he was unable to be transferred from the post-anesthesia care unit to the neurosurgical unit. APMS was consulted for intractable headache, and performed bilateral ultrasound-guided T4 ESP blocks as previously described. Fifteen minutes following the block he endorsed a reduction in his pain score from 10 to 2. He was monitored for 30 mins following completion of the block and was then transferred to the neurosurgery unit. On postoperative day 1, the patient reported improved functional status and mobility, with a headache pain score of four.\n\nDiscussion\nCervical and high thoracic ESP has been described at multiple spinal levels including at C7 for shoulder disarticulation surgery, T2 and T3 for chronic shoulder pain, axillary pain, and cervical spine surgery, as well as at T4 for tension headaches and carotid endarterectomy surgery.17–22 Although the ESP block is currently primarily used for acute thoracoabdominal pain, it may also be a reasonable adjunct therapy when conventional treatment for headache and cervical pain fail. We reported four cases in which bilateral T4 ESP blocks provided significant relief of head and neck pain and secondary headache.\n\nPeripheral nerve blocks and ganglion blocks are established treatments for primary and some secondary headaches. GON blocks have been used to treat migraine, occipital neuralgia, cluster, cervicogenic, post-concussive, and post-dural puncture headaches.23–29 SPG block has also been used to relieve headaches, including migraine, cluster and PDPH.29–33 Stellate ganglion blockade was studied in the treatment of posttraumatic headache.34 ESP blocks have demonstrated effectiveness in relieving tension headaches, a type of primary headache.17 This is the first case series reporting successful treatment of secondary headaches with ESP blocks.\n\nFor the patient in case one, we opted not to utilize an SPG block since the patient reported greater pain scores in her neck than her head, and we hypothesized that the ESP block would more adequately cover the two regions than the SPG block. In case two, the decision to perform ESP blocks was made due to the location of the surgical incision (see Figure 1), which limited access for GON and LON blocks. The patient in case three presented with post-craniotomy head and neck pain with no dermatomal pattern, which was refractory to medical management for almost 4 years. ESP block was performed given the dual location of pain in his head and neck. The patient in case four also endorsed pain in the head and neck which we believed would be amenable to ESP blockade.\n\nMost regional anesthetic techniques used to relieve headaches are simple to perform and involve small amounts of local anesthetic.35 The transnasal SPG block can be performed with an intranasal catheter or by inserting a local anesthetic soaked cotton-tipped applicator above the middle turbinate until contact is made with the posterior nasopharynx. GON and LON blocks can be performed with landmark technique or ultrasound-guidance and require less than 5 mL of local anesthetic per side. Supraorbital, supratrochlear, and auriculotemporal nerve blocks are landmark-based and are performed with one or two mL of local anesthetic. However, high thoracic ESP blocks require ultrasound-guidance to ensure proper injection of a large volume of local anesthetic, usually 20 mL per side, into the correct fascial plane between muscles, as intramuscular injection of local anesthetic will result in block failure. When injecting high doses of cardiotoxic local anesthetics, it is recommended to use standard American Society of Anesthesiologists monitors and have appropriate resuscitation medications (ie lipid emulsion) and intubation equipment readily available. Despite the ESP block being perceived as technically simple, pneumothorax has been reported.36,37 Two alternative scanning and needling approaches have been proposed to prevent pneumothorax during ESP block. Aksu et al recommend placing the ultrasound probe in the transverse position and inserting the needle out-of-plane; however, the pleura can still be violated with this technique.38 To prevent inadvertent pleural puncture, an in-plane approach visualizing the needle tip at all times is preferred as described by Piraccini et al.39 With cervical and high thoracic ESP block, there is a concern for phrenic nerve blockade and associated respiratory distress. Because we performed bilateral ESP, we chose high thoracic over cervical ESP. There are far more reports of T4 ESP than cervical ESP. Phrenic nerve blockade after high thoracic ESP has been examined in a study by Ueshima et al, and despite visualization of the spread of local anesthetic to the cervical nerve roots, hemidiaphragmatic paresis has not been shown. The investigators retrospectively analyzed the rate of hemidiaphragmatic paresis after T4 ESP block for carotid endarterectomy: the study concluded that high thoracic ESP block did not anesthetize the anterior branches of the cervical spinal nerves or phrenic nerve.40 Paravertebral spread of local anesthetic is likely after ESP block as evidenced by the following complications: Harlequin syndrome, a self-limited partial autonomic neuropathy after a T3 ESP block, and an unexpected bilateral sensory deficit after T9 ESP block have been reported and attributed to paravertebral spread.41,42 Thus, patients should not be considered as candidates for high thoracic ESP if they would not tolerate a high thoracic epidural or paravertebral block. The American Society of Regional Anesthesia (ASRA) Guidelines recommend avoiding deep peripheral nerve blocks in anticoagulated patients.43 Although concerns regarding the risks of epidural hematoma after ESP block have been raised, there are no major neurovascular structures in the area of injection and are no reported cases of ESP block causing clinically significant bleeding.44 Local anesthetic spread into the paravertebral space may occur due to high pressures achieved during manual injection with a syringe, however, should vascular injury occur during the ESP block, it is unlikely that bleeding from a vessel would achieve the same level of pressure, and spread into the epidural space. ESP block should be performed by a physician experienced with ultrasound-guided regional anesthesia techniques, and management of possible complications.\n\nInterventional headache management includes trigger-point injections, peripheral nerve stimulators, as well as peripheral nerve and ganglion blocks using steroids, local anesthetics and other adjuvants. ESP block is generally performed using long-acting local anesthetics with or without steroids. It has been suggested that local anesthetics break the headache cycle through central pain modulation at the level of the spinal cord by lowering peripheral afferent excitability and blocking synaptic transmission.45 Another proposed mechanism of action is autonomic blockade including both sympathetic and parasympathetic nuclei which leads to control of intracranial vasomotor function. Local anesthetics also have significant anti-inflammatory properties, blocking the release of cytokines and interfering with the migration of inflammatory cells.46 We believe the local anesthetic injected in a T4 ESP blocks the upper cervical nerve roots via the trigeminocervical complex disrupting central sensitization implicated in headaches, meningeal inflammation and referred pain.8 Despite the varying etiology of secondary headaches, it is possible that the end result is activation and excitation of the autonomic system and trigeminocervical complex, and thus treatment with local anesthetic injected in an ESP block ameliorates headache pain as described above.\n\nConclusion\nWhen medical management is inadequate, several interventions have been described for the treatment of headache, especially primary headaches. The ESP block may be an additional tool in the treatment of medically refractory secondary headaches and should be considered over other peripheral nerve blocks in patients with concomitant neck pain in addition to severe headache. There is growing literature for the efficacy of ESP block and refractory or intractable secondary headache management is another potential indication.\n\nAcknowledgments\nThe authors would like to acknowledge the Memorial Hermann Health System.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Schulman \nEA , Lee Peterlin \nB , Lake \nAE , et al. Defining refractory migraine: results of the RHSIS survey of American headache society members\n. Headache . 2009 ;49 (4 ):509 –518\n. doi:10.1111/j.1526-4610.2009.01370.x 19245385 \n2. Arnold \nM . Headache classification committee of the International Headache Society (IHS) the international classification of headache disorders, 3rd edition\n. 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Best Pract Res Clin Anaesthesiol . 2017 ;31 (4 ):513 –521\n. doi:10.1016/j.bpa.2017.05.005 29739540\n\n",
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"issn_linking": "1178-7112",
"issue": "13()",
"journal": "Local and regional anesthesia",
"keywords": "craniotomy pain; erector spinae plane block; head pain; neck pain; refractory headache; scalp pain",
"medline_ta": "Local Reg Anesth",
"mesh_terms": null,
"nlm_unique_id": "101566276",
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"pages": "49-55",
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"pmid": "32606918",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29368949;30776880;30660813;31515135;30774251;17682008;19245385;3692815;31684742;14732831;18412667;16527404;19019052;29684726;30522818;29739540;23406160;24710060;30553221;30639943;29561531;29862074;20430319;20618813;31807394;29414613;30475238;3994568;10961763;29134518;31021847;27501016;31364008;25441250;30496919;30532584;1335856;31181372;31114943;20456082;31161549;18549410;17309715;29684727;28272292;31678959",
"title": "Relief of Secondary Headaches with High Thoracic Erector Spinae Plane Block.",
"title_normalized": "relief of secondary headaches with high thoracic erector spinae plane block"
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}
],
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},
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"literaturereference": "HERNANDEZ N, GUVERNATOR G, ANSOANUUR G, GE M, TABANSI P, LE T, OBEIDAT S, HAAN J. RELIEF OF SECONDARY HEADACHES WITH HIGH THORACIC ERECTOR SPINAE PLANE BLOCK. LOCAL AND REGIONAL ANESTHESIA. 2020 JAN?13:49?55. DOI:10.2147/LRA.S249250",
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},
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},
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"transmissiondate": "20201103"
}
] |
{
"abstract": "The use of dexamethasone in preterm infants developing bronchopulmonary dysplasia has been proven to be effective. Hypertrophic cardiomyopathy is a frequently reported, although transient, side effect of high-dose dexamethasone administration. The recent introduction of very low dexamethasone dose, called 'Minidex', promised equal effectiveness compared to high-dose dexamethasone without relevant side effects. Our study presents two patients developing hypertrophic cardiomyopathy with intraventricular cardiac obstruction after administration of 'Minidex'. Marked cardiac side effects may occur even during very-low-dose dexamethasone treatment in preterm neonates. Betablocker and discontinuation of dexamethasone seem to allow spontaneous reversal of myocardial hypertrophy and obstruction. After all, systematic surveys of the incidence of cardiac complications in a larger population of preterm infants treated with very low doses of dexamethasone are needed.",
"affiliations": "Department of Pediatric Cardiology, University of Leipzig-Heart Center, Leipzig, Germany.;Department of Neonatology, University of Leipzig, Leipzig, Germany.;Department of Neonatology, University of Leipzig, Leipzig, Germany.;Department of Neonatology, University of Leipzig, Leipzig, Germany.",
"authors": "Paech|C|C|;Wolf|N|N|;Thome|U H|UH|;Knüpfer|M|M|",
"chemical_list": "D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1038/jp.2013.171",
"fulltext": null,
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"issn_linking": "0743-8346",
"issue": "34(3)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
"keywords": null,
"medline_ta": "J Perinatol",
"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D006332:Cardiomegaly; D003907:Dexamethasone; D004452:Echocardiography; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D014694:Ventricular Outflow Obstruction",
"nlm_unique_id": "8501884",
"other_id": null,
"pages": "244-6",
"pmc": null,
"pmid": "24573211",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9097827;12438668;23992673;9577285;21115554;10423352;19160190;11583475;9527943;11150359;8459811;7575834",
"title": "Hypertrophic intraventricular flow obstruction after very-low-dose dexamethasone (Minidex) in preterm infants: case presentation and review of the literature.",
"title_normalized": "hypertrophic intraventricular flow obstruction after very low dose dexamethasone minidex in preterm infants case presentation and review of the literature"
} | [
{
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},
{
"reactionmeddrapt": "Hypertrophic cardiomyopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "PAECH C, WOLF N, THOME UH, KNUPFER M. HYPERTROPHIC INTRAVENTRICULAR FLOW OBSTRUCTION AFTER VERY-LOW-DOSE DEXAMETHASONE (MINIDEX) IN PRETERM INFANTS: CASE PRESENTATION AND REVIEW OF THE LITERATURE. J PERINATOL. 2014;34(3):244-6.",
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{
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}
],
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}
] |
{
"abstract": "Trimethoprim-sulfamethoxazole (TMP/SMX) treatment for pneumocystis pneumonia (PCP) in patients with autoimmune diseases who developed PCP was conducted in a retrospective study of the following: dosage, frequency of side effects and persistence rate of TMP/SMX and prognosis of patients. Seven patients (two males and five females, mean age: 72 years) were hospitalized between April 1, 2013 and August 31, 2015, and their underlying diseases were rheumatoid arthritis (six patients) and microscopic polyangiitis (one patient). Moderate-dose TMP/SMX (TMP equivalent to TMP/SMX, average: 9.6 mg/kg/day, range: 5.1-12.5 mg/kg/day) was used for PCP treatment. As a result, patients experienced the following side effects: hyponatremia in five patients (71.4%), exanthema in four patients (57.1%), and thrombocytopenia in two patients (28.6%). Elevated creatinine level, increased blood pressure, malaise, and hyperkalemia were experienced by each patient. Six patients (85.7%) discontinued TMP/SMX treatment due to side effects, but once they had recovered, desensitization to TMP/SMX was used to treat them. Eventually, four patients were successfully treated with TMP/SMX (final persistence rate, 57.1%). Their prognoses were good, and no patients died for at least 60 days after admission. Moderate-dose TMP/SMX treatment for PCP in patients with autoimmune diseases who developed PCP may have therapeutic effects equal to high-dose TMP/SMX treatment, and therefore collecting more case studies is expected.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital.",
"authors": "Shibata|Tomohiko|T|;Tonooka|Kumiko|K|;Tsuchida|Kosei|K|;Mitomi|Hirofumi|H|;Shibata|Toshiko|T|;Katsuyama|Naooki|N|",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Japan",
"delete": false,
"doi": "10.2177/jsci.39.213",
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"issn_linking": "0911-4300",
"issue": "39(3)",
"journal": "Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology",
"keywords": null,
"medline_ta": "Nihon Rinsho Meneki Gakkai Kaishi",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D055953:Microscopic Polyangiitis; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9505992",
"other_id": null,
"pages": "213-8",
"pmc": null,
"pmid": "27320937",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective investigation of side effects and prognoses of moderate-dose trimethoprim-sulfamethoxazole treatment for pneumocystis pneumonia that developed in patients with autoimmune diseases.",
"title_normalized": "retrospective investigation of side effects and prognoses of moderate dose trimethoprim sulfamethoxazole treatment for pneumocystis pneumonia that developed in patients with autoimmune diseases"
} | [
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{
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}
],
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"reactionmeddraversionpt": "19.1",
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},
{
"reactionmeddrapt": "Pneumocystis jirovecii pneumonia",
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},
{
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},
{
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},
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"medicinalproduct": "PREDNISOLONE."
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],
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"reaction": [
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"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pneumocystis jirovecii pneumonia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
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"literaturereference_normalized": "retrospective investigation of side effects and prognoses of moderate dose trimethoprim sulfamethoxazole treatment for pneumocystis pneumonia that developed in patients with autoimmune diseases",
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},
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},
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{
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{
"abstract": "Mitomycin C (MMC) as an alkylating agent is miscellaneous an antineoplastic, antibiotic and ophthalmic agent. Here we aim to report a case of inadvertent intravitreal MMC injection instead of Avastin in case of diabetic macular edema.\nA 53 years old woman was planned to receive intravitreal Avastin injection, but accidentally, 0.05 ml of MMC 0.2% was injected. Best corrected visual acuity (BCVA) was 20/160 before injection. After 2 days, patient was referred to a tertiary referral eye center. BCVA was hand motion at presentation. Intraocular pressure was 4 mmHg. In slit lamp exams, conjunctival injection, corneal edema, Descemet fold, anterior chamber and anterior vitreous cells were presented. Pars plana vitrectomy with peripheral vitreous shaving and silicone oil tamponade was performed. Electroretinography showed undetectable responses. Ultrasound biomicroscopy showed ciliary body shortening and detachment. Optical coherent tomography showed diffuse retinal edema the day after surgery, subretinal fluid pockets in 2 weeks, and atrophy with undetectable and intertwined layers 2 months later. Gradually, like the retina, iris became atrophic and pigments were dispersed diffusely over the lens and endothelium.\nMMC is showed to be severely toxic to intraocular tissues. In our case, iris and ciliary body became atrophic. Ciliary body detachment induced hypotony. Moreover, MMC induces retinal necrosis and atrophy. Visual outcome is profoundly poor.",
"affiliations": "1Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;1Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;1Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.;2Eye Research Center, Khatam Eye Hospital, Mashhad University of Medical Sciences, Qarani Blvd., Mashhad, 9195965919 Iran.",
"authors": "Mirshahi|Ahmad|A|;Lashay|Alireza|A|;Mehrabi Bahar|Mohammad Reza|MR|;Abrishami|Mojtaba|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40942-018-0110-6",
"fulltext": "\n==== Front\nInt J Retina VitreousInt J Retina VitreousInternational Journal of Retina and Vitreous2056-9920BioMed Central London 11010.1186/s40942-018-0110-6Case ReportConsequences of inadvertent intravitreal Mitomycin C injection Mirshahi Ahmad 1Lashay Alireza 1Mehrabi Bahar Mohammad Reza 1Abrishami Mojtaba [email protected] 21 0000 0001 0166 0922grid.411705.6Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran 2 0000 0001 2198 6209grid.411583.aEye Research Center, Khatam Eye Hospital, Mashhad University of Medical Sciences, Qarani Blvd., Mashhad, 9195965919 Iran 12 2 2018 12 2 2018 2018 4 78 11 2017 16 1 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nMitomycin C (MMC) as an alkylating agent is miscellaneous an antineoplastic, antibiotic and ophthalmic agent. Here we aim to report a case of inadvertent intravitreal MMC injection instead of Avastin in case of diabetic macular edema.\n\nCase presentation\nA 53 years old woman was planned to receive intravitreal Avastin injection, but accidentally, 0.05 ml of MMC 0.2% was injected. Best corrected visual acuity (BCVA) was 20/160 before injection. After 2 days, patient was referred to a tertiary referral eye center. BCVA was hand motion at presentation. Intraocular pressure was 4 mmHg. In slit lamp exams, conjunctival injection, corneal edema, Descemet fold, anterior chamber and anterior vitreous cells were presented. Pars plana vitrectomy with peripheral vitreous shaving and silicone oil tamponade was performed. Electroretinography showed undetectable responses. Ultrasound biomicroscopy showed ciliary body shortening and detachment. Optical coherent tomography showed diffuse retinal edema the day after surgery, subretinal fluid pockets in 2 weeks, and atrophy with undetectable and intertwined layers 2 months later. Gradually, like the retina, iris became atrophic and pigments were dispersed diffusely over the lens and endothelium.\n\nConclusion\nMMC is showed to be severely toxic to intraocular tissues. In our case, iris and ciliary body became atrophic. Ciliary body detachment induced hypotony. Moreover, MMC induces retinal necrosis and atrophy. Visual outcome is profoundly poor.\n\nKeywords\nMitomycin CRetinal toxicityIntravitreal injectionElectroretinographyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nMitomycin C (MMC) is miscellaneous an antineoplastic, antibiotic and ophthalmic agent. It acts as an alkylating agent and produces DNA cross-linking, mostly on guanine and cytosine pairs, inhibiting synthesis of DNA and RNA and degrading DNA by nuclear lysis and formation of giant cells. MMC has its maximum effect against cells in late G and early S phases [1]. In glaucoma filtration surgeries, MMC applied topically, and is believed to alter conjunctival vascular endothelium and inhibit fibroblast proliferation [2]. Systemic absorption following ocular administration is unknown, however, it should be far lower than when it is administered parenterally as a chemotherapy agent [1]. The use of MMC in keratorefractive surgeries became widespread as it effectively reduced haze formation after surgery and improve the predictability of visual outcomes following refractive surgery [3]. Moreover, in glaucoma and pterygium surgeries, topical solution is applied by sponges to surgical site, usually for 2 min [2].\n\nLenticular changes and cataract is reported in topical applications [2]. Inadvertent corneal and/or scleral damage, including thinning or perforation, may occur with use of MMC solution in concentrations > 0.2 mg/mL or for time periods > 2 min [2]. There are several reports of complications after MMC usage even many years after topical application of the drug [4, 5]. As a result, many studies were designed to evaluate the effect of MMC usage in refractive surgery on the corneal endothelium. Some studies have reported significant corneal endothelial toxicity, while others failed to detect significant change in corneal endothelial density or morphology [6].\n\nPrevious reports were focused on topical application of the MMC. Here we report accidental intravitreal MMC injection in a case of diabetic macular edema instead of Bevacizumab.\n\nCase description\nA 53 years old woman with diabetic macular edema in her right eye and decreased vision to 20/160 was recommended to have an intravitreal bevacizumab injection. In the operating theater, however, 0.05 ml of 0.2% Mitomycin C solution inadvertently was injected intravitreally. The ophthalmologist immediately referred the patient to the emergency department of a tertiary referral center for urgent vitrectomy, but the patient presented to the hospital 2 days later. Due to the distance, she came late till visual loss became severe.\n\nAt presentation, visual acuity was hand motion (HM), with relative afferent pupillary defect (RAPD). In slit lamp exam, conjunctival injection, corneal edema with Descemet fold, and deep anterior chamber with inflammatory cell was seen. Intraocular pressure (IOP) was 4 mmHg. Cataract was nuclear sclerosis, and red reflex was reduced. Anterior vitreous cell was observed. Optic disc was round in shape, erythematosus, with sharp borders and cup/disc ratio of 0.4. Fundus exam revealed macular edema with hard exudates and diabetic retinopathy as mild to moderate non proliferative diabetic retinopathy. Visual acuity of her left eye was 20/20 with mild non proliferative diabetic retinopathy.\n\n23 gauge pars plana deep vitrectomy with posterior vitreous detachment induction and peripheral vitreous shaving was performed. Retinal venular tortuosity, arterial narrowing and diffuse retinal edema were seen. No retinitis or infarction was observed. As the patient was hypotonic, silicone oil tamponade was used. Sclerotomies were sutured and subtenon triamcinolone acetonide (TriamHEXAl, Hexal AG, Holzkirchen, Germany) was injected.\n\nThe day after vitrectomy, visual acuity was HM. Cornea was still edematous. Retina was attached and featureless, and arteries became narrower. IOP was 8 mmHg. Fundus photograph, fluorescein angiography, optical coherent tomography (OCT) and electroretinography were requested (Fig. 1). In fluorescein angiography, due to media opacity, details were not evaluated. Only large vessels were visible. Vascular stating and tortuosity was remarkable. In OCT, although the quality of the images was low due to haziness of the media, retina was shown edematous with cystic changes. In electrophysiology, undetectable flat ERG response was recorded in right eye and normal responses in the left eye. Patient was discharged and followed by 10 days topical Ciprofloxacine (Ciplex, Sina Darou, Tehran, Iran) every 8 h, high frequency (every 3 h) topical Betamethsone (Betasonate, Sina Darou, Tehran, Iran) and every 8 h cycloplegic as Homatropine (Homydrin, Sina Darou, Tehran, Iran). Moreover, topical NaCl 5% (Natrisalt, Sina Darou, Tehran, Iran) eye drop every 6 h and ointment for nights was prescribed. Two weeks later, IOP reduced to 6 mmHg. The ultrasound biomicroscopy (UBM) showed ciliary body shortening and detachment. Retina was attached with patchy intraretinal hemorrhages. In OCT evaluation, edema was less and small pockets of subretinal fluid were seen. In temporal to macula, retinal thickness was reduced and atrophy was initiated (Fig. 2a–d) After 2 months, visual acuity declined to poor light perception. Corneal edema was mild. Iris became atrophic with pigments distributed on the endothelium, over the lens and also the spongy iris stroma. Retina was clinically attached and became atrophic and featureless. Optic disc became semi-pale. In OCT, atrophy with all layers became intertwined and indistinguishable (Fig. 2e–f). After 1 year, visual acuity was no light perception. IOP was 4 mmHg. Patient had mature cataract, diffuse iris atrophy, mid dilated iris and mild corneal edema (Fig. 3). In specular microscopy, cell density was near half of the other eye (1670 vs. 2409) and mean cell size was half larger (598 vs. 415 µm2).Fig. 1 a Optical coherent tomography image of the macula, showing retinal thickening, cystoid intraretinal spaces, and small subretinal fluid pockets. b Electroretinogram of the right eye shows both dark adopted maximal combined response and light adopted 30 Hz flicker response shows undetectable electroretinogram response. c Fundus photograph showing macular exudates, dilated veins and retinal hemorrhages. d Fluorescein angiography shows vascular staining and leakage and hypofluorescence due to ischemia\n\n\nFig. 2 a Fundus photograph showing patchy intraretinal hemorrhages 20 days after vitrectomy. b Slit photograph showing mild corneal edema and mild patchy iris atrophy. c Ciliary body detachment and cleft and atrophy in UBM scan. d OCT scan shows small pockets of subretinal fluid. Retina showed atrophic changes in temporal retina and also reduce in retinal thickness. Edema was reduced 22 days after MMC injection. e Two months later, retina became atrophic and all layers became intertwined. Subretinal fluid was remained. f Iris atrophy progressed and pigment dispersed all over in the anterior chamber over the lens, iris and endothelium\n\n\nFig. 3 Slit lamp photograph of the patient showing mature cataract, mild corneal edema and diffuse spongy iris atrophy, one year after intravitreal MMC injection\n\n\n\n\nDiscussion and conclusions\nMitomycin C is mainly as an alkylating agent. MMC has a variety of specific biological effects in mammalian cells, including selective inhibition of DNA synthesis, mutagenesis, and stimulation of genetic recombination, chromosome breakage. Although DNA alkylation may occur at any stage in the cell cycle, it affects DNA synthesis, particularly during the late G1 and S phases [8]. MMC, therefore, works as a genotoxic antibiotic, and at high concentrations, cellular RNA and protein syntheses are also suppressed [9]. Therefore, it induces apoptosis and necrosis in high doses.\n\nIn an electroretinography and also histopathologic study, Kawashima et al. evaluate the retinal toxicity of MMC injection in the rat eye. Three different concentrations of MMC (0.2, 0.3 and 0.4 mg/ml) were injected into either the vitreous cavity or the anterior chamber of the experimental eyes. A full-field electroretinogram was recorded before injection and 2, 4 and 7 days after injection. The retinas of all eyes were examined by light and electron microscopy. They have found no evidence of electroretinography and histologic changes 2 and 7 days after injection of 0.4 mg/ml of MMC into the anterior chamber. However, profound electroretinography changes did follow injection of the drug into the vitreous. These were absent with the 0.2-mg/ml solution at 7 days, mild with the 0.3-mg/ml solution at 7 days and profound with the 0.4-mg/ml solution as early as 2 days. Intravitreal injection of 0.4 mg/ml, however, showed selective degeneration of Müller cell process at day 2, retinal pigment epithelium changes at day 4 and irregular arrangement of the outer nuclear layer and photoreceptors at day 7. It was concluded that intravitreal injection of MMC in high doses, as used as routine clinical doses, could cause retinal functional and histological disorders [7].\n\nIn a case report, Nuyts et al. claimed that there is a correlation between diffusion of MMC into the vitreous cavity and retinal vasculature occlusion. In a 45-year-old male who underwent a trabeculectomy with MMC for a secondary glaucoma after complicated cataract surgery, due to early bleb failure, a needling procedure with subconjunctival injection of MMC was performed. Five days postoperatively, a combined occlusion of both central retinal artery and vein occlusion occurred. They have concluded that a relation between the diffusion of MMC into the vitreous cavity, because of opening of the posterior capsule, and the development of retinal toxicity may exist [10].\n\nIn this case report, we have reported the outcomes of inadvertent intravitreal MMC injection. MMC application in the ophthalmology have been evaluated mostly in the field of ocular surface and orbital surgeries. Reported side effects in this issue is limited mostly on ocular surfaces or corneal endothelium or cataract formation. The only available report was in a case who had undergone vitrectomy after injection. In that case the patient suffered cystoid macular edema, iris atrophy and mild corneal temporal edema 6 months after vitrectomy. It was a photo essay and comprehensive report of that case was not available [11]. In our patient, due to distance, patient was referred late to our center. Although we performed vitrectomy less than 4 h from the first visit, retina became necrotic and atrophic. In early phase retinal edema converted to intraretinal hemorrhages. Electroretinography was undetectable since the early phase. Gradually IOP decreased and subretinal fluid pocket were appeared. Iris became atrophic and pigments dispersed in the anterior chamber. Although we performed deep vitrectomy, used long term topical and subtenon corticosteroid, and also cycloplegic, no one could arrest the inflammatory and destructive effects of intravitreal injection of MMC. One year follow up also showed toxic effects of MMC or inflammatory responses, continued to affect the ocular tissues. Lens became cataractous and iris became atrophied. As electroretinography showed, the MMC may affect retina very soon. It also affects profoundly on uveal tissue as iris atrophy progresses and iris became atrophic.\n\nAuthors’ contributions\nAll the authors contributed significantly to this case report, and all authors agree to be accountable for all aspects of the work. All authors contributed equally in acquisition of clinical data about the patient and preparing the draft of the manuscript. MA performed the vitrectomy under the supervision of AL contributed in revising and finalizing the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank Roghayeh Shafei B.A. and Alireza Haddadpour B.Sc., Audiovisual Department, and Leyla Javdane B.Sc. and Maryam Nemati Soldarogh B.Sc., Angiography Department of Farabi Eye Hospital for their help in the process of this report. It is a pleasure for us to appreciate kindness of Ms. Mahbobeh Najafi M.Sc.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\n\nConsent for publication\nWritten and comprehensive informed consent were obtained from the patient and she agreed to publish her data anonymously.\n\nEthics approval and consent to participate\nThe patient was completely notified about the procedure, and signed the written informed consent.\n\nFunding\nThe authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Lockwood A Brocchini S Khaw PT New developments in the pharmacological modulation of wound healing after glaucoma filtration surgery Curr Opin Pharmacol 2013 13 1 65 71 10.1016/j.coph.2012.10.008 23153547 \n2. Bindlish R Condon GP Schlosser JD D’Antonio J Lauer KB Lehrer R Efficacy and safety of mitomycin-C in primary trabeculectomy: five-year follow-up Ophthalmology 2002 109 7 1336 1341 10.1016/S0161-6420(02)01069-2 12093659 \n3. Schipper I Suppelt C Gebbers JO Mitomycin C reduces scar formation after excimer laser (193 nm) photorefractive keratectomy in rabbits Eye (Lond) 1997 11 649 655 10.1038/eye.1997.171 9474312 \n4. Wan Norliza WM Raihan IS Azwa JA Scleral melting 16 years after pterygium excision with topical Mitomycin C adjuvant therapy Cont Lens Anterior Eye 2006 29 4 165 167 10.1016/j.clae.2006.08.001 16938484 \n5. Tsai YY Lin JM Shy JD Acute scleral thinning after pterygium excision with intraoperative mitomycin C: a case report of scleral dellen after bare sclera technique and review of the literature Cornea 2002 21 2 227 229 10.1097/00003226-200203000-00022 11862102 \n6. Teus MA de Benito-Llopis L Alió JL Mitomycin C in corneal refractive surgery Surv Ophthalmol 2009 54 4 487 502 10.1016/j.survophthal.2009.04.002 19539836 \n7. Kawashima S, Mizota A, Adachi-Usami E, Kimura T. Effects of mitomycin C on the rat retina. Doc Ophthalmol. 1996–1997;92(3):229–41.\n8. Verweij J Pinedo HM Mitomycin C: mechanism of action, usefulness and limitations Anticancer Drugs 1990 1 5 13 10.1097/00001813-199010000-00002 2131038 \n9. Tomasz M Mitomycin C: small, fast and deadly (but very selective) Chem Biol 1995 2 575 579 10.1016/1074-5521(95)90120-5 9383461 \n10. Nuyts RM Van Diemen HA Greve EL Occlusion of the retinal vasculature after trabeculectomy with mitomycin C Int Ophthalmol 1994 18 3 167 170 10.1007/BF00915967 7852024 \n11. Ryoo NK Kim MK Wee WR Consequences of accidental mitomycin C intraocular injection JAMA Ophthalmol 2013 131 9 1197 10.1001/jamaophthalmol.2013.347 24030332\n\n",
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