A female neonate was noted to have a mass on the left maxillary gingiva. The infant was unable to breast-feed, but there was no concern for airway compromise, so she was placed under general anesthesia and the mass was excised and left to heal by secondary intention.What is congenital epulis?How does congenital epulis commonly present?What is thought to be the cause of congenital epulis and why?What are the management options for congenital epulis?-4Congenital epulis was first described by Neumann in 1871 and as a result has been called Neumann's tumor.1,4,1,2,4,5,1-7Congenital epulis commonly presents in neonates, with a mass noted to arise from the gingiva. The lesions are often covered with smooth pink to red mucosa and are sometimes ulcerated. The most common location is the anterior part of the maxillary alveolar ridge, usually in the region of the lateral incisors or canines. It has been reported to arise from the mandibular gingiva or tongue, as well as at multiple locations simultaneously.2-5,1-3,6The cause of congenital epulis is unknown. Microscopically, it is often composed of large sheets or ribbons of polygonal or rounded cells with a small, dark basophilic nucleus and eosinophilic granular cytoplasm. There is often a prominent vascular network and overlying stratified squamous epithelium with the absence of rete ridges. Immunohistochemical studies show positivity for vimentin but will be negative for S-100 and laminin. Adult granular cell tumors are considered to arise from Schwann cells and stain positive for S-100 and laminin. There are multiple theories as to the pathogenesis of congenital epulis. One theory is that given the female predominance, the growth of tumor stopping after birth, and the fact that some tumors have been shown to spontaneously regress, the cause may be influenced by maternal or fetal hormones during pregnancy; however, estrogen and progesterone receptors have not been found to be positive in congenital epulis.22 laser use with general anesthesia. Congenital epulis has never been reported to undergo malignant transformation or to continue growth after birth. Even with incomplete excision, no recurrence has been reported. Spontaneous regression has been reported when surgical management is not attempted.1-6,1-2,8Congenital epulis has classically been managed by complete surgical excision under general or local anesthesia. There has also been a case report of COCongenital Epilus is a rare, benign gingival mass that occurs in newborns. It can be managed non-operatively or via excision. If the mass is causing issues with feeding or respiration, intervention is recommended.


Mixed germ cell tumours of the ovary are malignant neoplasms of the ovary comprising of two or more types of germ cell components. Most of the malignant mixed germ cell tumours consists of dysgerminoma accompanied by endodermal sinus tumours, immature teratoma or choriocarcinoma. There are only few case reports of mixed germ cell tumours with different combinations of malignant components.We report a very rare case of mixed germ cell tumours consisted of malignant components of endodermal sinus tumour, emryonal carcinoma, and benign component of teratomatuos and trophoblastic differentiation. This is the first case report in the literature with both benign and malignant component of type described to best of our knowledge.Patient was an 18 year old girl, who presented with pain abdomen, abdominal mass and irregular bleeding. Ultrasound and CT scan showed a huge mass with solid and cystic component. Tumour markers i.e alpha feto- protein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenate (LDH) and Ca-125 were raised. We performed fertility sparing surgery by preserving one ovary, tube and uterus.Malingnant mixed germ cell tumours of ovary are highly aggressive neoplasm and early intervention and fertility sparing surgery is required for any adolescent girl presenting with rapidly enlarging pelvic mass. Ovarian germ cell tumours arise from primordial germ cell derived from the embryonal gonads. Malignant germ cell tumour comprise less than 5% of all ovarian neoplasms. The incidence range from 1 to 6% in west and from 8 to 19% in Asia . EmbryonAn 18 year old girl presented with chief complaint of abdominal mass and pain of one month duration. She also complained of fever and poor appetite. Her menstrual history revealed that she had experienced menarche at the age of 12 and her cycles were regular with normal flow in the past but had irregular bleeding in last two cycles. Her physical examination revealed severe pallor and pedal edema. Her vital signs showed tachycardia (pulse rate 120/min), blood pressure 100/70 mm Hg and respiratory rate 18/min. On abdominal examination a huge mass up to the level of xiphisternum could be palpated. There was no guarding or rebound tenderness.3 and on peripheral blood film there was microcytic hypochromic type of anemia. Serum biochemistry was normal. USG revealed a huge solid cystic mass occupying the whole abdomen. Right ovary was not separately visualised from the mass but left ovary was normal looking. There was no evidence of free fluid in abdomen. CT scan revealed no retroperitoneal lymphadenopathy. Tumour markers levels were CA-125 -259.3 IU/ml, Carcinoembroyonic antigen (CEA) 4.3 ng/ml alpha feto protein (AFP) 489.9 ng/ml, human chorionic gonadotropic levels (hCG) 3751.5 IU/ml and Lactate dehydrogenate (LDH) 3600 IU/ml.Investigations revealed haemoglobin 4.9 gm/dl, total count 7700, platelet count 437 × 10Intraoperatively there was a huge mass arising from right sided ovary with intact capsule. There was no free fluid in the abdominal cavity and peritoneal washings were taken. Abdominal cavity was explored and there was no evidence of malignant disease elsewhere. Leftsided ovary and uterus was normal looking. Tumour was removed and biopsy was taken from left ovary and infracolic omentectomy and pelvic and paraaortic lymhphadenectomy was done for staging of the tumour. Frozen section could not be done as the machine was out of order.On gross examination Figure  tumour mFinal histopathological diagnosis was: Mixed germ cell tumour with components of yolk sac tumour, mature teratoma, embryonal carcinoma and trophoblastic giant cells.Patient was discharged in satisfactory condition and received four cycles of bleomycin, etoposide and cisplatin combination chemotherapy. Patient is on follow up and on 3 and 6 month follow up patient did not show any evidence of recurrence.Rare combination of uncommon germ cell components, huge size and capsule being intact, very high levels of tumour markers makes this case unusual.Most mixed germ cell tumour consist of combination of dysgerminoma with endodermal sinus tumour accounting for one-third of the cases . Other cThe average age of presentation of germ cell tumour is 13.8 years 4–27 years) . Most co years . Ovarian endodermal sinus tumours are highly aggressive but with surgery and combination chemotherapy, the five year survival with stage 1 tumours and more advanced disease are 92% and 29% to 44% respectively . EmbryonMalingnant mixed germ cell tumours of ovary are highly aggressive neoplasm and early intervention and fertility sparing surgery is required for any adolescent girl presenting with rapidly enlarging pelvic mass.Written informed consent was obtained from the patient for the publication of this report and any accompanying images.


A 58-year-old female with a past medical history of hepatitis C virus-induced cirrhosis presented to the emergency department with three days of increasing abdominal pain, chills, and nausea and vomiting. Abdominal physical examination revealed gross ascites with fluid wave. Diagnostic paracentesis resulted in the aspiration of approximately 60mL of white turbid peritoneal fluid .The differential diagnosis of turbid peritoneal fluid includes spontaneous bacterial peritonitis, chylous ascites, and pseudochylous ascites. Spontaneous bacterial peritonitis is suggested by a predominance of polymorphonuclear cells, a positive Gram stain or a positive culture.1Given the patient’s established history of chronic liver disease, the inpatient team focused on spontaneous bacterial peritonitis as the potential etiology for the turbid peritoneal fluid. The patient was treated empirically with antibiotics. Formal abdominal ultrasonography affirmed a cirrhotic liver with large volume ascites and no evidence of mass. Peritoneal fluid cultures were negative for bacterial growth, suggesting that the fluid represented sterile ascites. Triglyceride assays were not performed. Repeat paracentesis on hospital day 3 revealed straw-colored peritoneal fluid. The patient was discharged home on hospital day 4 after clinical improvement.


Although neuroendocrine tumours (NETs) of primary hepatic origin are extremely rare, most of NETs present with liver metastasis. When a NET is found in the liver, it must be treated to exclude metastasis from extrahepatic primary sites. The patient was a 38-year-old female. Abdominal ultrasound showed an 8 cm tumour in liver during a routine examination. Liver biopsy was done. The tumour was first considered a metastatic hepatic tumour on histopathological examination. No clues to the origin of a primary tumour were found. Upper and lower endoscopy of the GI tract and chest CT were performed to search for a primary tumour and were negative for any tumour. One month later, more extensive areas of the tumour were seen on histopathological examination of second liver biopsy with the same morphologic characteristics as the first biopsy. Immunohistochemically, there was positive staining for synaptophysin, CD 56, and S-100 in the tumour cells. These findings suggested the diagnosis of NET. The diagnosis of primary liver NET was considered in a multidisciplinary meeting. Then, left hepatectomy was performed. The final pathologic diagnosis of the tumour in the resected liver specimen was Grade II NET. The patient was doing well at postoperative 28-month follow-up. Neuroendocrine tumours (NETs) are rare tumours that originate from dispersed neuroendocrine cells distributed throughout the body. NETs can be either functioning or nonfunctioning. Functioning NETs produce vasoactive hormones such as serotonin, gastrin, insulin, glucagon, and somatostatin, which may cause carcinoid syndrome .NETs are also called carcinoid tumours. According to the World Health Organisation (WHO) 2000 classification, classic carcinoids were classified as well-differentiated endocrine tumours; however, in the WHO 2010 classification, they were classified as NET Grade I. Well-differentiated endocrine carcinomas were classified as NET Grade II, and poorly differentiated endocrine carcinomas were classified as neuroendocrine carcinomas (NECs), large-cell or small-cell type [NETs are seen most frequently in the bronchopulmonary tree or gastrointestinal tract, but they may be seen in nearly every organ , 4. PrimThe incidence of NETs in the United States is 2-3/100.000 per year , 6. HoweA 38-year-old female complained of abdominal discomfort and pain. Her past medical history was not significant. Physical examination and all biochemical laboratory results were within normal limits, including liver function tests, tumour markers , and chromogranin A. Abdominal ultrasound showed an 8 cm tumour in liver segment IV. Characteristics of abdominal CT  and MRI Liver biopsy was done. Histopathological examination revealed a tumour that consisted of epithelial cells with round basophilic uniform nuclei, inconspicuous nucleoli, and pale eosinophilic granulated cytoplasm. The architectural pattern was trabecular, ribbonlike, and partly acinar. No significant cytologic atypia, mitosis, or necrosis was present . ImmunohMorphology was not characteristic for HCC, and at first the tumour was considered a metastatic hepatic tumour. No clues to the origin of a primary tumour were found. Further evaluations and examinations were undertaken to search for a primary tumour. Chest CT and upper and lower endoscopy of the GI tract were performed and were negative for any tumour.One month later, a second liver biopsy was done, and histopathological examination showed the same morphologic characteristics as the first biopsy, but more extensive areas of the tumour were seen. Immunohistochemically, there was diffuse and strongly positive staining for synaptophysin, CD 56, and S-100 in the tumour cells. These findings supported the diagnosis of NET. Additionally, there was negative staining for Heppar-1, AFP, pCEA, and TTF-1 and positive staining for CK 8/18, and the Ki 67 proliferation index was 5-6%.Given these findings, the pathological diagnosis was Grade II NET. At first, it was considered a metastatic NET, so Gallium 68 peptide PET scintigraphy was done to search for a primary tumour. But this test was negative, and another tumour could not be detected. A multidisciplinary meeting confirmed the diagnosis of primary liver NET, and laparotomy was decided upon for surgical resection.The patient underwent laparotomy, and, during the exploration, intraoperative ultrasound was done, finding no other tumour. An anatomical left hepatectomy was performed. The patient's postoperative course was uneventful, and she was discharged on postoperative day 10.An 8 cm tumour was found upon macroscopic evaluation of the specimen . The tumThe final pathologic diagnosis was Grade II NET Figures –8. SurgiPrimary hepatic NETs characteristically grow slowly and become clinically evident only at an advanced stage . In mostThe histogenesis of primary hepatic NET is not clear. According to one theory, it originates from neuroendocrine cells scattered in the intrahepatic biliary epithelium. A second theory speculates that chronic inflammation in the biliary system causes intestinal metaplasia and NET . In our Symptoms of primary hepatic NET differ from those of HCC and other hepatic tumours. Clinical manifestation may vary according to carcinoid syndrome presence. Early and definitive diagnosis prior to biopsy or resection is difficult due to nonspecific clinical presentation and rarity . There iMisdiagnosis is frequent prior to pathological examination for primary hepatic NETs. CT scan and MRI are two useful tools for diagnosis and treatment planning . The chaOn histopathological examination, NETs (classic carcinoid tumours) are composed of uniform round or polygonal cells having monotonous round centrally located nuclei with finely stippled chromatin, small nucleoli and wide pale eosinophilic granulated cytoplasm, infrequent mitosis, and no necrosis. The tumour may have various patterns such as solid, trabecular, ribbonlike, or acinar. Poorly differentiated malignant forms of these tumours are either (1) large-cell NECs , which consist of large atypical cells with marked cellular pleomorphism, large irregular hyperchromatic nuclei, prominent nucleoli, and tumour necrosis and mitosis or (2) small-cell NECs, which consist of small atypical cells with extremely high nucleocytoplasmic ratios, homogeneously dark nuclear chromatin, inconspicuous nucleoli, scanty cytoplasm, and numerous mitoses .The WHO classification used for the histopathological differentiation of NET and NEC was revised in 2010. According to the new classification, mitosis number and Ki 67 proliferation index are important determining factors for grading and classifying NETs. In histopathological examination of primary hepatic NETs, the concomitance of HCC and NET is extremely rare but can be either the combined type or the collusion type. Our case was diagnosed as Grade II NET according to the 2010 WHO NET classification, and pure NET areas were observed.Long-term follow-up for treatment of primary NETs has not been reported on sufficiently. However, the prognosis seems favourable. Aggressive treatment is not required . When lyWhen a hepatic tumour is considered to be NET, first a detailed systemic search for a primary tumour is mandatory to exclude metastatic NET, as primary hepatic NETs are very rare compared to metastatic ones. Upon exact diagnosis of primary hepatic NET, liver resection is the treatment of choice for successful long-term treatment. However, further studies with larger numbers of patients and long-term follow-up are needed to better understand the outcomes and nature of this rare type of tumour.


An investigation is performed to study the effect of suction/injection on unsteady hydromagnetic natural convection flow of viscous reactive fluid between two vertical porous plates in the presence of thermal diffusion. The partial differential equations governing the flow have been solved numerically using semi-implicit finite-difference scheme. For steady case, analytical solutions have been derived using perturbation series method. Suction/injection is used to control the fluid flow in the channel, and an exothermic chemical reaction of Arrhenius kinetic is considered. Numerical results are presented graphically and discussed quantitatively with respect to various parameters embedded in the problem. Suction or injection on the boundary layer control played significant role in the field of aerodynamics and space sciences. Shojaefard et al.  used sucThe investigation of the flow of an electrically conducting fluid in a porous channel in the presence of a transverse magnetic field is important because of its widespread engineering and industrial applications such as MHD marine propulsion, electronic packages, microelectronic devices, thermal insulation, petroleum reservoirs, MHD stirring of molten metal, exothermic reaction in packaged reactors, and magnetic-levitation casting. On the other hand, Soret or thermal diffusion is important where more than one chemical species are present under very large temperature gradients, such as chemical reactions and isotope separation, and in mixtures of gases with very light molecular weight such as hydrogen or helium and of medium molecular weight such as nitrogen or air. Because of the applications of MHD and Soret, many authors investigated their effects on natural convection heat and mass transfer flow. Postelnicu  reportedThe aim of the present analysis is to study the effect of suction/injection on unsteady hydromagnetic convective flow of viscous reactive fluid between two infinite vertical parallel porous plates in the presence of transverse magnetic field and thermal diffusion. In this paper, an exothermic chemical reaction of Arrhenius kinetics is employed and suction/injection is used to control fluid flow in the channel.B0; see t′ ≤ 0, both the fluid and the plates are at rest and at the same temperature and concentration T0′ and C0′, respectively. At t′ > 0, the temperature and concentration of the plate y′ = 0 are raised to Tω′ and Cω′ and thereafter remain constant and those of y′ = H are lowered to T0′ and C0′, where Tω′ > T0′ and Cω′ > C0′. It is assumed that the flow is subjected to suction of the fluid from one porous plate and at the same rate fluid is being injected through the other porous plate. We chose a Cartesian coordinate system with the x′ axis along the upward direction and the y′ axis normal to it. The physical properties are assumed to be constant excluding density in the buoyancy term. The fluid is assumed to be Newtonian and obeys the Boussinesq's approximation. Under the previous assumptions, the momentum, energy, and concentration equations in the dimensional form are the following: σ is the conductivity of the fluid, B0 is the electromagnetic induction, β is the coefficient of thermal expansion, β* is the coefficient of concentration expansion, Q is the heat of reaction, A is the rate constant, E is the activation energy, R is the universal gas constant, ν is the kinematic viscosity, C0′ is the initial concentration of the reactant species, g is the gravitational force, Cp is the specific heat at constant pressure, k is the thermal conductivity of the fluid, ρ is the density of the fluid, Dm is the coefficient of mass diffusivity, Tm is the mean fluid temperature, and kT is the thermal diffusion ratio.Consider the transient natural convection and mass transfer flow of viscous reactive, incompressible, and electrically conducting fluid between infinite vertical parallel porous plates under the influence of a transversely magnetic field of strength In order to solve  to 2), , 2), we y=y′H,   ρ. Using  to (2) cu/∂t = 0, ∂θ/∂t = 0, and ∂C/∂t = 0 into  a au/∂t = , we get −γ∂u∂y=∂2llowing: u=0, θ=1,follows: u=u0+λu1,, we get −γ∂u∂y=∂2ituting Δt/Δy2, r3 = Δt/Δy, r4 = SrΔt/Δy2, and 0 ≤ ξ ≤ 1. We chose ξ = 1; the detailed reasons to this particular selection are documented in [The complete forms of  are solvented in . Also th−r1uj−1(Nλ), the Soret number (Sr), the magnetic parameter (M), the thermal Grashof number (Gr), the solutal Grashof number (Gc), the nondimensional time (t), the Schmidt number (Sc), which is inversely proportional to the mass diffusivity of the working fluid, and suction/injection parameter (γ), which were simultaneously applied each to opposite porous plates of the channel at the same rate. For the purpose of discussion, some numerical calculations are carried out for dimensionless velocity (u), temperature (θ), concentration (C), skin friction, rate of heat transfer in terms of Nusselt number, and the rate of mass transfer in terms of Sherwood number. Unless otherwise stated, the values λ = 0.1, Gr = 0.1, M = 1, Gc = 0.1, Sr = 0.1, θT = 1, CT = 1, Pr = 0.71, Sc = 0.62, t = 0.1, γ = 0.5, and ε = 0.01 are used for the investigation. Results obtained are displayed graphically for velocity, temperature, concentration, skin friction, Nusselt number, and Sherwood number for various flow parameters.The numerical results are obtained by solving  using thλ) and suction/injection (γ) on the temperature profiles. From λ in case of suction and injection, respectively. This is physically true since an increase in λ leads to significant increases in the reaction and viscous source terms and hence significantly increases the fluid temperature. It is evident from λ) and suction/injection parameter (γ) on velocity distribution, respectively. λ accelerates the velocity of the fluid in case of suction and injection. It is evident from this figure that the velocity is higher in case of injection than suction. From y = 0) and, in case of injection, the maximum velocities are shifted towards the right porous plate (y = 1).M) in the presence of suction and injection parameter. γ) on the concentration distribution are shown graphically in Figures y = 0), where suction takes place more than at the wall (y = 1) where injection takes place. From In λ is illustrated in y = 0 and y = 1, respectively. From λ increase until a steady-state condition is reached in case of suction and injection. λ is displayed in y = 0 and y = 1 for different values of λ, respectively. From λ until a steady-state condition is attained in case of suction and injection. It is also evident from y = 1 increases as time and λ increase until a steady-state value is achieved. From this figure, it is seen that Nusselt number is higher in case of injection than suction. The skin friction on suction/injection parameter for varying values of the Soret number is illustrated in y = 0 and y = 1, respectively. From y = 0 and y = 1. Sherwood number decreases as Sr increases in case of suction and injection; see The wall shear stress dependence on reaction parameter M at the plates y = 0 and y = 1 for varying values of nondimensional time in case of suction and injection. Figures y = 0 and y = 1, respectively. M reduce the skin friction in case of suction and injection. Reduction is noticed in case of injection more than suction. From M increases the skin friction decreases in the presence of suction and injection. Further, it is observed from M is large. The wall shear stress dependence on Gr for varying values of time at the porous plates y = 0 and y = 1 when suction and injection take place is illustrated in y = 0 and y = 1, respectively. y = 0 and y = 1, respectively. Figures In the present study, the effect of suction/injection on transient hydromagnetic convective flow of viscous reactive fluid between vertical porous plates in the presence of transverse magnetic field and thermal diffusion is investigated. It is found that suction/injection, thermal diffusion, reaction consumption, and thermal and solutal buoyancy play an important role in controlling the transport phenomena. Formation of the minimum flow occurs near the wall where suction takes place, while the maximum flow forms near the wall where injection takes place except in the concentration distribution for varying values of thermal diffusion. It is hoped that the present work may be useful in engineering applications where the formation of boundary layer is to be delayed or enhanced.


Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ.Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate . Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of 111In-octreotide was quantified using SPECT/CT until day 39 after treatment. Based on these results, seven different 177Lu-octreotate and TMZ combination schemes were evaluated for therapy response, varying the order and time interval of the two therapies and compared with single treatments.We performed molecular imaging studies in mice bearing SSTR-expressing H69  tumours after single intravenous (i.v.) administration of 30 MBq 111In-octreotide until day 13. In the subsequent therapy study, 90 % of animals receiving 177Lu-TATE at day 14 after TMZ treatment showed complete response, being the best anti-tumour results among groups.PRRT and TMZ both resulted in tumour size reduction, accompanied by significant changes in MRI characteristics such as an enhanced tumour perfusion. Moreover, TMZ treatment also resulted in increased uptake of the SST analogue Molecular imaging studies indicated that PRRT after TMZ treatment could induce optimal therapeutic effects because of enhanced tumour uptake of radioactivity after TMZ, which was confirmed by therapy responses. Therefore, clinical translation of TMZ treatment prior to PRRT might increase tumour responses in NET patients as well. Systemic internal radiation therapy using radiolabelled peptides, specifically targeting receptors overexpressed on tumour cells, is an attractive cancer treatment. A high absorbed radiation dose is being delivered to tumours with a tolerable toxicity in normal non-targeted tissues. This so-called peptide receptor radionuclide therapy (PRRT) has been shown to be a most effective treatment option for patients with SSTR-expressing neuroendocrine tumours (NETs) –3.111In-DTPA-octreotide (111In-octreotide) or 177Lu-DOTA,Tyr3-octreotate (177Lu-TATE), show a high binding affinity for the somatostatin receptor type 2 (SSTR2), which is overexpressed on the vast majority of NETs [Most NETs are slowly proliferating tumours, making them relatively resistant to most chemotherapeutics. In more than 50 % of the patients, NETs are diagnosed at a relatively late stage, often with metastatic spread , which l177Lu-TATE and capecitabine or both capecitabine and TMZ, are ongoing. The first analyses showed promising results [PRRT has proven to be an effective therapy in most patients with NETs , 6. Neve results , 10.177Lu-TATE [111In-octreotide SPECT. The results from these imaging studies were applied in the design of different therapeutic schemes to stratify maximum therapeutic efficacy using TMZ and PRRT.When PRRT with chemotherapeutics are being combined, also potential negative interactions between the two therapies should be taken into consideration. Chemotherapy might affect the SSTR2 expression on tumour cells, on which PRRT depends for targeting of radionuclides, for example , 12. Mor7Lu-TATE . To obta177Lu-TATE to determine which dose resulted in clear tumour responses but without complete cure to allow detection of additional effects during combination therapy. Three groups (n = 7) of H69-tumour-bearing mice were treated with 10, 20 or 30 MBq 177Lu-TATE and compared with untreated control animals. Monitoring of body weight and tumour size was performed until day 28 after the start of treatment.We have started a pilot study in which H69 tumour-bearing mice were treated with increasing amounts of 177Lu-TATE was used.For TMZ treatment, different dosing schedules have been reported, including a total administered dose of >1000 mg/kg  or the a177Lu-TATE on day 1, and the TMZ group was treated with 50 mg/kg TMZ administered orally for 2 weeks, starting at day 0. The control group received saline. The timeline for these studies is shown in Fig. Three groups of mice were included in this imaging study Table . The PRRn = 4) received a baseline DCE-MRI scan 1 day prior to administration of 50 MBq 177Lu-TATE. During follow-up of the therapy, MRI scans were acquired on days 4, 7, 11, 15, 20 and 28. Moreover, a SPECT/CT scan to determine the tumour uptake of 177Lu-TATE was performed 24 h after administration.Mice (n = 7) received one baseline DCE-MRI scan 2 days prior start of TMZ treatment, which was repeated once weekly during and after TMZ treatment until day 28. To determine the level of radiopeptides uptake, 111In-octreotide SPECT/CT scanning was performed 1 day prior start of TMZ treatment and repeated once weekly for 6 weeks during and after TMZ. At day 1 (before TMZ), day 14 (after TMZ) and day 28, when tumours showed maximal response, three mice where sacrificed to collect the H69 xenograft to determine the level of SSTR expression by in vitro autoradiography using 111In-octreotide.Mice (n = 3) received four DCE-MRI scans: at days 1, 5 and 12.Non-treated mice  Table . Uptake The SSTR2-expressing human small cell lung cancer cell line H69 was obtained from ECACC  and grown in RPMI medium  supplemented with 10 % heat-inactivated foetal bovine serum.7 H69 cells in 0.2-ml HBSS. For all experiments, animals were randomized into matching treatment groups regarding tumour size at the start of treatment 4 weeks after tumour inoculation. Randomized treatment groups were created by matched pairs randomization. Three times a week, mice were weighed and length and width of the tumour were measured using a calliper by a person blinded for the treatment. Tumour volume was calculated using the formula 0.5(length × width)1.5 adapted from the SWOG criteria. Mice were euthanized when >10 % loss of body weight (BW) since start of the experiment was observed or when tumour volume exceeded 1800 mm3.All animal experiments have been conducted with prior approval of the animal ethics committee of our institution and performed in accordance with Dutch laws. Male NMRI nu/nu mice (body weight ~33 g) were obtained from Harlan . One week after arrival, at the age of 5–7 weeks, mice were inoculated subcutaneously with 10Temozolomide was obtained from Sun Pharmaceutical Industries Europe B.V. . In the pilot study, TMZ was dissolved as 8 mg/ml 50 % glucose jelly and 200 μl was administered orally. For the imaging and final therapy studies, a 8 mg/ml solution TMZ was prepared in Oraplus  and 200 μl aliquots were administered by oral gavage 5 days a week for 2 weeks resulting in a dose of 50 mg/kg/day TMZ.3-octreotate was obtained from Mallinckrodt, St Louis, MO, and 177LuCl3 was obtained from NRG Petten, The Netherlands. 177Lu-TATE was prepared as described previously [111In-DTPA-octreotide  was performed as described at a specific activity of 30 MBq/1.0 μg DTPA-octreotide [DOTA,Tyr2 gas anaesthesia was applied at 0.5 ml/min. Twenty-four hours after injection of 177Lu-TATE or 111In-octreotide, helical SPECT/CT of the tumour region was performed with a four-headed NanoSPECT/CT system  with nine pinhole mice collimators (diameter 1.4 mm) per head. The scans were obtained using 24 projections of 120 s per projection and a quality factor of 0.7. SPECT scans were reconstructed iteratively on a 256 × 256 matrix, using HiSPECT NG software  and ordered subset expectation maximization (OSEM). The total amount of radioactivity (MBq) in the tumour was quantified by 3D quantification using InVivoScope software . To achieve accurate quantification, the camera was calibrated by scanning a 20-mL polypropylene tube phantom filled with a known amount of 177Lu or 111In radioactivity. During scanning, body temperature of the mice was maintained using a heated bed.During scanning experiments, 2.0 % isoflurane/OImaging was performed on a pre-clinical 7.0T scanner  with the standard imaging gradient set . A 150-mm transmit coil and four-channel surface coil (5 cm FOV) were used to acquire all images.3 . Four k-space segments were acquired using a segmented readout sequence called TRICKS [DCE-MRI data were acquired following a bolus i.v. injection of Gadobutrol . The acquisition parameters used were repetition time (TR) = 10 ms, echo time (TE) = 2 ms, flip angle 12°, matrix size = 116 × 116 and slice thickness = 0.8 mm with a total imaging volume of 50 × 50 × 32 mmd TRICKS . This reAnalysis of the SPECT data: the concentration of activity in the tumours was calculated by dividing the total amount of activity in the tumour determined by 3D quantification with HiSPECT NG software through the 3D tumour volume determined during this quantification.trans and kep, calculated according to Tofts perfusion model [trans is the calculated rate constant for the passage of contrast agent into the tissue. The rate constant kep is the reflux of contrast agent from tissue back to the blood. The results presented show the ktrans which performed slightly better than the kep in this model due to the limited amount of wash-out in the 10-min scantime.For analysis of the DCE-MRI data, we used two methods: semi-quantitative and quantitative analysis. All calculations were performed using Matlab (Mathworks co.). In semi-quantitative analysis, the signal-intensity time curves were used to determine the time to peak (TTP), maximum signal enhancement (Smax) and the area under the curve (AUC) for the total curve and also for the first 60 s (AUC60). The AUC and AUC60 were calculated using a triangulation algorithm. Furthermore, the wash-in was calculated as a linear slope from the first point before contrast enhancement to the first maximum. The wash-out was calculated from the slope of the first maximum to the measurement at 60 s after injection. The wash-out curve was not necessarily linear in shape, but using this method, we were able to discriminate the wide variety in wash-out kinetics. In order to calculate quantitative parameters from the DCE-MRI data, the signal-intensity time curves were converted to contrast-concentration time curves using a T1-map calibration. A pharmacokinetic compartment model could be fitted to these contrast-concentration time curves. Quantitative analysis consisted of calculation of kon model . A populon model  was used−9M 111In-octreotide with and without an excess (10−6M) of unlabelled octreotide. Adjacent sections were stained with haematoxylin/eosin. Tumour sections were exposed to SR phosphor imaging screens  in X-ray cassettes. After 48-h exposure, screens were read by a Cyclone phosphor imager and analysed using OptiQuant 03.00 . Autoradiogram quantification was expressed in density light units (DLU) per square millimetre.Sections of 10 μm were sliced from frozen tumours , mounted on Superfrost plus slides  and incubated with 10Prism software version 5.0 (Graph Pad) was used to analyse tumour growth and determine statistical significance between groups. One-way ANOVA was used for statistical analysis of tumour uptake, and results are given as mean ± SD. A log rank test was performed for curve comparison.177Lu-TATE groups showed delay of tumour growth compared with the control group  at 24 h after administration of 50 MBq 177Lu-TATE. Maximum reduction of tumour volume was reached at ~day 14, after which the tumours increased in size again. After an average of 43 days, euthanasia was needed because the maximal allowed tumour size (1800 mm3) was reached.The average 3.In mice treated with TMZ, the tumour volumes increased until day 9 reaching maximum tumour sizes, after which decrease of tumour sizes was observed. At day 51, at the end of the imaging study, the average tumour volume increased again; however, at that time, none of the tumours exceeded a volume of 1800 mm177Lu-TATE initially showed a fast decrease in ktrans, reaching minimum values at day 4 ((2.2 ± 2) × 10−3 min−1 for 177Lu-TATE) or day 5 ((2.0 ± 2) × 10−3 min−1 for TMZ). When tumour size decreased, an increase in ktrans was measured. The local maximum in ktrans values was reached approximately 2 weeks after (start of) treatment. Tumours in the group receiving TMZ showed the highest ktrans values at day 13 ((11 ± 1) × 10−3 min−1); the 177Lu-TATE group’s maximum ktrans value was reached at day 15 ((5.8 ± 2) × 10−3 min−1). During further follow-up, the ktrans values decreased again in both the TMZ and 177Lu-TATE group.Tumours subjected to TMZ and vitro autoradiography results showed no difference in SSTR2 expression of H69 xenografts before (day 0) or after (day 15 and day 28) TMZ treatment , the average radioactivity after injection of 111In-octreotide was 0.4 ± 0.2 kBq/mm3 (1.5 ± 0.4 %IA/g) H69 xenograft, while after 14 days of TMZ treatment, this was increased until 0.9 ± 0.3 kBq/mm3 (2.9 ± 0.9 %IA/g) (average tumour volume 442 mm3). When the administration of TMZ was discontinued, the 111In-H69 uptake dropped again to 0.5 ± 0.2 kBq/mm3 (1.7 ± 0.5 %IA/g) at day 18 and 0.5 ± 0.2 kBq/mm3  at day 27, further declining until day 39  or TMZ (group 3), albeit with a significant delay of 20–50 days  and group 4 (TMZ 14 days after 177Lu-TATE) was significant (p = 0.046), whereas the other combination groups performed even better. Thus, the applied treatment schedules in these three groups had a striking impact on tumour response. In group 4, still 57 % of tumours reached a volume of 1800 mm3 before the end of the study at day 123. When 177Lu-TATE and TMZ were combined from the start (group 5), only 25 % of tumours reached this maximum size. By far, the best result was obtained in group 6 with 177Lu-TATE administered after 14 days TMZ treatment. Only one tumour (10 %) escaped from treatment, whereas the other tumours showed complete response.In all three groups treated with a combination of 177Lu-TATE in H69 tumours was quantified 24 h after administration of 30 MBq 177Lu-TATE based on SPECT/CT imaging. As reference, the average 177Lu-tumour uptake was 1.7 ± 0.2 kBq/mm3 without previous treatment. When after 14 days a second dose of 177Lu-TATE was given, a comparable 177Lu-tumour concentration of 1.7 ± 0.1 kBq/mm3 (5.6 ± 0.3 %IA/g) was found. However, in mice receiving 177Lu-TATE on day 14 after initial TMZ for 14 days, a significantly higher uptake of 2.2 ± 0.5 kBq/mm3 (7.5 ± 1.5 %) was determined (p = 0.013)  [177Lu-TATE PRRT.Despite the fact that significant tumour response rates have been reported after treatment of NET patients with DOTATOC) , 22, comDOTATOC) . TMZ (+ DOTATOC) , 25. The177Lu-TATE leading to a significant delay of H69-tumour size increase.In this pre-clinical study, we aimed to elucidate the most effective treatment schedule of the TMZ and PRRT combination. We applied a TMZ dose of 50 mg/kg daily for 2 weeks, which appeared to be an effective dose in our H69 model not resulting in complete responses. The same was true for a dose of 30 MBq 177Lu-TATE for PRRT of H69 tumour-bearing mice [3 at day 0), increasing growth delays using doses of 45, 60 and 120 MBq or two fractions of 45 MBq 177Lu-TATE were found [The human small cell lung cancer (SCLC) H69 cell line, used in our studies, expresses SSTR2 in high densities. As a subtype of NETs, SCLC accounts for about 20 % of all lung cancers  and showing mice , 29. In ing mice . In a thIn the clinical trials in which PRRT was combined with capecitabine and TMZ, the focus mainly has been on the radio-sensitizing effects of the chemotherapeutics , 30, not177Lu-uptake in H69 tumours after 177Lu-TATE administration was significantly higher when mice were pre-treated for 14 days with TMZ. This was not the case when pre-treatment consisted of an additional dose of 177Lu-TATE.In this study, we measured an increase of H69-tumour perfusion after TMZ treatment. The highest values after 14 days of TMZ treatment coincide with a peak in the uptake of radiolabelled octreotide. The latter observation was confirmed during therapy, as 3, demonstrating that the peak of radioactivity uptake at day 13 was not influenced by tumour volume. At later time points, when tumour sizes continued to decrease as a result of TMZ treatment, also the concentration of 111In-octreotide decreased.This increased tumour uptake/retention of radioactivity after TMZ treatment can be explained by different phenomena. A relation between tumour volume and concentration of radioactivity has been described, indicating an increased concentration of radioactivity in smaller tumours . In our vitro studies, Fueger et al. showed increased SSTR2 expression in pancreatic tumour cells 4 days after exposure to several chemotherapeutics, not including TMZ [111In-octreotide peaked.An increased level of SSTR2 expression might also explain the peak of radiopeptide uptake after 14 days of TMZ. Using in ding TMZ , 12. Thi111In and 177Lu tumour uptake, as was explored and confirmed by application of measurement of perfusion parameters by DCE-MRI.Therefore, increased tumour perfusion caused by TMZ treatment offers the best explanation for the raised levels of In multiple studies, TMZ, when administered in a metronomic  schedule, has been demonstrated to have anti-angiogenic effects that may result in normalized tumour vasculature depending on the administered TMZ dose , 32. Thep = 0.28) difference was found between group 5 (concurrent 177Lu-TATE and TMZ) and group 6 (177Lu-TATE after 14 days TMZ treatment) regarding CR, with 75 versus 90 % CR, respectively. However, when we compare group 6 with group 4 (the group in which 177Lu-TATE was administered at day 1 and TMZ treatment started at day 14), a striking and significant difference (p = 0.046) between those groups was found, in agreement with the fact that TMZ potentiates the effect of 177Lu-TATE.Considering the anti-tumour response, a small but not significant (177Lu-TATE after TMZ treatment might be based on a combination of factors:177Lu-TATE because of enhanced perfusion resulting in a higher absorbed tumour radiation dose and therefore an increased anti-tumour response [Increased uptake of response .O6 position of guanine combined with an additional alkylation at the N7 position. TMZ has been reported to act synergistically with radiation therapy, as alkylated guanine has been reported to be radio-sensitizing [177Lu is 6.7 days [177Lu-TATE at the same day that TMZ treatment was started might have had some benefit from the radio-sensitizing effects of TMZ.Increased radiosensitivity induced by TMZ. The cytotoxicity of TMZ is primarily due to alkylation at the sitizing , as was sitizing , 36. As 6.7 days , also th177Lu-TATE treatment might be enhanced when tumour oxygenation is improved. The mice receiving 177Lu-TATE 14 days prior to TMZ treatment did not have this benefit.Increased oxygenation might have contributed to improved therapeutic responses, as was demonstrated for radiation therapy . After bTherefore, the optimal response found in the group receiving Despite the fact that our model has been carefully chosen, it has important differences from the patient situation. Differences in, e.g. tumour growth rate might influence the outcome of these studies in a clinical setting. Therefore, the translational value of our findings into the clinic remains to be proven.During our combination therapy study, no signs of severe toxicity like, e.g. remarkable loss of weight have occurred. Nevertheless, during PRRT as well as chemotherapy, toxicity is an aspect of great concern. In a clinical study, a treatment scheme in which PRRT was combined with capacetabine and TMZ has been shown to be safe . Conside177Lu-TATE as proven by SPECT/CT, was reflected by the induced therapeutic effects we observed.The use of SPECT/CT and MRI enabled us to optimize a treatment schedule for the combination of PRRT and TMZ in H69-xenografted nude mice. Increased perfusion following TMZ pre-treatment, determined by DCE-MRI, coinciding with increased uptake of All applicable international, national and/or institutional guidelines for the care and use of animals were followed.


The aim was to evaluate whether changes in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values predict early response in patients receiving neoadjuvant chemotherapy (NACT) for breast cancer and to assess the effect of tumour marker clip placement on ADC values.Twenty patients with invasive breast carcinoma underwent MRI at three time points: at baseline (TP0) and following the first (TP1) and second (TP2) cycles of NACT. 3T MRI  was performed using a standard protocol including diffusion-weighted and diffusion tensor imaging. Baseline and sequential data in responder and nonresponder groups were compared. To assess the effects of a commercially available titanium-hydrogel clip on ADC values, DWI was performed on a phantom consisting of a clip embedded in a tumour-mimicking target.-3 mm2/second) was statistically lower than disease-free fibroglandular breast tissue (1.75 × 10-3 mm2/second) (P < 0.0001). Mean FA values of tumour (FA = 0.139) and disease-free tissue (FA = 0.135) were similar. Compared with baseline values, tumour ADC of responders significantly increased at TP1 (P < 0.0001) and TP2 (P < 0.0001) while a significant increase in tumour FA of responders was seen at TP2 (P < 0.008). No statistical change occurred in tumour ADC or FA values of the nonresponder group. The ADC value of the clip in the phantom (1.7 × 10-3 mm2/second) was higher than the ADC value of surrounding tumour (1.4 × 10-3 mm2/second).At baseline, mean tumour ADC (0.92 × 10Changes in ADC and FA values early in the course of treatment may predict response in patients receiving NACT for breast cancer. The gel-containing clip used for tumour marking prior to NACT results in a source of error when calculating tumour ADC values and should be avoided when drawing regions of interest.


Breast MRI can be performed in the preoperative workup of patients with biopsy-proven breast cancer to size lesions, if there is discrepancy regarding the extent of disease from clinical, mammography or ultrasound assessment, and to identify multicentric or multifocal disease. The purpose of breast MRI is to plan the optimum surgical procedure, thus reducing the local tumour recurrence rate and the need for the patient to undergo additional surgery.In this poster we have reviewed breast MRI examinations from patients with a new diagnosis of breast cancer, who had a preoperative MRI.There were 75 scans in total. Patients who had MRI occult disease or neoadjuvant chemotherapy were excluded, leaving a total of 51 breast MRI scans. Invasive tumour size and total tumour size (invasive tumour + DCIS) as seen on MRI were compared with the size reported in the surgical pathology specimen. There was accurate correlation in invasive tumour size in 81% and significantly discordant sizing in 19%. Correlation in overall tumour size including DCIS was 70% and significantly discordant in 30%. In three patients in whom the total tumour size was overestimated, the patients consequently had complete local excision with wide excision margins. In another patient, in whom the total disease extent was underestimated on MRI, following complete local excision, repeat surgery was required for positive margins. In these four patients the MRI was misleading for guiding the optimum surgical procedure.MRI tumour size assessment particularly for DCIS should be interpreted with caution.


We intend these resources to be used for quality control procedures when analysing data derived from this platform.Genome-wide analysis of DNA methylation has now become a relatively inexpensive technique thanks to array-based methylation profiling technologies. The recently developed Illumina Infinium MethylationEPIC BeadChip interrogates methylation at over 850,000 sites across the human genome, covering 99% of RefSeq genes. This array supersedes the widely used Infinium HumanMethylation450 BeadChip, which has permitted insights into the relationship between DNA methylation and a wide range of conditions and traits. Previous research has identified issues with certain probes on both the HumanMethylation450 BeadChip and its predecessor, the Infinium HumanMethylation27 BeadChip, which were predicted to affect array performance. These issues concerned probe-binding specificity and the presence of polymorphisms at target sites. Using  Changes in DNA methylation are observed in normal development, in response to environmental stimuli, and in certain disease states The Infinium HumanMethylation450 BeadChip has recently been superseded by the Infinium MethylationEPIC BeadChip. This array interrogates DNA methylation at over 850,000 sites, including > 90% of the HumanMethylation450 array's targets. This substantial increase in coverage, coupled with a continuing trend for interest in the role of DNA methylation, is likely to result in wide-spread use of this array. As such, it is essential that its potential shortcomings are thoroughly understood. In order to generate a resource that will be of use to researchers using the MethylationEPIC BeadChip we have identified probes that may perform sub-optimally. This work, therefore, represents an update of Chen et al.'s via single base extension of a fluorescent-labelled nucleotide.Like its predecessor, the MethylationEPIC BeadChip uses two types of probe chemistry (Type I and Type II) to interrogate methylation. The differences between the two chemistries and the situations in which they are used have been described fully in previous publications in silico analyses to identify probes on the Infinium MethylationEPIC BeadChip that are predicted to hybridise to multiple genomic regions, as well as probes where signal may be affected by polymorphisms at the target site, which could alter probe binding. Both of these factors should be taken into account when performing quality control of data produced using this technology.Taking the differences between Type I and Type II assays into consideration, we have performed 33.1Probes potentially affected by polymorphisms at the target site were identified following methods described previously The signal-generating process of single-base extension requires end-nucleotide matching for both Type I and Type II probes. Therefore, we limited our query to target CpGs and sites of single-base extension, as polymorphisms at these sites are most likely to generate spurious signals.Using information from the Infinium MethylationEPIC BeadChip manifest file , we generated a list of genomic coordinates  of the target cytosine base (C) and guanine base (G) for all probes on the array. For Infinium Type I probes we also included the base before the target CpG, as this is the site of single base extension for these probes. We cross-referenced these coordinates to those of variants listed by the 1000 Genomes Project (phase 3) 3.2Probes with the potential to cross-hybridise were identified following methods described previously 3.2.1Many Infinium Type II probe sequences contain an “R” nucleotide representing either an adenine (A) or guanine (G) base, depending on whether the underlying target cytosine is methylated or unmethylated. All possible combinations of Type II probe sequences were generated, and combined with a list of the Type I probe sequences.3.2.2https://genome.ucsc.edu/) as a reference, excluding alternative assemblies (e.g. chr17_ctg5_hap1) to avoid duplicated results (date of download: 11 January 2016). From this, we generated four modified reference genome sequences. A bisulphite-converted methylated forward genome sequence was generated in silico by converting all non-CpG cytosine bases to thymine (T) bases in the reference sequence. The same process was performed for the reverse complement of the reference sequence to generate a bisulphite-converted methylated reverse sequence of the human genome. Bisulphite-converted unmethylated forward and reverse sequences were generated by converting all C bases to T in the forward reference sequence and its reverse complement.The GRCh37 release of the human genome sequence was downloaded from the University of California, Santa Cruz (UCSC) Genome Browser website  44.1Coordinates for 866,836 probes were obtained from the Infinium MethylationEPIC BeadChip manifest downloaded on 8th February 2016. Excluding control probes, the manifest file contained 142,262 Type I probes , and 724,574 Type II probes , giving a total of 1,875,934 sites which were interrogated for genetic variation.We identified 340,327 sites with either single nucleotide polymorphisms (SNPs), insertions or deletions (indels), or structural variation. These sites were targeted by 297,744 unique probes: 34% of the total probe content of the Infinium MethylationEPIC BeadChip. Of these, 23,399 probes (2.7%) targeted polymorphic sites with a minor allele frequency (MAF) of ≥ 5% in at least one population studied. A table of probes affected by polymorphisms, with minor allele frequencies corresponding to African, admixed American, European, South Asian, and East Asian populations  is available in the supplementary information of this paper . We identified 44,210 probes  with ≥ 47 nucleotide off-target matches including the end base, which were defined as potentially cross-hybridising. A list of these probes is available in the supplementary information of this paper  with potential off-target binding sites and 23,399 probes  whose target site contains a polymorphism with a MAF ≥ 0.05 in at least one population studied, which may lead to artefactual signal due to impaired probe-binding. We recommend that users take these probes into consideration when analysing data on this platform, applying the appropriate filtering criteria in a population-specific manner, where possible. We recognise that there may be some situations where retaining probes mapping to polymorphic target sites will be desirable. For example, a difference in methylation due to a SNP that creates or destroys a CpG at a target site may be informative if it confers a change in disease risk.Our Chen et al. (2013) In summary, we have produced lists of probes on the new Illumina Infinium MethylationEPIC BeadChip that measure methylation at sites affected by polymorphisms and/or have the potential to cross-hybridise. Based on the wide-spread use of the HumanMethylation450 BeadChip, we predict that the Illumina Infinium MethylationEPIC BeadChip will play a central role in epigenome-wide association studies (EWAS) over the next few years. As such, it is essential that factors affecting the performance of the array, such as probe specificity and sequence polymorphisms, which we have demonstrated to potentially affect a substantial proportion of probes, are taken into consideration. We recommend that the resources supplied with this paper be used in conjunction with additional standard quality control measures, such as excluding probes with low signal-to-background ratios, omission of samples with a high proportion of such probes, and appropriate data normalisation strategies (for review see Wilhelm-Benartzi et al., 2013 Table of Infinium MethylationEPIC probes with potentially polymorphic targetsSupplementary Table 1List of potentially cross-hybridising CpG-targeting probesSupplementary Table 2List of potentially cross-hybridising non-CpG-targeting probesSupplementary Table 3The following are the supplementary data related to this article.The authors declare no conflicts of interest.


Imaging determines the optimal treatment for rectal cancer patients. High-resolution magnetic resonance imaging (MRI) overcomes many of the known limitations of previous methods. When performed in accordance with the recommended standards, MRI enables accurate staging of both early and advanced rectal cancer, accurate response assessment, the delineation of recurrent disease and planning surgical treatment in a safe and effective manner. Tumour-related high-risk features with known adverse outcomes can be preoperatively identified and treated with neoadjuvant chemoradiotherapy. Further, MRI post-treatment tumour response assessment using TRG grading system also predicts the likely survival outcomes and in the future will be used to modify treatment further by stratification into good and poor responders. There is a paucity of literature with validated outcome data concerning use of diffusion-weighted imaging and positron emission tomography (PET)/computed tomography (CT), and in the absence of any validated methods and outcome data, their use in the initial assessment and restaging after treatment is limited to research protocols. Combination MRI and CT is essential for distant spread assessment and recurrent disease, and currently PET-CT is sometimes used in the workup of patients with recurrent and metastatic disease. Preoperative assessment of tumour spread has become essential for both early and locally advanced rectal cancer, response assessment to neoadjuvant chemoradiotherapy (CRT) and resectability of recurrent disease. A number of different imaging modalities have been used to assess locoregional and distant tumour spread, with magnetic resonance imaging (MRI) use predominating for rectal cancer staging in the last 10 years. Nowadays, for the majority of colorectal units, imaging assessment of the primary tumour helps to determine the surgical procedures and the necessity for preoperative treatment.Implementation of bowel cancer screening programs has increased the rate of patient identified with early rectal cancers   and MR pImaging is becoming necessary for tumour response assessment when patients have completed neoadjuvant therapy. Although histopathology remains the so-called gold standard for evaluating tumour response within the final specimen, the opportunity to modify treatment before definitive surgery takes place is missed. Thus, preoperative identification of imaging complete responders (cr) will enable detection of patients who could potentially undergo organ-preserving treatment in the future and trials are underway to test the performance of MRI in the identification and surveillance of such patients. Conversely, preoperative detection of poor responders may lead to further consolidation therapy in order to reduce risks of local and distant failure. Thus, the post-treatment assessment of response using high-resolution MRI may in the future become a crucial step in the management of patients with advanced rectal cancer (TRIGGER: EudraCT Number 2015-003009-40).Patients with locally recurrent rectal cancer form a challenging group for cure due to limited treatment option as CRT and surgery have usually been offered previously. The importance of accurate imaging has been recognised for these patients; a risk stratification staging system is based on number and location of pelvic compartments involved as identified on high-resolution MRI. This method of assessment has been shown to predict clinical and survival outcomes , 6•.Imaging modalities involved in the local and distant staging of rectal cancer are the following: endorectal ultrasound (ERUS), MRI, computed tomography (CT) and positron emission tomography (PET)/CT (a summary of different methods performance is listed in a Table p = 0.73) [ERUS with the rigid probe has a number of imaging limitations including inability to stage high, bulky and structuring tumours . Use of  = 0.73) . As an a = 0.73) .The overall multidetector CT accuracy of T staging is around 86 % ; howeverFor lymph node assessment, size is most commonly used CT criterion for differentiating benign from malignant lymph nodes; however, Bipat et al. meta-analysis showed that CT had 55 % sensitivity and 74 % specificity for predicting lymph node involvement in rectal cancer patients .Nevertheless, published data suggests that such risk factors of tumour spread as mucinous content and presence of EMVI could be identified on CT scans. Heterogeneous enhancement and presence of areas of hypoattenuation are more frequently identified within the mucinous tumour vs non-mucinous . It has MRI has become the optimal modality for the local staging of primary and recurrent rectal cancer. There are several advantages over alternative techniques: it enables to stratify tumours depending on the presence of several high-risk features that are not limited to T and N stage . These have all been proven to influence disease-free and overall survival rates in prospective multicentre studies. In recurrent rectal cancer, MRI allows the delineation of tumour extent within the pelvic compartments, can assess the pattern and mode of local recurrence and predict resectability of the disease.Small FOV (not more than 160 mm) coronal, sagittal and axial slicesSlice thickness (no more than 3 mm and voxel size less than 1.5)Correct scan plane alignment Specific imaging parameters should be followed to achieve optimal results of the MRI technique. Good quality high-resolution scan can be achieved if the following technique criteria are satisfied Table :Small FOThe voxel and FOV size increase will cause loss of resolution, so that assessment of tumour morphological characteristics becomes challenging. Incorrect imaging plane incline usually leads to tumour overstaging.Intravenous contrast to assess primary rectal cancer or recurrence is not recommended as there is no evidence that its use improves accuracy or gives additional prognostic staging information.On high-resolution MRI scans, rectal wall anatomy is clearly depicted so depth of tumour invasion can be correctly assessed. Not only is extension into the mesorectum can be evaluated but also tumour spread within the layers of the bowel wall. Therefore, MRI enables to identify patients with early rectal tumours eligible for organ-sparing surgical treatment  and those with high-risk tumours, when preoperative treatment is mandatory.All rectal cancers apart from mucinous tumours demonstrate intermediate signal intensity (SI), whereas the submucosal layer shows hyperintensity and the muscularis propria (MP) low-intensity MR signal. The presence of a hyperintense stripe between the tumour and muscularis at the level of tumour advancing border (not the rolled edges) should be interpreted as full or partial preservation of submucosa and indicates a likely T1sm1/2 at most; on the contrary, absence of preserved submucosa but unaffected MP suggests T1sm3/T2 —from the clinical point of view, there is no need in differentiating these two stages (sm3/T2); if no macroscopic invasion of the mesorectal fat is present and no low signal intensity line identified between intermediate SI tumour and hyperintense mesorectal, tumour should be staged as T2 (with full thickness of MP invasion)/T3a (<1 mm tumour spread beyond the muscularis propria)—prognosis and outcomes of patients with these T stages are no different, so their distinction is unnecessary.Macroscopic spread of tumour beyond the MP associated with worsening prognosis. Tumour spread <5 mm is associated with identical prognosis as T2 tumours provided that there is no CRM involvement by tumour. More advanced penetration into the mesorectum (T3c-d disease) is associated with increasing rates of disease recurrence , 25. SubThe outermost boundary of the mesorectum is defined by the mesorectal fascia (MRF), which acts as a barrier to tumour spread and demarcates the CRM during surgical excision. MRI has been proven to accurately identify potential distance from tumour to CRM within 1 mm, which is recognised by pathologist as a clear margin , 27–29. According to the TNM classification system, tumours invading the mesorectal fascia are not T4—therefore, the predicted MRI CRM status must always be reported in addition to the TNM. A measured distance of 1 mm or less from the primary tumour, tumour/vascular deposit, or invaded extramural vessels to the MRF is one of the major prognostic factors for local recurrence, poor disease-free survival and poor overall survival and should always be stated in the MRI reports.Nodal staging is of questionable importance as a predictor for local recurrence in patients receiving radical surgery for primary tumours; however, it still should be assessed if local excision is considered. Some authors continue to suggest using size criteria when determining the nature of mesorectal nodes; however, there is no rational basis for this and all published pathology data indicates that there is no relationship between the size of a lymph node and its likelihood of malignancy . In a hiMRI EMVI defined as tumour signal within the vasculature outside the muscularis propria has been proven to correlate with histopathology findings  and survAssessment of tumour resectability is one of the crucial things in recurrent rectal cancer patients. Offering the best soft tissue contrast compared to the rest of the available imaging modalities MRI enables evaluating relationship of recurrent tumour to important landmarks—pelvic viscera, peritoneum, bones, nerves, muscles, fasciae and ligaments. It has been highlighted that accurate delineation of disease extent in relation to pelvic compartments is essential to plan the most appropriate treatment for this group of patients •.After preoperative CRT, up to 30 % of patients will develop complete pathological response defined as no tumour identified on the final histology examinations. Modified Mandard grading system of tumour response was tested in MERCURY study and has been proven to be a reliable tool for assessing tumour response in rectal cancer ••. This b value DW images should not be offered watch and wait policy [p = 0.82) [Some studies suggest using DW-MRI in order to increase accuracy of tumour response assessment and specificity for selecting patients eligible for deferral of surgery trial, proposing that patients showing residual diffusion restriction on high t policy , 40. How = 0.82) . The datThe role of an imaging modality that provides a combination of functional information (18F-FDG-PET) and morphologic information (CT) has not yet been defined for rectal cancer staging. This method is not recommended in the international standards of rectal cancer patients’ management or guidelines for local spread assessment . It has The high cost and lower availability of PET are not the only disadvantages of the method. It has been shown to be inaccurate in differentiating changes within the mesorectal and pelvic lymph nodes , 44, it A meta-analysis published by Huebner et al. included 11 studies and 577 patients showed that FDG-PET had 97 % sensitivity and 76 % for detecting recurrent colorectal cancer . However


Our goal was to study the feasibility of predicting fluid responsiveness by transcutaneous partial pressure of oxygen (Ptc02) in the critically ill patients.This was a single centre prospective study conducted in the intensive care unit of a tertiary care teaching hospital. Patients for whom the attending physician decided to perform a fluid challenge or presence of at least one clinical sign of inadequate tissue perfusion in the absence of contraindication for fluid infusion were eligible to participate in the study. Ptc02 was used to continuously record at baseline, during a passive leg raising (PLR), and then during a 250 ml rapid saline infusion in 10 minutes. Fluid responsiveness is defined as a change of stroke volume≥10% after 250 ml volume infusion.Twenty-three patients were included; of whom, 9 responded to volume expansion. In the 9 responders, heart rate, mean arterial pressure, pulse pressure, central venous pressure, cardiac output, stroke volume, Ptc02 all increased significantly (p < 0.05). Fluid responsiveness was predicted by the PLR-induced change of 13.9% in Ptc02 (area under receiver-operating characteristic curve 0.932) with a sensitivity of 77.8% and a specificity of 100%.In this prospective study, it is suggested that the newly defined parameter, Ptc02 changes during the volume expansion or PLR appears to be a good parameter to predict fluid responsiveness.NCT02083757


Percolation is a concept widely used in many fields of research and refers to the propagation of substances through porous media , or the behaviour of complex networks . Percolation theory asserts that most percolative processes are universal, that is, the emergent powerlaws only depend on the general, statistical features of the macroscopic system, but not on specific details of the random realisation. In contrast, our computer simulations of the leakage through a seal—applying common assumptions of elasticity, contact mechanics, and fluid dynamics—show that the critical behaviour  solely depends on the microscopic details of the last constriction. It appears fundamentally impossible to accurately predict from statistical properties of the surfaces alone how strongly we have to tighten a water tap to make it stop dripping and also how it starts dripping once we loosen it again. Seals and gaskets are crucial components in many hydraulic systems such as water taps, pipes, pumps, or valves235In a previous publication34Although Persson theory has proven successful in describing leakage over a broad parameter range, one cannot expect it to hold near the sealing transition. One reason is that mean-field theories like Bruggeman’s, which is part of Persson’s approach to leakage, are known to fail near critical points, even if they perform quite well outside the critical region12In this work, we investigate the fluid leakage through a mechano-hydraulic interface by means of computer simulations. In contrast to previous studies915We begin the analysis of leakage near the percolation threshold by simulating our “default model”. It is based on approximations that are commonly made to study either the contact-mechanics or the fluid-mechanics aspects of our leakage problem: self-similar surface roughness, linearly elastic bodies, small surface slopes, and absence of adhesion between the surfaces. Fluid flow through the interface is treated in terms of the Reynolds equation. Some of the approximations of our default model are relaxed below. More details are given in the method section.L is the absolute load squeezing the surfaces together and Leakage flow for our default system is shown in β is the conductance exponent. The value of β deduced from the data is consistent with the one we identified for isolated, single-wavelength constrictionswhere To rationalise how the mean fluid flow develops as a function of load, it is instructive to visualise the spatially resolved fluid pressure and current density for a particular random realisation. This is done in Our system can be characterised as having correlated disorderIn the critical regime, the pressure drops predominantly at a single constriction. One might argue that large systems have a smaller critical regime, because significant pressure drops can then occur at several constrictions. We therefore analysed how the size of the critical regime depends on the system size. For this, we changed the ratios We also changed Conductance exponents in percolation theory frequently turn out to be universal, that is, they remain unaltered when details of a model change. In view of this finding, we explore whether the conductance exponent also remains unaltered with small alterations to the default leakage model. One simple modification is to assume that the fluid flow velocity does not extrapolate to zero precisely at the walls  but already a distance In the present context, one could argue that a negative slip length accounts for the finite size of particles to lowest order: the fluid particles can only penetrate gaps with a height greater than where the proportionality factor is linear in the viscosity of the fluid and also depends on the geometry of the constriction. Inserting our Taylor series approximations for effective height, width, and length of the constriction into Eq. We now turn our attention to surfaces that attract each other via adhesive forces. The fluid flow has stick boundary conditions again. In a previous workAn interesting aspect of We now address the question of whether the crossover of exponents presented in From the three leakage models analysed in this study, it has become clear that seal systems are unlikely to belong to a (unique) universality class of percolation theory, even though one might consider flow through a seal as a paradigm percolation problem. When adding small alterations to our default model, in which common approximations of lubrication theory are made, we observe qualitative changes in the transition between finite and zero conductance. In fact, it appears as though the default model represents a multi-critical point, because the conductance exponent changes when an arbitrarily-small negative slip length is introduced and/or the transition changes from continuous to discontinuous when short-range adhesion between the surfaces is introduced. In practice, many additional complications can and in general will affect the leakage problem, most notably the formation of fluid capillaries, clogging by contaminating particles, as well as viscoelastic deformation and ageing of the sealing material. These complications are likely to correspond to relevant perturbations affecting the nature of the percolation transition as well.While it is certainly possible to predict leakage over a broad pressure range from statistical properties of the surfaces alone, it appears impossible to do so accurately when the load exceeds 80% or 90% of the critical load, above which no open channel percolates from one side of the interface to the other side. At such high loads, most of the pressure pushing the fluid through the interface drops at a single constriction. The  properties of this constriction then determine the behaviour of the whole system. This is one reason why it is impossible to predict with great accuracy how strongly we have to tighten a water tap to make it stop dripping and also how it starts dripping once we loosen it again.q its magnitude. Simulations are run in a force-controlled fashion. After the external load has changed by a small amount, all degrees of freedom are relaxed until convergence is attained.The contact mechanics treatment and its description is in large parts identical to that presented in our study on isolated constrictionsTwo surfaces interact with a hard-wall constraint, i.e., they are not allowed to overlap. In addition, we assume a finite-range surface energy xy-plane so that the local height in real space can be written as a Fourier sum The linear size of the solids is denoted by H ≈ 0.8H indicates that height spectra increase in magnitude at long wavelengths relative to short wavelengths. Sometimes λ constrictions discussed in ref. Most technical and natural surfaces are self-affine rough, e.g., ground steel, asphalt, human skin, and sandblasted plexiglass show self-similar height spectra over a broad range with Hurst roughness exponent of The roughness spectra For the fluid-mechanics-related calculations, we assume a reservoir of liquid on the left side of the system hypre packagehypre using the CG (conjugate gradient), or GMRES  methodsLike the contact-mechanics aspects, all solution strategies including their descriptions are in large parts identical to those presented in our study on isolated constrictionsThe fluid pressure and its gradients are assumed small enough to not deform the walls. We verified that our results for the conductance exponent do not depend on this approximation, by including the coupling of the fluid pressure  to the wall for an isolated  constriction. We merely observed an increase in the percolation load, a shift in the location of the critical constriction, and a reduction of symmetry of the gap and contact line profiles. Coupling to GFMD is done through an iterative perturbation treatment, in which the Reynolds output is fed back into the contact mechanics calculation.How to cite this article: Dapp, W. B. and Müser, M. H. Fluid leakage near the percolation threshold. Sci. Rep.6, 19513; doi: 10.1038/srep19513 (2016).


Angiogenesis modelling is an important tool to understand the underlying mechanisms yielding tumour growth. Nevertheless, there is usually a gap between models and experimental data. We propose a model based on the intrinsic microscopic reactions defining the angiogenesis process to link experimental data with previous macroscopic models. The microscopic characterisation can describe the macroscopic behaviour of the tumour, which stability analysis reveals a set of predicted tumour states involving different morphologies. Additionally, the microscopic description also gives a framework to study the intrinsic stochasticity of the reactive system through the resulting Langevin equation. To follow the goal of the paper, we use available experimental information on the Lewis lung carcinoma to infer meaningful parameters for the model that are able to describe the different stages of the tumour growth. Finally we explore the predictive capabilities of the fitted model by showing that fluctuations are determinant for the survival of the tumour during the first week and that available treatments can give raise to new stable tumour dormant states with a reduced vascular network. Angiogenesis, the formation of new vessels from pre-existing ones, is a normal and vital process in growth and development of animal organisms. It is required during the repair mechanism of damaged tissues like wound healing processes. However, angiogenesis is also essential in the transition of avascular forms of solid tumours into cancers that are able to metastasise and cause the lethal outcome of the disease. Hence, angiogenesis promotes cancer growth.3 the necrotic core inside the tumour is formed et al. 21].In contrast, the microscopic description is intrinsically stochastic, formally described by a multivariate birth-death process , that caAdditionally, to give soundness to the prediction of the model we use experimental data to give meaningful values to each parameter of the model. The result is a working model able to predict the dynamics of the Lewis lung carcinoma.N, and the effective number of blood vessel cells, V, or to be precise the number of endothelial cells that lines the interior surface of blood vessels. This interaction takes place by means of VEGF, the regulating proteins secreted by the tumour cells that promote the angiogenesis process, P. It is also useful to define the relative quantity E ≡ V/N, which measures the number of vessel cells that are available per tumour cell i.e. gives a measure of the amount of nutrient each tumour cell receives.The dynamical evolution of the tumour is determined by the non—linear interactions between the tumour cells, N/V/P, respectively) while others depend on the concentration of each of those species in the system Ω is the parameter relating concentrations with the number of cells (or molecules), giving a measure of the size of the system. The larger is Ω for a certain concentration, the greater will be the corresponding number of cells (proteins). The parameters used to describe the particular reactions are summarised in The different events characterising the dynamics of the system take place at a microscopic level as a set of events changing individually the population of each species. Following the molecular analogue, such events will be referred here on as reactions. Some of these reactions depend on the absolute number of tumour cells/vessels/proteins  is a decreasing function capturing intracellular competition for resources. Such a competition will increase with tumour cell concentration N*, causing a reduction in the proliferation rate. On the other hand, the proliferation capability increases with the amount of nutrients that the tumour cells receive through the vessels f1(E). These assumptions capture a switching behaviour in which the cells proliferate if the environmental conditions are favourable (N* < K + f1(E))  = 1), while the division decay for a lower concentration of nutrients (limx → ∞gb(x) = 0). In particular, we assume that gb(·) has the Hill formn1 > 0.The first considered reaction is the cell proliferation in which a cell can divide giving place to two daughter cells,+ f1(E)) . Thus, fK + f1(E)) depends non-linearly on the concentration of endothelial cells through E and it is related to the maximal tumour size that can be reached assuming the effective vessel density is equal to E. The parameter K corresponds to the maximal tumour size if no vasculature is present. Thus, following the ideas of a2 and itl muscle , where tl muscle . Additio made in  where doδP of the three isoforms can be considered comparable and determined from in vitro half-life measurements [−1. Again, this datum correspond to a different tissue, in this case human cells. Thus, we treat that estimation as a reference for the mouse tumour.On the other hand the VEGF degradation rate urements , 43, obti.e. the tumour cell proliferation rate with nutrient profusion has been reported for the lung carcinoma (Lewis) C57BL/6 [α in the range 0.41–0.69 day−1.The maximal tumour growth rate  C57BL/6  showing μm [7–7.87 × 107 (cells).On the other hand, in the absence of nutrient supply from blood vessels the growth of the tumour is hindered reaching a maximal number of tumour cells that in our model comes described by the parameter product  2–3 mm, , 2. Sinc mm, [μm , the aveAll the estimated parameters above mentioned, their ranges and their bibliographical sources are summarised in V. For instance, in [V. Similar problems are found in measures of VEGF such as Fig 5B in [Note, that due to a lack of experimental data, none of our estimations take into account the number of vessel cells ance, in  the finaance, in  for the ig 5B in , where tr = 3.5 μm the volume measurements of LLC cultivated in vivo can be directly converted to number of cells. The resulting profile of number of cells in time can be compared with realisations of the model for different parameter values. The optimal values of the parameters can be found by optimising a distance function between the experimental data and the model prediction. In this case we minimise the mean square error (MSE) between bothM is the number of experimental measurements, ® implementation of the algorithm.With the parameter ranges obtained, a further inference can be carried out by using volume data growth for the Lewis lung cancer (LLC) published in . Again, er space , 47. TheThe resulting optimal set of parameters shows a good agreement with the experimental data (MSE = 0.07%) predicting LLC volume growth during the first months . The corC coexisting with unstable states A and B. Thus, the model suggests that the natural growth of the tumour results as the evolution towards the state C, which describes a large tumour with well developed vasculature. This dynamic shows a very rapid secretion of the VEGF proteins within few first hours, that is followed by the fast increase of the vessels network  within few first days of the experiment, see The fitted model predicts a single stable state δP and b3 dominate on determining the number of tumour cells N and effective vessel E, whereas m3 and a3 are also important for determining the number of regulating proteins P. It is interesting to point out that the sensitivity of P to different parameters strongly changes during the evolution of the tumour. On the other hand, the analysis shows that K and tumour cell death rate δN are the parameters with less influence i.e. the ones with correlation coefficient in the interval . Including the initial conditions P(0) and E(0) in the sensitivity analysis (N(0) is given by experimental conditions) did not change the sensitivity results (results not shown), suggesting that the results are robust to small perturbations of the initial conditions.The performed sensitivity analyses see  shows thA. For the estimated parameters, the survival of the tumour is determined during the first week when the population of the different species is small , revealing that the increase in the intensity of the noise between days 2 and 4 is the aftermath of the fast vascularisation predicted during the first days of the tumour growth.A close analysis of the first days of the tumour growth shows that the noise has almost no influence on the dynamics of the model during the first two days see . At the C). Nevertheless, a further analysis on the dependence of the steady states with biological meaningful changes in the parameters shows that new steady states Ci can arise, for details see For the parameters inferred, there is only one stable state , a humanised monoclonal antibody, that binds the vascular endothelial growth factor A (VEGF-A) and thus inhibits VEGF-A binding to receptors on the surface of endothelial cells, effectively increasing δP.This is the case of VEGF degradation δP reveals that for higher values of δP new stable states Ci arise. Concretely, over a threshold δPcr,1 ≃ 160 day−1 two stable steady C1, C3 coexist  is of order 10−4, that is around nine orders of magnitude lower than the one for the untreated value of δP = 8.9 day−1, preventing active support of the cancer cells in nutrients and in turn also preventing the fast tumour growth , the tumour reaches an avascular state (vicinity of state B) or the tumour evolves towards a discrete set of tumour morphologies (states Ci). This kind of behaviour is not observed in a family of classical Hahnfeldt et al. [In this paper we have investigated the microscopic foundations of the types of model of tumour angiogenesis proposed in , 20 and t et al.  angiogent et al. , there cN, P, 0) or the spontaneous death of the tumour.The microscopic description opens the door to the study of the fluctuations intrinsic to reactive systems. This stochasticity allows the transition between the different tumour steady states, providing new behaviours such as reaching the avascular absorbing set of states . Moreover, we hope that the general description of the model makes the analysis easily transferable to other types of cancer motivating the use of experimental data in, otherwise, purely theoretical models.S1 TextTheorems and proofs concerning the existence, uniqueness, boundedness of the solutions; as well as the existence of the positive steady states and conditions for the stability of the steady states for the macroscopic model.(PDF)Click here for additional data file.S2 TextDetailed information and results of the sensitivity analysis of the estimated parameters in (PDF)Click here for additional data file.S1 FigN* tumour cells at different times. Results correspond with same parameters used in Histogram showing the probability per trajectory of having (EPS)Click here for additional data file.S2 FigN* tumour cells at different times. Results correspond with the same parameters used in N = V = P = 0 (cyan).Histogram showing the probability per trajectory of having (EPS)Click here for additional data file.


To report on a case of bilateral retrobulbar optic neuritis in a patient with acquired immune deficiency syndrome (AIDS) caused by varicella-zoster virus (VZV); and to review the literature focusing on: cases reported, epidemiology, pathophysiology, diagnosis and treatment.A 38-year-old woman with AIDS presented with a 10-day history of progressive bilateral visual loss and ocular pain. She had bilateral dilated pupils with no light perception; the fundoscopic examination was normal. Facial herpes zoster lesions appeared on the second day of hospitalization Magnetic resonance imaging (MRI) findings were compatible with a bilateral optic neuritis; the cerebrospinal fluid (CSF) showed pleocytosis, increased proteins and a positive VZV-DNA PCR. She was treated with intravenous acyclovir and corticosteroids and was able, when discharged 2 weeks after admission, to carry out activities of daily living.VZV retrobulbar optic neuritis has previously been reported in 12 patients with AIDS, more than half of the cases had concomitant herpes zoster and an associated retinopathy. A positive VZV-DNA in the CSF is indicative of VZV infection, initial use of intravenous acyclovir is recommended, and the concomitant use of corticosteroids would be a prudent choice; the duration of antiviral therapy remains undefined.VZV retrobulbar optic neuritis in AIDS patients can occur with or without herpes zoster. It is a sight-threatening infectious and inflammatory process requiring the advice of specialists in infectious diseases, ophthalmology, neurology and viral microbiology. VZV is a highly communicable herpesvirus and in the prevaccine era serologic evidence of previous infection was present in 90% of persons by the age of 15 .Herpes zoster ophthalmicus affects the ophthalmic division of the trigeminal nerve, is associated with severe complications and the risk for human immunodeficiency virus (HIV) positive patients is 6.6 higher . The ocuA 38-year-old woman was transferred to our hospital because of decreased visual acuity, with inability to perceive light in both eyes. She had a history of headache, ocular pain and blurred vision in both eyes for 10 days, the visual acuity decreased progressively, two days before admission she required assistance to walk and on the day of admission she was unable to perceive light. She had a history of untreated HIV infection for 7 years; her absolute CD4 cell count was 15 cells/uL and serum HIV RNA level was 169,000 copies/uL.2O. The CSF was clear with 16 white blood cells/uL, 14 neutrophils and 2 lymphocytes, normal glucose level and protein level of 74 mg/dL. Results of VDRL, cryptococcus antigen, acid-fast and Gram stains were negative.The physical examination was remarkable for underweight with a body mass index of 18 kg/m2, temporal wasting and oral thrush. She had dilated pupils with no light perception bilaterally, eye movements were normal but painful. The corneas and fundoscopic examination were normal. The rest of the physical exam, including a detailed neurologic examination, was normal. CT scan of the brain with contrast showed mild brain atrophy. Initial lumbar puncture disclosed an opening pressure of 34 cm HOne day after admission, a vesicular rash was noted on the left side of her face involving the lips, bridge of the nose, and eyelids. Acyclovir 10 mg/kg intravenously every eight hours and prednisone 1 mg/kg were started. MRI with gadolinium of the brain and optic nerves showed diffuse bilateral enhancement of the optic nerves.Mycobacterium tuberculosis, Epstein-Barr virus, herpes simplex virus 1 and 2, cytomegalovirus and John Cunningham polyomavirus were negative, VZV-DNA PCR was positive. Cultures for viruses, fungi, bacteria and mycobacteria remained negative.The results of CSF PCR reaction for One week after admission the patient was no longer requiring opiate analgesics for the headache, there was light perception and a second lumbar puncture showed: normalization of the opening pressure, no cells, normal glucose level, total protein level of 49 mg/dL and the DNA PCR for VZV was still positive. The patient's vesicular rash resolved in 10 days.The patient was discharged 2 weeks after admission on oral acyclovir. She was able to carry out activities of daily living without assistance. She did not returned to the outpatient clinic for follow up.We have presented the case of a woman with AIDS in whom bilateral retrobulbar optic neuritis developed as a result of VZV infection. We discuss below the epidemiology, pathophysiology, diagnosis and treatment.Alphaherpesviridae [In 1943 Ruska reported the VZV in electron microscopic studies of chickenpox vesicle fluids, ten years later Weller induced similar cytopathic changes from vesicular fluids of chickenpox and shingles in culture . VZV is zoster sine herpete [Herpes zoster usually presents as a painful cutaneous vesicular eruption in a dermatomal distribution and the cranial nerve dermatomes are involved in 20%-25% of cases . However herpete . The oph herpete . Optic n herpete .The risk of herpes zoster is higher in HIV-seropositive patients, a cohort study on homosexual men, 287 HIV-seropositive and 499 HIV-seronegative showed an incidence of 29.4 cases/1000 person-years and 2 cases/1000 person-years, respectively . VZV retThe histopathology of VZV optic neuritis shows demyelination with mononuclear cell infiltration and intranuclear inclusions ,17,18. NOptic neuritis usually presents with headache and/or eye pain followed by a variable degree of visual loss (scotoma) affecting mainly central vision. An afferent pupillary defect is present if the lesion is unilateral or asymmetric and the fundoscopic examination shows absence of optic disc involvement in retrobulbar optic neuritis. The differential diagnosis of optic neuropathy in AIDS patients includes: central nervous system lymphoma, cryptococcus, cytomegalovirus, hepatitis B virus, histoplasmosis, HIV itself, syphilis and VZV ,14.The twelve HIV-seropositive cases with VZV retrobulbar optic neuritis reported in the literature had AIDS -14, in 5VZV retrobulbar optic neuritis may precede a necrotizing retinopathy ,17; it mHerpes zoster can usually be diagnosed clinically, when the diagnosis is uncertain, swabs from a fresh lesion or tissue biopsy, can be submitted for culture, direct fluorescent antibody or PCR . In the A positive CSF analysis for VZV-DNA PCR or anti-VZV IgG is consistent with VZV infection of the central nervous system , in the Intravenous acyclovir remains the treatment of choice in immunosuppressed patients with VZV neurological complications ,2,15,17.Intravenous foscarnet is recommended to treat patients with proven or suspected acyclovir-resistant VZV . IntraveBecause initiation of antiretroviral therapy (ART) has been associated with VZV mediated vasculitis in the context of central nervous system – immune reconstitution inflammatory syndrome  and becaRetrobulbar optic neuritis caused by VZV is a rare presentation in immunocompromised and immunocompetent patients, in HIV-seropositive patients have been reported exclusively in patients with AIDS; we believe that our case is the thirteenth reported. Retinopathy was documented on admission or during the course of the disease in the majority of patients and retinal detachment is a common complication.VZV retrobulbar optic neuritis can occur with or without herpes zoster lesions. Diagnosis and management are challenging and requires the involvement, at an early stage, of specialists in infectious diseases, ophthalmology, neurology and viral microbiology.The optimal treatment has not been defined. Because the optic neuritis is sight-threatening and the histopathology demonstrates inflammatory infiltrates, it seems reasonable to use intravenous acyclovir and corticosteroids initially.It seems prudent to delay initiation of ART because it has been associated with VZV neurological complications and an increased risk of herpes zoster.Written informed consent was obtained from the patient for publication of this case report, personal identifiers were not included.


The Funding statement is incorrect. The publisher apologizes for the error. The complete, correct Funding statement is: This work has been supported partially by a grant from Fundación de Investigación Médica Mutua Madrileña (ref number AP27072008), a grant from Universidad Europea de Madrid (project number 2013/UEM31) and by the help of Cátedra Florencio Tejerina-UEM in blood sample collection. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Acute viral (RSV and non-RSV) pneumonia is one of the most common causes of lower respiratory tract infection in infants and children. Although only 2 to 3% of infants with bronchiolitis require hospitalized management based on published literature, in recent years we see more children requiring hospitalization in high-dependency units. Most of these children require intravenous fluid therapy and some form of oxygen supplementation. As there is no standardized evidence-based parenteral fluid therapy protocol specific for acute severe viral pneumonia available, we decided to retrospectively analyze the result of our restrictive fluid therapy protocol.All children less than 5 years age admitted to our PICU from June 2013 to December 2013 with etiological evaluation confirmed acute severe viral (RSV and non-RSV) pneumonia who received a minimum 48 hours of parenteral fluid therapy were enrolled and the data retrieved from the case sheet. The data analyzed were duration of PICU stay, hospital stay, oxygen therapy requirement, duration of oxygen therapy and their relationship to fluid balance on restrictive fluid regimen.P = 0.45) or the duration of ventilation (P = 0.60). Fluid balance in the first 72 hours correlated positively with change in serum sodium levels indicating a fall in sodium levels with more positive fluid balance (Spearman coefficient of 0.452 (P = 0.16)). There was no significant correlation between fluid balance and duration of PICU/hospital stay (P = 0.58/0.75). eGFR calculated using modified Schwartz formula did not correlate with treatment parameters like duration of ICU/hospital stay, mechanical ventilation, and CPAP.A total of 32 children met the criteria for inclusion in the study period, 23 boys (71.9%) and nine girls (28.1%). The median age of children was 9.5 months (IQR 3.3 to 27.3). Of 32 children, 4/32 (12.5%) required invasive mechanical ventilation; 5/32 (15.6%) required NP-CPAP; 12/32 (37.5%) were on HHFNC; and nasal prong oxygen supplementation in 26 (81.3%) children. The median duration of ICU stay was 68.9 hours (IQR 39.2 to 80.2), that of hospital stay was 116.5 (IQR 92 to 179.2). Fluid balance at the end of 72 hours of ICU stay did not significantly differ the need for ventilation  parenteral fluid therapy. eGFR at admission did not influence the fluid balance when they were uniformly initiated on restrictive parenteral fluids. Further studies with calculated sample size may help to confirm the observations.