Breast cancer has overtaken lung cancer as the most commonly diagnosed malignancy and is the leading cause of cancer-related death in women. Surgery is the only possible cure for breast cancer, and the incidence of acute postoperative pain (APP) is high in breast surgery. Previous reports suggested that ultrasound-guided deep serratus anterior plane block (dSAPB) provided effective blockade to relieve pain after modified radical mastectomy for breast cancer. In fact, despite the long-acting local anesthetic agents used, the patient’s pain cannot completely be eliminated due to the short duration of anesthesia. Dexmedetomidine as an adjunct to local anesthetics can prolong peripheral nerve block duration. However, no study has investigated the role of dSAPB with dexmedetomidine in the quality of recovery scores undergoing modified radical mastectomy. Thus, this study was conducted aiming at this aspect.This single-center, double-blind, randomized clinical trial was conducted at Bethune International Peace Hospital. A total of 88 participants of elective modified radical mastectomy were enrolled from May and November 2021. Ultrasound-guided dSAPB combined with 30 ml of 0.375% ropivacaine or 30 ml of 0.375% ropivacaine with dexmedetomidine (1 μg/kg) was administrated before anesthesia at the fourth to fifth ribs of the axillary midline. The primary outcome was quality of recovery, measured 24 h postoperatively using the QoR-15. Secondary outcomes were the Visual Analogue Scale (VAS) scores at rest and movement at 1, 6, 12, 24, and 48 h after surgery, 48 h sufentanil consumption postoperatively, the incidence of postoperative nausea and vomiting (PONV), length of post-anesthesia care unit (PACU) stay, dizziness, delirium, SAPB-related adverse events, and patient’s satisfaction with pain management.Among the 88 participants, 8 did not meet the inclusion criteria; the other 80 were randomized to receive dSAPB combined with ropivacaine  and dSAPB combined with ropivacaine plus DEX , of which a total of 7 (4 in Group R and 3 in Group RD) were excluded due to protocol deviation. Eventually,73 participants (36 in Group R and 37 in Group RD) were included for final analysis, with age , body mass index (BMI) , and median preoperative global QoR-15 score (interquartile range (IQR), 127[123.25–131] vs. 126[121–130], p=0.662). The median postoperative global QoR-15 score , VAS score at rest at 12th hour , VAS score in movement at 12th hour  and at 24th hour , and median sufentanil rescues consumption  of Group RD were significantly higher than those of the Group R.The ultrasound-guided dSAPB combined with dexmedetomidine plus ropivacaine may improve the QoR-15 in patients undergoing modified radical mastectomy and indicates that it may be a useful intervention to aid recovery following breast cancer surgery. Furthermore, participants in the ropivacaine with DEX group met the superior pain relief in the early postoperative period, reduced postoperative cumulative opioid consumption, increased patient satisfaction, and no increase in the incidence of complications. Breast cancer has overtaken lung cancer as the most commonly diagnosed malignancy and is the leading cause of cancer-related death in women , 2. DuriThe incidence of acute postoperative pain (APP) is high in breast surgery, and opioids are the most commonly used drugs to treat APP. However, they are not without systemic side effects, which may increase comorbidities . AlthougThere are some local or regional nerve blocks in breast cancer performed as core components of multimodal analgesia and enhanced recovery after surgery (ERAS) , includi2 and American Society of Anesthesiologists (ASA) I–II who were scheduled for modified radical mastectomy for breast cancer between May and November 2021 were included in this study. The exclusion criteria included a history of allergy to any trial drugs, presence of coagulation disorders, infection at the nerve block puncture site, ingestion of any analgesic drug within 48 h before surgery, history of chronic pain medication use, trauma or history of thoracic spine surgery, sinus bradycardia, and atrioventricular block and any other conditions that were not appropriate for this study.The study was a prospective, single-center, parallel-group, randomized, double-blind clinical trial, approved by the ethics committee of Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China (2021-KY-128), and registered in the Chinese Clinical Trial Registry (ChiCTR2100045264). This study followed the Consolidated Standards of Reporting Trials (CONSORT) statement and principles of the Declaration of Helsinki. One day before surgery, all patients were evaluated and signed written informed consent to participate in the trial. A total of 88 female patients aged 33–65 years with BMI ≤30 kg/mThe study participants were using a computer-generated list of random numbers, randomly grouped on a scale of 1:1. The distribution results were sealed in an opaque envelope and kept by the study manager. On the surgical day, the study administrator handed the envelope to the anesthesia assistant who dispensed the anesthetic fluid. The patients were randomly assigned to two groups: the ropivacaine group (Group R) and the ropivacaine plus dexmedetomidine group (Group RD), with 36 patients in each group. An indwelling intravenous needle and noninvasive blood pressure, electrocardiogram, oxygen saturation, and Bispectral index were monitored to the patient who entered the operating room. Before the nerve block, all patients received intravenous 1 μg/kg of dexmedetomidine for 10 min, and 5 ml of 0.9% isotonic saline was prepared for positioning. The anesthesia assistant prepared a total of 30 ml of 0.375% ropivacaine or 30 ml of 0.375% ropivacaine with dexmedetomidine (1 μg/kg). The assistant handed the syringe filled with the potion to the anesthesiologist, who has mastered the anesthesia but did not know which group the patient belongs to. Thus, group assignments were blinded by patients, healthcare providers (anesthesiologists who performed SAPB and were responsible for intraoperative care and surgeons), and data collectors.After patients entered the operating room and received intravenous dexmedetomidine of 1 μg/kg for 10 min, the patient was placed in the lateral decubitus position, facing upward, with the patient’s independent arm comfortably resting above the head, exposing the lateral chest wall. A 6–13-MHz linear array ultrasonic sensor probe  identified the fourth to fifth ribs of the axillary midline. Intercostal muscles between the ribs and the serratus anterior muscles and the latissimus dorsi muscles on the surface of the ribs were identified. The thoracic dorsal artery is also identified as an additional anatomical marker to identify the serratus anterior superficial plane. The skin at the needle insertion site was sterilized with 1% iodophor, and 1% lidocaine was used for local anesthesia where block needles enter into the skin. Under the guidance of continuous ultrasound, a short inclined non-stimulating puncture needle  was inserted through the skin wound, and the needle was pushed with saline until the puncture tip was on the appropriate plane; then, ropivacaine with or without dexmedetomidine was deposited and adequately spread in schedule, respectively, and confirmed by direct ultrasound visualization.2) between 35 and 45 mmHg. At the end of the surgery, if necessary, 1 mg of neostigmine and 0.5 mg of atropine were antagonized with neuromuscular blockers. After the LMA was removed, the patients were transferred to the post-anesthesia care unit (PACU) for observation. The postoperative analgesic regimen consisted of routine intravenous administration of 50 mg of flurbiprofen every 12 h and patient-controlled intravenous analgesia (PCIA) accompanied by sufentanil (PCIA), which was set to deliver a bolus dose of 4 μg sufentanil (2 μg/ml) on-demand, with a lockout interval of 15 min and without basal infusion. Postoperative pain was assessed using a Visual Analogue Scale (VAS) on a scale of 0 (no pain) to 10 (the worst pain imaginable). If the VAS pain score exceeded 3 or the patient required, intravenous 2 μg of sufentanil was administered as a rescue analgesic by using the PCIA device. Five milligrams of tropisetron and 10 mg of metoclopramide were administered intravenously, if postoperative nausea or vomiting occurred, as rescue antiemetics.Standardized general anesthesia regimens for all patients. After a 3-min preoxygenation, general anesthesia was induced with 0.1 mg/kg of dezocine, 2 mg/kg of etomidate, 2 mg/kg of propofol, and 0.4 μg/kg of sufentanil intravenously after the nerve block was completed. Upon loss of consciousness, 0.6 mg/kg of rocuronium was used for laryngeal mask airway (LMA) placement. All patients were given 10 mg of dexamethasone and 5 mg of tropisetron immediately after induction of anesthesia. To maintain anesthesia in the patients, 4–6 mg/kg of propofol and 0.1–1 μg/kg of remifentanil were used; 0.2 mg/kg rocuronium was maintained for 40–60 min intraoperatively. Sufentanil (0.1 μg/kg) was intravenously injected when the patient’s hemodynamic parameters exceeded 20% of the baseline. Patients were given 0.25 mg of atropine at a heart rate below 50 beats/min. The bispectral index system value during anesthesia maintenance was between 40 and 60. Pressure-controlled ventilation was used to maintain end-tide partial pressure of carbon dioxide , length of PACU stay, dizziness, delirium, SAPB-related adverse events, and patient’s satisfaction with pain management. The interval as PACU admission to the Aldrete score reaching 9 was defined as the length of PACU stays . PatientThe sample size was calculated based on global QoR-15 points 24 h after surgery. A change of 8.0 on the QoR-15 score was considered as a clinically significant improvement in QoR after surgery and anesthesia . Accordi2-test. Fisher’s precise test was used to compare rates of dizziness or delirium between groups. In addition, analysis of variance was performed on multiple comparisons to assess pain scores within 24 h after surgery. A p-value <0.05 was considered statistically significant in the two-sided test.All statistical analyses were performed using IBM SPSS software Version.23.0 . The normality of quantitative variables was examined with the Kolmogorov–Smirnov test. Quantitative variables are expressed as mean or median (IQR). Student’s t-test was used to compare the mean values of age, weight, height, operation time, and PACU discharge time. The overall QoR-15 score and the cumulative use of sufentanil after surgery are reported as the median (interquartile range [IQR]) and were analyzed using the Mann–Whitney U-test. A 95% CI of differences was given for each statistical comparison. Categorical variables were reported as numbers and percentages. The proportion of ASA classification and the number of PONV patients were compared by χThe CONSORT 2010 flowchart is shown in The global QoR-15 scores are shown in Preoperative dSAPB administration of 0.375% ropivacaine with DEX reduced acute VAS pain scores at rest at 12th hour, exercise at 12th and 24th hour after surgery (both p < 0.05, As shown in Consistent with the recent focus on functional recovery, rather than simply measures of postoperative opioid consumption and pain scores . Our stuRecovery after surgery and anesthesia is a multidimensional, inter-related, and complex process that involves many areas beyond the scope of postoperative pain . QoR-15 Dexmedetomidine has an anti-sympathetic effect that activates the vagus nerve and reduces plasma catecholamine levels, thereby providing stable hemodynamics. The analgesic effect of dexmedetomidine is the result of multiple mechanisms. A previous study suggested that the addition of dexmedetomidine to ropivacaine for sciatic nerve block in rats not only prolonged the duration of sensory and motor block of the sciatic nerve but also markedly alleviated ropivacaine−induced neurotoxicity by decreasing caspase−3−dependent sciatic nerve cell apoptosis . IntrathThe analgesic effect of postoperative single nerve block remains to be further elucidated due to the unsatisfactory and difficult management of indignant peripheral nerve catheter . RopivacReducing perioperative opioid use is one of the current goals of enhanced recovery after surgery, which aims to reduce potential opioid-related side effects. Regional nerve block plays an important role in opioid reduction. In this study, dexmedetomidine combined with ropivacaine can reduce the postoperative dosage of sufentanil and improve patient satisfaction. Previous reports indicate that dexmedetomidine combined with a paravertebral block was found to reduce opioid dosage during thoracoscopic surgery . ParaspiFirst, despite the results showing a statistically significant difference in postoperative QoR-15 scores between the two groups, the difference was not clinically significant. More patient enrollment is needed to reduce this bias. Second, this study is a single-center randomized controlled study, which requires more centers and more cases to verify our conclusions. Third, we did not investigate the different doses of dexmedetomidine on the intrathecal ropivacaine for modified radical mastectomy. Fourth, the study also did not evaluate preoperative skin diffusion of the blocker as a proxy for analgesic efficacy. Fifth, we did not regulate the postoperative pain management of patients after discharge from the hospital. With focusing on short-term pain, we also need to focus on chronic pain in patients. The last but not least, some confounding factors, such as environment, anxiety, stress, and post-traumatic stress disorder, may affect the resolution of postoperative pain. We did not include all confounding factors affecting postoperative pain, and further relevant studies are needed.In conclusion, under the conditions of the present study, the ultrasound-guided deep serratus anterior plane block combined with dexmedetomidine plus ropivacaine may improve the QoR-15 with ropivacaine alone in patients undergoing modified radical mastectomy and indicate that it may be a useful intervention to aid recovery following breast cancer surgery. Furthermore, participants in the ropivacaine with DEX group met the superior pain relief in the early postoperative period, reduced the postoperative cumulative opioid consumption, and increased patient satisfaction, and there was no increase in the incidence of complications.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the ethics committee of Bethune International Peace Hospital. The patients/participants provided their written informed consent to participate in this study.YW was involved in the conception and design of the study. YK collected the data. YL prepared the placebo tablets. BF analyzed the data. YW drafted the first and final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: The prognostic significance of pulmonary venous (PV) flow reversal in degenerative mitral regurgitation (dMR) is not well-established. Objective: We aimed to assess whether reversed PV flow is associated with adverse outcomes in patients with significant dMR. Methods: We retrospectively analyzed consecutive patients referred to a tertiary center for evaluation of dMR of greater than moderate degree, who had normal sinus rhythm, had a left ventricular ejection fraction of above 60%, and did not suffer from any other major valvular disorders. The primary outcome was the combined rate of all-cause mortality, mitral intervention, or new-onset atrial fibrillation (AF) at 5 years following index echocardiogram. Secondary outcomes included individual components of the primary outcome. Results: Overall, 135 patients  years; 93 (68.9%) males; 89 (65.9%) with severe MR) met the inclusion criteria and were followed for 115.2  months. Patients with a reversed PV flow pattern (PVFP) (n = 34) more often presented with severe MR compared to those with a normal (n = 49) and non-reversed PVFP (n = 101) . At 5 years, they experienced the highest cumulative incidence of the primary outcome . Furthermore, a reversed PVFP was independently associated with a higher risk of the primary outcome compared to normal PVFP  and non-reversed PVFP . Conclusion: PV flow reversal is associated with a worse 5-year composite of mortality, mitral intervention, or AF in patients with significant dMR. Degenerative mitral regurgitation (dMR) is the second-most common form of chronic mitral regurgitation (MR) in developed nations . AffectiThis is a single-center, retrospective analysis of consecutive patients with dMR of greater than moderate grade who were referred to transesophageal echocardiography (TEE) at Rabin Medical Center (RMC), Israel, between May 1995 and June 2017.Inclusion criteria comprised the following: 1. absence of documented AF or flutter prior to the TEE; 2. normal left ventricular (LV) systolic function, defined as an LV ejection fraction (LVEF) of above 60% on the transthoracic echocardiogram (TTE) part of the index examination; and 3. an isolated degenerative mitral pathology not accompanied by other valvular disorders of greater than mild-to-moderate grade. Patients that underwent any previous valvular intervention, as well as those without complete baseline data  were excluded. Follow-up duration spanned the timeframe between the date of echocardiogram and either death or 30 April 2020.The primary outcome was defined as the composite of all-cause mortality, any form of invasive mitral intervention, and new-onset AF or flutter during the first 5 years of follow-up, excluding arrhythmic events in the first post-interventional month. Secondary outcomes included single components of the primary outcome.Data regarding endpoints were retrieved using Ofek Software , which is a web-based medical chart platform shared by most of Israel’s public medical providers. Atrial arrythmias were ascertained by inspecting patient files for any mention of obvious AF or flutter on a 12-lead electrocardiogram (ECG) and/or an irregular ventricular electrical activity without discernible P waves on a 30-s strip .The study was conducted in accordance with the Declaration of Helsinki and received Institutional Review Board (IRB) approval. The requirement for informed consent was waived due to the study’s retrospective nature.All echocardiograms were performed and interpreted by level-III-trained sonographers and echocardiologists. Echo systems used included Vivid 3 Premium and Vivid E95 , Agilent 5500 , HP 77020 , and IE33 and EPIQ . Diagnostic measurements and conclusions made at each study were based on criteria set forth by the relevant American Society of Echocardiography guidelines ,9. MitraThe study cohort was split into three main groups according to baseline PVFP, namely normal, reversed, and non-reversed, with the latter comprising patients exhibiting either normal or blunted flow patterns in the PVs. In each group, continuous variables were expressed as means and standard deviations (SDs) or as medians and interquartile ranges (IQRs). Categorical variables were reported as frequencies and percentages. Between-group comparison of continuous variables with normal distribution was performed using Student’s t test, while that of continuous variables demonstrating non-normal distribution was performed using the Mann–Whitney U test. Categorical variables were compared using Pearson’s chi-squared test or Fisher’s exact test. Importantly, only two groups were compared at a time.p-value of <0.1 were integrated into a multivariable model.The risk for the development of the primary outcome according to PVFP was graphically displayed using the Kaplan–Meier method, with comparisons of cumulative survival across strata conducted using the log rank test. To identify independent associations between the primary outcome and baseline variables, particularly different forms of PVFP, univariable Cox regression analysis was employed, after which parameters showing a p-value of <0.05 was considered to represent statistical significance. All analyses were performed using SPSSTM Statistic for Windows software, version 24 .Patients with missing data were censored from the relevant analyses. A two-sided Out of 485 patients that underwent TEE for an evaluation of chronic dMR at RMC between May 1995 and June 2017, a total of 135 met the study inclusion criteria . The medBaseline clinical and echocardiographic characteristics of the study cohort are presented in p < 0.001).Overall, 49 (36.3%) patients exhibited a normal flow pattern in the PVs on both sides and 86 (63.7%) patients had an abnormal PVFP on at least one side. Among the latter, 34 (25.2%) were diagnosed with a reversed PVFP and 52 (38.5%) had a blunted PVFP. The proportion of PV flow reversal was considerably higher among individuals with severe MR compared to those with moderate-to-severe MR  patients died, 87 (64.4%) underwent mitral intervention, and 22 (16.3%) developed AF or flutter . Intervep = 0.004 and p = 0.018, respectively). This was reflected in significantly shorter event-free survival durations within the reversed PVFP group  (p = 0.022). By contrast, patients with PV flow blunting experienced a non-statistically higher rate of the primary outcome compared to that of patients with a normal PVFP   patients and proved significantly more frequent in those with reversed PVFP at baseline  . Notably= 0.137) .p = 0.011) and non-reversed PVFP .According to a Cox proportional hazard model, presented in Of the secondary outcomes, mitral interventions (but not deaths and AF or flutter) occurred earlier and more frequently during 5 years of follow-up in patients with reversed PVFP compared to patients with normal or non-reversed PVFP . After mOur study examined the prognostic utility of PV flow reversal, as observed on TEE, in patients with significant dMR, normal LV systolic function, and normal sinus rhythm. Based on a retrospective, single-center analysis of 135 consecutive cases, we observed the following: 1. a reversed PVFP was evident in approximately one-quarter of the cohort and among almost all patients with severe MR; 2. its presence was associated with a more severe MR and a higher pulmonary arterial pressure, as well as with a lower functional status at baseline; 3. patients with PV flow reversal experienced a higher cumulative incidence of deaths, mitral interventions, or new-onset AF during 5 years of follow-up compared to those with either normal, non-reversed, or blunted PV flow patterns; and 4. PV flow reversal independently predicted a higher risk for mitral interventions and the composite of the three separate endpoints, more than doubling the risk for both compared to normal and non-reversed PVFP.As a surrogate of altered LA hemodynamics , abnormaIn line with prior studies that have linked a reversed PV flow with severe MR , a largeOn a final note, our findings may have therapeutic implications, particularly among dMR patients who do not fulfill current practice guideline criteria for intervention ,21. As mA single-center, retrospective design may undermine the external validity of the study results. Nevertheless, we employed the largest cohort to date of significant dMR patients with normal LV function and sinus rhythm that were specifically assessed for PVFP. Moreover, baseline patient characteristics were apparently comparable to those presented by previous reports of dMR populations  and echoIn our single-center experience, patients with significant dMR, normal LV systolic function, and normal sinus rhythm experienced earlier, more frequent composite events of death, mitral intervention, or new-onset AF at 5 years when faced with a reversed PVFP. Furthermore, PV flow reversal was independently associated with more than twice the risk for the composite outcome compared to normal and non-reversed flow patterns, regardless of MR severity, LA diameter, or pulmonary arterial systolic pressure.


Patients with precursors to multiple myeloma are dichotomised as having monoclonal gammopathy of undetermined significance or smouldering multiple myeloma on the basis of monoclonal protein concentrations or bone marrow plasma cell percentage. Current risk stratifications use laboratory measurements at diagnosis and do not incorporate time-varying biomarkers. Our goal was to develop a monoclonal gammopathy of undetermined significance and smouldering multiple myeloma stratification algorithm that utilised accessible, time-varying biomarkers to model risk of progression to multiple myeloma.In this retrospective, multicohort study, we included patients who were 18 years or older with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma. We evaluated several modelling approaches for predicting disease progression to multiple myeloma using a training cohort . We created the PANGEA models, which used data on biomarkers  and haemoglobin trajectories from medical records to predict progression from precursor disease to multiple myeloma. The models were validated in two independent validation cohorts from National and Kapodistrian University of Athens , University College London , and Registry of Monoclonal Gammopathies . We compared the PANGEA models (with bone marrow [BM] data and without bone marrow [no BM] data) to current criteria .We included 6441 patients, 4931 (77%) with monoclonal gammopathy of undetermined significance and 1510 (23%) with smouldering multiple myeloma. 3430 (53%) of 6441 participants were female. The PANGEA model (BM) improved prediction of progression from smouldering multiple myeloma to multiple myeloma compared with the 20/2/20 model, with a C-statistic increase from 0·533 (0·480–0·709) to 0·756 (0·629–0·785) at patient visit 1 to the clinic, 0·613 (0·504–0·704) to 0·720 (0·592–0·775) at visit 2, and 0·637 (0·386–0·841) to 0·756 (0·547–0·830) at visit three in validation cohort 1. The PANGEA model (no BM) improved prediction of smouldering multiple myeloma progression to multiple myeloma compared with the 20/2/20 model with a C-statistic increase from 0·534 (0·501–0·672) to 0·692 (0·614–0·736) at visit 1, 0·573 (0·518–0·647) to 0·693 (0·605–0·734) at visit 2, and 0·560 (0·497–0·645) to 0·692 (0·570–0·708) at visit 3 in validation cohort 1. The PANGEA models improved prediction of monoclonal gammopathy of undetermined significance progression to multiple myeloma compared with the IMWG rolling model at visit 1 in validation cohort 2, with C-statistics increases from 0·640 (0·518–0·718) to 0·729 (0·643–0·941) for the PANGEA model (BM) and 0·670 (0·523–0·729) to 0·879 (0·586–0·938) for the PANGEA model (no BM).Use of the PANGEA models in clinical practice will allow patients with precursor disease to receive more accurate measures of their risk of progression to multiple myeloma, thus prompting for more appropriate treatment strategies.SU2C Dream Team and Cancer Research UK. Evidence before this studyPrediction models are used to predict future outcomes through the analysis of large datasets. We searched for evidence of time-varying prediction models in precursor disease through PubMed, Google Scholar, and MEDLINE from database inception to April 31, 2022, in the English language. Terms included in this search were “monoclonal gammopathy of undetermined significance”, “MGUS”, “smoldering multiple myeloma”, “SMM”, “multiple myeloma”, “progression”, “prediction”, and “modeling”. Results included primarily analyses of current standard risk criteria for precursor disease progression. There were no prediction models that used multivariable, time-varying biomarkers to predict the risk of precursor disease progression to multiple myeloma.Added value of this studyThe PANGEA project is, to our knowledge, the largest international project of time-varying biomarker data on patients with precursors to multiple myeloma. Our findings show that the PANGEA models are more accurate than current precursor progression risk criteria including the International Myeloma Working Group (IMWG) risk stratification for monoclonal gammopathy of undetermined significance and the 20/2/20 risk stratification for smouldering multiple myeloma. These accuracy improvements were also demonstrated in large, independent validation cohorts.Implications of all the available evidenceThe improved accuracy of the PANGEA models over current risk criteria suggests that models that incorporate dynamic measurements of myeloma-specific parameters can improve clinician's ability to make therapeutic decisions for individual patients. The PANGEA models can be directly accessed in clinic and are appropriate replacements of the IMWG risk stratification criteria for patients with monoclonal gammopathy of undetermined significance and 20/2/20 risk criteria for patients with smouldering multiple myeloma.Multiple myeloma is often preceded by two precursor conditions, monoclonal gammopathy of undetermined significance and smouldering multiple myeloma, with current diagnostic criteria differentiating these from symptomatic multiple myeloma,Current risk stratification criteria are also limited by variation in the availability and measurement of bone marrow biomarkers. Smouldering multiple myeloma progression risk is often estimated using BMPC%, and the arbitrary cutoff of 10% BMPC is used to dichotomise monoclonal gammopathy of undetermined significance and smouldering multiple myeloma. However, the use of discrete BMPC% categories is limited by heterogeneity of the involved marrow, an absence of early-stage biopsies, and heterogeneous interpretations by pathologists., which uses time-varying clinical biomarkers to model how precursor progression risk to multiple myeloma evolves for a single patient over time, both with and without bone marrow biopsies. We assembled a cohort of patients with monoclonal gammopathy of undetermined significance and patients with smouldering multiple myeloma with serial laboratory measurements and we developed multivariate Cox models with time-varying patient profiles to predict precursor progression to multiple myeloma. Our hypothesis is that disease progression from monoclonal gammopathy of undetermined significance or smouldering multiple myeloma to overt multiple myeloma can be anticipated by trends in clinical values that are associated with clonal proliferation and that modelling these changes can improve predictions of progression risk. We strove to develop models with commonly available biomarkers to allow for broad clinical application, and we validated these models in two independent cohorts. This validation illustrates that both PANGEA models (with [BM] and without bone marrow biopsy [no BM]) outperform the prediction accuracy of previous models in multiple cohorts. Finally, we provide an online calculator implementing the PANGEA model that allows clinicians and patients to assess individual risk of progression and consider early therapeutic interceptions.To address this need, we developed the Precursor Asymptomatic Neoplasms by Group Effort Analysis (PANGEA) modelIn this retrospective, multicohort study, we included an international cohort of patients with precursor disease to multiple myeloma with serial clinical and biological variables. Patients were identified retrospectively at oncology centres , and the cancer group Registry of Monoclonal Gammopathies .This study was approved by the DFCI Institutional Review Board (21–127) and done in accordance with the Declaration of Helsinki. Consent was waived due to the non-invasive nature of this research.The PANGEA project included patients with smouldering multiple myeloma and monoclonal gammopathy of undetermined significance within three independent cohorts: the training cohort, which included patients at DFCI ; the validation cohort 1, which included patients at University of Athens  and patients at UCL ; and validation cohort 2, which included patients at RMG  coincided in all cohorts .We retrieved patient information for total protein, IgA via nephelometry, IgM, IgG, κ-free light chain (FLC) and λ-FLC via Optilite , FLC ratio (involved and uninvolved), calcium, creatinine, albumin, haemoglobin, lactate dehydrogenase, β2-microglobulin, M-protein, and bodyweight from medical records. Serial values were annotated on average at 5 (IQR 3–8) month time intervals from the date of monoclonal gammopathy of undetermined significance or smouldering multiple myeloma diagnosis, censoring at the date of progression to active multiple myeloma, last follow-up, initiation of precursor treatment, or death. We also retrieved data on gender, race, ethnicity, age at diagnosis, height, progression, survival status, immunofixation isotype, and bisphosphonate use. For all bone marrow biopsies, plasma cell percentages were collected from core biopsy samples and FISH results from bone marrow aspirates .We built the PANGEA model, a multivariate Cox regression with time-varying biomarkers, by selecting clinically significant predictors of progression  identified using the training cohort. FLC ratio and creatinine concentration were log-transformed to reduce outlier effect. We also evaluated whether biomarker trends correlated with the progression risk and selected decreasing haemoglobin concentration as a categorical trend variable . We compWe developed two versions of the PANGEA model (BM and no BM). Our final Cox model (named the PANGEA model [BM]) included age, FLC ratio, M spike concentration in g/dL, creatinine concentration in mg/dL, BMPC%, and the haemoglobin trajectory variable . We thenPANGEA app outputs a patient's risk of progression using these biomarkers  using the Shiny R package (1.7.1). The resulting The main outcome measure, time to progression, was defined as the time from precursor disease diagnosis per IMWG criteriaWe used bootstrapping and calibration analyses  and SchoThe C-statistic is a standard metric used to compare prediction models. A C-statistic of 0·5 indicates that the model performs no better than random chance and a C-statistic of 1 indicates perfect prediction. For the PANGEA models, we computed C-statistics for visits 1, 2, and 3 for validation cohort 1 and at visit 1 for validation cohort 2. For the baseline models, we fit a Cox model in the training cohort to estimate the hazard ratios (HRs) for risk groups and computed the Cox linear combination of predictor and C-statistics in the validation cohorts. For the rolling models, we fit a time-varying Cox model in the training cohort to estimate HRs and computed the C-statistics at visits 1, 2, and 3 in validation cohort 1. The C-statistic estimates for validation cohort 1 and validation cohort 2 are representative of model accuracy in two cohorts independent from the training cohort used for developing the PANGEA models.To visualise the time to progression for the validation cohorts, we divided patients into quartiles  based on their predicted risk from the PANGEA models. This discretisation is only used when needed for graphical summaries and for comparisons with models that define risk groups. We visualised these groups using Kaplan-Meier curves for time to progression or death (with patients censored at treatment). In these analyses, we included patients who qualified for the PANGEA models by having all necessary biomarker values available at the visit of interest.We explored whether FISH biomarkers could provide additional prediction improvements to the PANGEA model (BM). Due to the frequent absence or failure of FISH testing and the rarity of some cytogenetic alterations, our training cohort was of small size. Therefore, we selected patients with one or more successful FISH panels and corresponding laboratory datasets, resulting in a subcohort of patients . We builThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.The training cohort comprised 1217 patients ; validation cohort 1 comprised 533 patients  at University of Athens and 109 patients with smouldering multiple myeloma (with 31 progressing to multiple myeloma) at UCL; and validation cohort 2 comprised 4582  at RMG . The disVariations in accuracy between the three modelling processes , as measured by C-statistics, were less than 2%. All variables selected for these models were identical except for the PANGEA model (no BM) produced by Bayes information criterion, which incorporated albumin and isotype. We selected the significant predictor model due to its accuracy and succinctness.FLC ratio, M-spike concentration, age, creatinine concentration, BMPC%, and haemoglobin trajectory were used in the PANGEA model BM; . DecreasThe PANGEA model (no BM) included haemoglobin trajectory, FLC ratio, M spike concentration, age, and creatinine concentration as significant progression predictors . Total pThe PANGEA model improved prediction of smouldering multiple myeloma progression to multiple myeloma compared with both 20/2/20 models (baseline and rolling) in validation cohort 1 and validation cohort 2, as indicated by a C-statistic increase of more than 10% . The PANThe PANGEA models outperformed the rolling IMWG model for patients with monoclonal gammopathy of undetermined significance with improvements of 24% (from 0·640 [0·518–0·718] to 0·729 [0·643–0·941]), C-statistics from the PANGEA model (BM), and 31% (from 0·670 [0·523–0·729] to 0·879 [0·586–0·938]) from the PANGEA model (no BM) in validation cohort 2 .The PANGEA models improved output probabilities of progression for individual patients with smouldering multiple myeloma in validation cohort 1 and validation cohort 2 and patients with monoclonal gammopathy of undetermined significance in validation cohort 2  when theMYC rearrangement (8q24) as a significant covariate in a subcohort of 957 patients from the training cohort and validation cohort 1 who were tested for this translocation . The parameters of the PANGEA models are concordant with recent research that found that decreasing haemoglobin is an independent predictor of smouldering multiple myeloma progression to multiple myeloma7A crucial difference between PANGEA and the 20/2/20 risk criteria is that the PANGEA models provide patient-specific probabilities of progression. PANGEA allows for improved prognostication, as validation analyses showed a relative precision improvement over current risk criteria. When models are applied to the same cohort, C-statistics allowed for direct comparison of predictive accuracy. Analysis of the PANGEA model compared with the baseline and rolling 20/2/20 models for patients with smouldering multiple myeloma and the rolling IMWG for patients with monoclonal gammopathy of undetermined significance all showed changes in C-statistic of greater than 10%. This increase in C-statistic was validated by early identification of patients who later progressed to overt multiple myeloma, with 58% of progressors identified as high risk by the PANGEA model and not by the rolling 20/2/20 model . Our comvs smouldering multiple myeloma risk groups) to a granular spectrum of the precursor population at the individual level. Regardless of a patient's bone marrow status, the PANGEA model can be used via the online PANGEA app to easily calculate progression risk of all precursor patients.A crucial goal of this project was to identify the role of bone marrow biopsies in risk prediction. Despite the reliance of current stratification models on BMPC%, many patients with precursors to multiple myeloma do not regularly undergo bone marrow biopsies or forgo them altogether. These patients cannot be adequately assessed by risk criteria that rely on BMPC%. The PANGEA model (no BM) shows that progression risk can be accurately estimated with trends in serum biomarkers. Specifically, both PANGEA models (BM and no BM) outperform the baseline and dynamic models for the IMWG monoclonal gammopathy of undetermined significance and 20/2/20 smouldering multiple myeloma criteria , table 2Genomic and epigenetic factors that lead to multiple myeloma progression are also a crucial part of a patient's progression risk..Together, PANGEA is a three-tiered model , which can take advantage of complex clinical tests or be readily available for patients with few data. FISH and bone marrow biopsies were included in our analysis because we acknowledge that both physicians and patients will continue to request them; however, patients without bone marrow biopsies and FISH results can receive accurate risk predictions with the PANGEA model (no BM) as it also outperforms existing modelsThe PANGEA models are inherently limited by the selected variables and modelling process, our prioritisation for model simplicity and interpretability, and our assumptions on proportional hazards and non-informative censoring. Larger datasets, advanced machine-learning, and extended validation cohorts have the potential to improve accuracy in the future. We plan to evaluate circulating tumour cells, cell-free DNA, immune variables, and other biomarkers to refine risk stratification. We also aim to use prospective cohorts for further validation and we look forward to ethically including more patients with precursors to multiple myeloma who identify as African American—a population with increased prevalence of precursor conditions. The hope is that the PANGEA models dramatically improve how clinicians can inform patients of their personalised risk of developing myeloma and aid decision making for early therapeutic interception, particularly when recommending follow-up testing to monitor time-varying biomarkers. The PANGEA model is freely accessible, using continuous variables available in all clinical settings, enabling its use at both the individual patient level and in clinical trials for the rapid development of therapeutic interventions.The PANGEA team encourages collaboration to further model development. Data from this project can be made available in aggregate and after deidentification to investigators who submit appropriate proposals approved by the study team. Please direct questions to irene_ghobrial@dfci.harvard.edu.This study was previously presented on April 12, 2022, at the 2022 American Association for Cancer Research Annual Meeting and on Aug 25, 2022, at the International Myeloma Society Annual Meeting. AC declares grants from the International Myeloma Society for travel and conference expenses. FF is employed by Biostatistics and Research Decision Sciences, Merck & Co. SSF declares that their salary is partly supported by research funding from International Business Machines (IBM) and has patent applications (EP14807512·0A and US16/084 890) and a provisional patent application (62/866 261). LA declares grants from the International Myeloma Society for travel and conference expenses. JR declares honoraria from Sanofi, Janssen, Amgen, GSK, and Bristol Myers Squibb; travel grants from BMS, Janssen, and Amgen; and funding from a consulting or advisory role from Sanofi, Janssen, Amgen, GSK, and BMS. EK reports honoraria from Amgen, Janssen, Takeda, Genesis Pharma, Pfizer, and GSK; travel grants from Janssen; and is an advisory board member at Janssen and Prothena. MAD declares honoraria from Amgen, BMS, Takeda, and Janssen and is an advisory board member at Amgen, BMS, Takeda, and Janssen. CRM reports research funding from GRAIL. GG declares honoraria for lectures from Society for Neuro-oncology, Society of Tumor Oncology, and MD Anderson; honoraria as a Paul C Zamecnik Chair in Oncology; research funding from IBM and Pharmacyclics; patents, royalties, other intellectual property as Inventor on patent applications related to MSMuTect, MSMutSig, MSIDetect, POLYSOLVER, and SignatureAnalyzer-GPU; and stock and other ownership interests from Founder as a consultant and has privately-held equity in Scorpion Therapeutics. IMG declares honoraria from Celgene, Bristol-Myers Squibb, Takeda, Amgen, Janssen, and Vor Biopharma; consulting or advisory roles at Bristol-Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GSK, AbbVie, Adaptive, and 10xGenomics; and a spouse who is the Chief Medical Officer at Disc Medicine and holds equity in the company. AC, FF, SSF, GG, LT, and IMG have applied for a patent for the application of the PANGEA models described in this paper.


Haglund's syndrome is a posterosuperior calcaneal prominence with posterior heel pain causing functional disability to the patient. Operative treatment is indicated after failure of conservative measures and includes resection of the bony hump along with retrocalcaneal bursectomy. This study aimed to evaluate the functional outcome and degree of patient satisfaction after endoscopic resection of Haglund's deformity with assessment of correlation with the length of bony exostosis. t test and the Wilcoxon signed-rank test compared the preoperative and final postoperative means. P < 0.05 was considered statistically significant.  Seventeen patients (21 feet) with a mean age of 44.7 ± 5.1 years were included in this study. Six females and 11 males underwent endoscopic calcaneoplasty. Clinical outcome evaluation included the assessment of the visual analog scale (VAS) and the American Orthopedic Foot and Ankle Society score (AOFAS). The preoperative and postoperative lengths of bony exostosis were measured radiologically. The paired P < 0.0001). There was a statistically significant correlation between clinical scores (AOFAS and VAS) and the final postoperative length of the bone above parallel pitch lines (PPLs). The patients were satisfied and returned to their previous activities without reporting major morbidities except one patient who had mild pain with exertion.  The mean follow-up period was 56.4 ± 5.1 months. Statistically significant improvements in the preoperative mean of AOFAS (from 55.7 ± 9.3 to 94.3 ± 7.1) and VAS (from 8.1 ± 1.4 to 0.7 ± 1.04) at the final follow-up were noted ( Endoscopic calcaneoplasty is a safe, less invasive surgical procedure for the management of Haglund's syndrome after failure of conservative treatment. It provided a satisfactory clinical result without serious complications at a minimum 4-year follow-up. Patrick Haglund, a surgeon, first described Haglund's syndrome as a prominence of the posterosuperior calcaneal tuberosity resulting in disabling posterior heel pain. Para tendinitis, insertional Achilles tendinosis, retrocalcaneal bursitis, and bony exostosis with persistent swelling adjacent to the Achilles tendon insertion are the main pathological findings –3.The incidence is more common in females in their late 30s with bilateral affection . The priThe chief complaints are posterior heel pain, swelling, and limping. The main clinical findings are tender posterior bony hump with exacerbation of pain during active and passive ankle dorsiflexion. Radiological diagnosis is made on lateral x-ray view to detect the prominence of posterosuperior calcaneal tuberosity. Magnetic resonance imaging (MRI) is helpful to identify bursal thickening, Achilles tendinosis, and signal changes in the bony insertion , 7.Conservative management is the mainstay of treatment, which includes activity level modification, heel elevation using cushion in shoes, nonsteroidal anti-inflammatory drugs (NSAIDs), local platelet-rich plasma injection, and ultrasound device. Extracorporeal shock wave therapy reduces pain and achieves 80% of patient satisfaction .Operative treatment is indicated after the failure of conservative treatment for at least 6 months. The goal of surgery was to remove the posterosuperior bony exostosis and debridement of the inflamed bursa. Open surgical resection is widely used among orthopedic surgeons; however, it had some complications, such as wound dehiscence, Achilles tendon avulsion, ugly scar, persistent heel pain, medial calcaneal sensory nerve lesion, sural nerve injury, painful neuroma, and prolonged immobilization and recovery –12.The endoscopic procedure is superior to open surgery because of the lower postoperative complications, early mobilization, faster rehabilitation, and rapid return to previous activities. The endoscopic technique provides excellent medial and lateral side visualization of the retrocalcaneal space especially at the Achilles tendon bony insertion .This study aimed to evaluate the functional outcome and patient satisfaction after endoscopic calcaneoplasty with a minimum 4-year follow-up. Moreover, we assessed the correlation of the clinical scores with the length of bony exostosis. We hypothesized that significant improvements in the postoperative clinical scores with low complications were observed.Our ethical institutional review board approved this study (ZU-IRB # 988/22-1-2016), and all patients waived informed consent for participation. Patients who suffered from chronic posterior heel pain due to Haglund's deformity underwent endoscopic calcaneoplasty between January 2016 and January 2022 at Zagazig University Hospitals. The patients had conservative treatment in the form of rest, physical therapy, NSAIDs, shock wave therapy, and local platelet-rich plasma injection for at least 6 months preoperatively. The criterion for inclusion was chronic heel pain (>6 months) refractory to conservative treatment. Patients with previous ankle or calcaneal fractures, painful insertional calcification, seronegative arthritis, ankle deformities, Achilles tendon degeneration >50% of thickness, and skeletally immature ankles were excluded from the study. All patients underwent clinical assessment through history taking, including the activity level, physical examination, and provocative tests preoperatively. The patients had swelling and tenderness at the sides of the Achilles tendon insertion. Pain was provoked by active and passive ankle extension. To assess the Achilles tendon integrity, we used the Thompson calf squeeze test. The length of bony exostosis above the parallel pitch lines (PPLs) was measured on lateral x-ray view of the calcaneus . MRI assAn intravenous antibiotic (cefotaxime 1 gm) was administered 30 minutes preoperatively. The patient was positioned prone with the foot hanging over the edge of the operating table . SurgeriThe antibiotic was continued for 48 hours, and the stitches were removed after 14 days postoperatively. The patients were instructed to elevate the limb during the first postoperative week. Active and passive motions were started immediately postoperative. Partial weight bearing was allowed in the first 2 weeks and full weight bearing after the third week. The patients returned to daily activities 6–8 weeks after the surgery. The clinical scores (AOFAS and VAS) and mean radiological length of the bony hump were recorded at the end of follow-up .t test, and nonparametric means were compared using the Wilcoxon signed-rank test. The postoperative length of the bony hump and final clinical scores were correlated using Pearson′s coefficient. A P value of < 0.05 was considered statistically significant. A priori sample size for the two-sided matched paired t test that provided 85% statistical power and large size difference at 0.05 α error was estimated using G-Power software calculator version 3.1. The Statistical Package for Social Sciences (SPSS) data editor version 16  was used for statistical analysis.The distribution of data was tested using the Kolmogorov–Smirnov test. Numerical data were presented as percentages and means with standard deviation. Normally distributed preoperative and final postoperative means were compared using the paired Seventeen patients (21 heels) with a mean age of 44.7 ± 5.1 (36–52) years underwent endoscopic calcaneoplasty for Haglund's deformity by the same surgeon. The mean duration of symptoms was 10.7 ± 2.6 (7–16) months. The mean time of operation was 52.3 ± 12.3 (35–75) minutes. The mean follow-up time was 56.4 ± 5.1 (48–64) months. No patients were missed during the follow-up.P < 0.00001) at the final follow-up. According to AOFAS, 12 patients had excellent (90–100 points), 4 good (80–89 points), and 1 fair (70–79 points) clinical results, respectively.The AOFAS ankle-hindfoot score increased from 55.7 ± 9.3 (37–68) preoperatively to 94.3 ± 7.1 (72–100) postoperatively with statistically significant improvement (P < 0.00001) (The VAS for pain improved from 8.1 ± 1.4 (6–10) preoperatively to 0.7 ± 1.04 (0–3) postoperatively. The means were compared using the Wilcoxon signed-rank test (0.00001) .P < 0.00001)  to −0.2 ± 1.1 (−2 to 2 mm) at the final follow-up with a significant statistical difference (0.00001) .R = −0.7; P=0.0004) and a positive correlation with the final VAS for pain  using Pearson's coefficient.We found a significant negative correlation between the final mean length of the bony hump and the final AOFAS score . Ninety-four percent of patients were satisfied and resumed their preoperative activities with a mean follow-up of 56.4 ± 5.1 months.The main finding of the study was statistically significant improvements in the functional scores (AOFAS ankle-hindfoot and VAS for pain) . Furthermore, our results were comparable with those of Kaynak et al. [P < 0.01).The final AOFAS score in this study was close to the results of Pi et al.  who repok et al.  and Ortmk et al.  who recoThe clinical results were graded as excellent (90–100 points), good (80–89 points), fair (70–79 points), and poor (<70 points) according to the AOFAS of the ankle-hindfoot score . We repoRegarding the VAS for pain, our results were comparable with those of Pi et al.  who repoP=0.115).We did not find a significant difference between our results and the final postoperative means of AOFAS and VAS scores that were reported in 20 patients who underwent open surgery by Pi et al. . Their fAn adequate resection of the bony hump intraoperatively is essential to avoid postoperative recurrence of symptoms with no consensus about the ideal radiographic measurement to judge the amount of resection ,24. We uR = −0.7) (P=0.0004) and a positive correlation with VAS (R = 0.63) (P=0.002), which were contrary to the previously reported results of Opdam et al. [We found a statistically significant correlation between the functional scores (AOFAS and VAS) and the postoperative length of the bony hump. We recorded a negative correlation with AOFAS ; one patient developed transient sensory sural nerve neuropraxia and the other, a female housewife, who developed mild pain with heavy exertion without limitations of daily activities. All patients regained their previous activity level, and 94.1% of patients were satisfied with the results. Similar results were recorded by Leitze et al.  who had Our study had some limitations. First, the number of included patients was small; however, it was enough based on the estimated power analysis, although a larger sample size is recommended for the generalizability of the results and conclusions. Second, there was no control group for comparison with other treatment options. Additionally, the endoscopic procedure needed a well-trained surgeon with a stepwise improvement of the learning curve. Finally, the healing process was not investigated.Endoscopic calcaneal resection of Haglund's deformity provided improvement in the clinical scores (AOFAS and VAS) with minor complications at a minimum 4-year follow-up. Approximately 94% of patients were satisfied and regained their previous activity level. Small wound, early recovery, direct visualization, and controlled bone resection are the main advantages of the endoscopic technique. We found a statistically significant correlation between the functional scores and the radiological length of bony exostosis. Further studies with a larger number of patients will be needed in the future to prove this correlation and investigate the nature of healing.


Conclusions: This reanalysis of an RCT with respect to gender differences is to our knowledge the first attempt to investigate the role of gender in pain perception and medication after lumbar spine sequestrectomy. In contrast to other studies, we were not able to show significant differences between male and female patients in all pain-related outcomes. Apart from well-established pain management, psychological reasons such as gender-specific response biases or the observer effect might explain our results. Trial registration: The study was registered as a regulatory phase IV study at the German Clinical Trials Register (DRKS), an open-access online register for clinical trials conducted in Germany (Reg-No: DRKS00007913). Background: Gender issues have received increasing attention in clinical research of the past years, and biological sex has been introduced as a moderating variable in experimental pain perception. However, in clinical studies of acute pain and gender, there are conflicting results. In particular, there are limited data on the impact of gender differences after spinal sequestrectomy. The aim of this work is to examine gender differences in postoperative pain and pain medication consumption in an inpatient clinical setting. Methods: Data of a completed double-blind RCT was subdivided by gender and reanalyzed by means of an analysis of variance in repeated measures. Outcomes included pain severity measured on a VAS, affective (SES-A) and sensory pain perception (SES-S) and morphine equivalent doses (MED) of analgesics after spinal sequestrectomy. Results: In total, 42 female (47.73%) and 46 male (52.27%) patients were analyzed. No differences in pain severity ;  According to recent statistics, the incidence of disc herniation is 5 to 20 cases per 1000 adults per year .Gender-specific perception of pain has been discussed frequently and has gained increasing attention in pain research in recent years . DiffereAlthough gender differences in pain perception is a current research topic, little is known about its role in the field of degenerative diseases of the lumbar spine. Given these challenges, Maclean et al.  recentlyHence, we aimed at reanalyzing a recently conducted randomized, controlled clinical trial of patients undergoing elective, monosegmental, lumbar sequestrectomy  with resHypericum perforatum to standard pain medication alone. The study was approved by the local ethics committee and the Federal Institute for Drugs and Medical Devices  [The original study was a regulatory, randomized controlled trial of phase IV, comparing additional treatment with potentized 1383-31) .A total of 114 study participants were recruited from November 2015 to August 2018 from patients receiving a monosegmental spinal sequestrectomy due to a lumbar disc herniation at the Department of Neurosurgery at the Community Hospital Herdecke. Of those, twelve patients were excluded and thus, a total of 88 patients were eligible for statistical analysis. Of those, two did not meeting inclusion criteria, ten declined to participate, twelve did not receive allocated intervention and two patients were excluded for other reasons. Thus, a total of 88 patients were included for statistical analysis. Patients were followed several times per day for their pain perception and medication use during their hospital stay. Standard pain medication included Ibuprofen and Metamizole, and in less frequent cases, Oxycodone, Tilidine or Tapentadol. If necessary, patients in few cases also received Morphine, Piritramide or Tramadol. Their number and dosages (mg) were extracted from the medical record folder and converted to morphine-equivalent doses (MEDs) in accordance with other trials on analgesic intake .Pain perception was measured on a 100-mm visual analog scale (VAS) four times each day and then averaged for further evaluation. In addition, the German Version of the Pain Perception Scale introduced by Geissner was used to access the dimensions of “Affective Pain” (SES-A) and “Sensory Pain” (SES-S). The SES was scored at baseline and during postoperative study visits on days one, three and five . Baseline summary data of the total study population subdivided by gender were calculated using descriptive analyses and univariate statistics. To test for gender differences in pain management and perception, outcomes were modeled as a function of gender, duration of surgery and pain intensity at baseline within an ANOVA, including days after surgery as repeated measures (SAS-procedure PROC MIXED). A two-tailed error probability of α = 5% was used to test for gender differences. Results were reported using mean values and standard deviations for sample description and 95% confidence intervals for inferential statistics.In total, 42 female (47.73%) and 46 male (52.27%) patients were analyzed.n = 34, 38.6%) were diagnosed with a herniated disc at lumbar segments L5–S1 and L4–L5, followed by L3–L4 in 14 cases (15.9%), L2–L3 in 5 cases (5.7%) and in one case, L1–L2 (1.1%). As shown in p = 0.741): in 15 female (35.7%) and 18 male patients (39.1%) the right side was affected, while the left side was affected in 27 female patients (64.3%) and 28 male patients (60.9%). In two cases  the location according to the classification given in [No significant differences were observed between the groups at baseline: female patients were aged between 25 and 82 years with a mean of 52.74 ± 12.85 years while male patients were aged between 18 and 79 years and on average 1.25 years younger (50.5 ± 14.42 years). Duration of surgery for all patients was about one hour (64.70 ± 24.73 min) without being significantly different between female (60.83 ± 23.35 min) and male (68.24 ± 25.66 min) patients. Body mass index also did not differ between females (26.93 ± 5.01) and males (28.02 ± 4.30). With respect to the indication of operation, an equal majority of the patients (given in  was exclp = 0.708) and for each of the single time points (p between 0.412 and 0.983). Data on affective (SES-A) and sensory pain perception (SES-S) are provided in p = 0.919; SES-S: Gender × Time F = 0.06; ; p = 0.939).In both groups there was a significant reduction in sensory pain perception, which resulted in almost identical values for affective pain perception  and sensory pain perception  on day five. Again, the linear mixed model did not reveal any significant differences in the course of time between the groups ; p = 0.227).Pain medication measured in MEDs increased from 129.94 ± 155.46 mg MED at admission to 149.97 ± 151.95 mg MED on day one and a maximum of 171.02 ± 148.16 mg MED on day 2 for all patients. Subdivided by gender pain medication showed an almost identical course in women and men, however, MEDs in men except for day three were always below the MEDs of the female patients  but withp = 0.47; This is also reflected in the statistical analysis of the total amount of medication in the inpatient period subdivided by gender. Although there is a lower amount of medication in men, the difference is not significant (This reanalysis of an RCT with respect to gender differences is to our knowledge the first attempt to investigate the role of gender in pain perception and medication after lumbar spine sequestrectomy. Clinical and anatomical data of our study i.e., data on the level of disc herniation, side and location is in accordance with published data provided in ,17,18. NAs mentioned in the introduction, most studies examining pain and gender differences find worse outcomes for women. Studies have shown this effect in both pre- and postoperative acute pain settings ,23, whicSex hormones are often listed as influencing factors for gender differences, in addition to endogenous opioid activation, neurochemical mechanisms or differences in neuroimmunology and genetic factors matter ,27. PossThe prevalence of chronic low back pain is higher in women than men and increases linearly from the third decade of life to age 60 . TherefoFinally, these findings may simply reflect gender-specific response biases. Men underreport pain and/or women overreport pain. Humans of different genders also differ in pain management strategies. Male patients tend to prefer problem-solving and instrumental strategies, whereas female patients are more likely to seek social support and tend to focus more on emotional aspects of the pain situation ,30. In aA systematic literature review found that a so-called observer effect often influences studies: female study participants tended to decrease pain when the investigator was of the opposite sex, while men tended to rate pain lower when the investigator was female . In our Hypericum perforatum as an add-on to standard postoperative pain management. Thus, the trial was not intended to detect small differences such as those in the present reanalysis with regard to gender. However, statistical results with p-values clearly above the threshold of significance do not suggest that the low sample size plays an important role. The sample size of the study was based on an efficacy trial investigating the treatment with homeopathic Hypericum perforatum; blinding of the patients was carried out properly, and no gender differences in the original study outcomes were observed. Thus, a contamination of the present results due to positive expectancy regarding the therapy, which might have influenced pain perception, can also be ruled out. Moreover, in the original trial, the additional treatment with Hypericum perforatum did not show a significant effect with respect to pain perception or opioid consumption. Thus, an influence of the additional treatment with Hypericum perforatum can also be excluded [All patients had been randomly assigned to receive either a placebo or excluded .The results of this reanalysis are contradictory to most other studies in the field of neurosurgery, as no significant gender differences in pain perception and analgesic consumption after lumbar spinal surgery could be presented. It is possible that biopsychosocial mechanisms and the role of psychological factors that may influence sex differences in pain do not occur during a short postoperative inpatient stay. This should be considered in future research. Moreover, a summary of existing findings, e.g., in terms of a systematic review or meta-analysis, would therefore be desirable.


N = 139) while adjusting for the effects of natural history and regression to the mean via a no treatment group. Results agree between the two placebo groups in each study: both placebo groups showed negligible semi-partial correlations between baseline variability and adjusted response . The no treatment group in Placebo I showed a negative correlation [−0.22 ], but the no treatment and drug groups in Placebo II's correlations were negligible . When modeled as a linear covariate, baseline pain variability accounted for <1% of the variance in post-intervention pain across both studies. Even after adjusting for baseline pain and natural history, the inability of baseline pain variability to account for substantial variance in pain response highlights that previous results concerning pain variability and treatment response may be inconsistent. Indeed, the relationship appears to be neither consistently specific nor sensitive to improvements in the placebo group. More work is needed to understand and establish the prognostic value of baseline pain variability—especially its placebo specificity and generalizability across patient populations.Previous research reports suggest greater baseline variability is associated with greater pain relief in those who receive a placebo. However, studies that evidence this association do not control for confounding effects from regression to the mean and natural history. In this report, we analyzed data from two randomized clinical trials (Placebo I and Placebo II, total  Randomized clinical trials are the principal method by which researchers assess treatment efficacy. Although clinical trials can provide valid evidence of a treatment's average effect (relative to some control), they often fail to demonstrate meaningful drug effects relative to placebo. Some researchers have cited high “placebo response” as the main cause of these “failures” –4, suggevia their “placebo response.” One of these identified correlates is pain variability, which has been shown to negatively correlate with subsequent pain relief in the placebo-treated group across several chronic pain conditions . This group was also removed in previous analyses of this trial , with no evidence of additional comorbid chronic pain, neurological, or psychiatric conditions. Individuals had to agree to stop any concomitant pain medications and had to be able to use a smartphone or computer to monitor pain twice a day. Additionally, the enrolled patients had to report a pain level of at least 5/10 during the screening interview, and their averaged pain level from the smartphone app needed to be higher than 4/10 during the baseline rating period before they were randomized into a treatment group. Here, we include 20 participants from the no treatment group and 43 participants from the placebo group. We excluded the trial's drug group because its small sample size . Patients were asked to enter their pain 2 times/day over the course of the entire study. For the purposes of demonstration, here we averaged pain ratings within a single day.The purpose of this study was to validate a prognostic model for classifying chronic pain patients based on their predicted improvement with placebo .Individuals with chronic low back pain were recruited for this study. Patients must have had low back pain for at least 6 months, with or without symptoms of radiculopathy, a minimum VAS score of 5/10 at the screening visit, and a minimum average pain of 4/10 over a 2-week period prior to their first visit. Patients were randomized to no treatment, placebo, or naproxen. Here, we include 11 participants from the no treatment group, 32 participants from the placebo group, and 33 participants from the naproxen group. The demographic characteristics of these patients are presented in Data were collected using a custom pain rating phone app through which patients could rate their pain (0–10 NRS), as in Placebo I. Patients were asked to enter their pain 2 times/day over the course of the entire study. For the purposes of demonstration, here we averaged pain ratings within a single day.baseline, calculated as the standard deviation of the pre-intervention phase) as independent variables and post-intervention pain (mean of the last 7 days in the intervention period) as the dependent variable. In addition to these three independent variables, we included the interaction between group and SDbaseline (herein referred to as group × SDbaseline interaction) to isolate the effect of SDbaseline on post-intervention pain by group. The effects of group and the group × SDbaseline interaction were computed using modified backward contrasts, in which each group was compared to the previous group  and no treatment was the intercept or reference group. This was done to compare the additive effect of placebo relative to no treatment and drug relative to placebo, meaning that the previous level controls the level succeeding it, thereby adjusting for natural history , regression to the mean (through the pre-intervention score covariate and no treatment group), and placebo effects. Specifically, the following contrast matrices were used to compare differences between the two groups:All analyses were performed using R . We builbaseline on post-intervention pain by group.The rows of these matrices denote the groups in each study  and the columns represent the weight of each parameter on that group. This is mathematically equivalent to dummy coding such that patients in the no treatment group receive a 0 for placebo and 0 for drug; patients in the placebo group receive a 1 for placebo and 0 for drug; and patients in the drug group receive a 1 for placebo and 1 for drug. These contrasts enabled us to isolate the effects of SDt is the t-statistic of the effect of interest, R2 is the model coefficient of determination, and df is the residual degrees of freedom) between SDbaseline and post by group. Compatibility intervals (CI) for rsp were calculated using the bias-corrected and accelerated bootstrap with 1,000 replicates. Data are depicted using adjusted effects  predictor increased Placebo I and Placebo II model R2's by 0.01. Our observed effects were not strongly influenced by any individual patient .  patient .via a no treatment control group . This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Under Grant No. DGE-1324585.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Morbidity occurred in 17%, and the 90-day mortality was 1%. Complete or partial pain relief was achieved in 65% of patients. No significant difference in morbidity was observed between the DPPHR and PD groups: 17% vs. 20% (p = 0.728). Pain relief did not differ between the groups . The frequency of performed DPPHR decreased, whereas the rate of PD remained unaltered. Surgical treatment for CP is safe and effective. DPPHR and PD are comparable regarding post-operative morbidity and are equally effective in achieving pain relief. Trends over time revealed PD as more commonly performed compared to DPPHR.Surgery for chronic pancreatitis (CP) is considered as a last resort treatment. The present study aims to determine the short- and medium-term outcomes of surgical treatment for CP with a comparison between duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD). The trends in surgical procedures were also examined. This was a retrospective cohort study of patients who underwent surgery for CP between 2000 and 2019 at the Karolinska University Hospital. One hundred and sixty-two patients were included. Surgery performed included drainage procedures ( Current treatment strategies for chronic pancreatitis (CP) follow a multidisciplinary step-up approach with medical therapy, endoscopic intervention and, lastly, surgery . The maiThe surgical armamentarium available for the treatment of CP can be divided into three categories: pancreatic ductal drainage  ; differeThe Karolinska University Hospital is a high-volume tertiary referral centre for pancreatic diseases, responsible for the medical, endoscopic and surgical treatment of CP. The primary aim of this study is to investigate the short- and medium-term outcomes of surgery for CP at this centre, with an emphasis on the comparison between DPPHR and PD. A secondary aim is to evaluate the trends in surgical procedures over time.This study was performed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines , and appThis was a retrospective observational cohort study on prospectively collected data of consecutive adult patients (age ≥ 18 years) who underwent elective surgical intervention for CP between 1 January 2000 and 31 December 2019 at the Karolinska University Hospital in Stockholm, Sweden. Patients who had no evidence of CP on the final pathology report were excluded.Patients were selected from a retrospectively maintained database of CP patients, and their medical records were analysed. The diagnosis of CP was established, based on the findings of clinical history, clinical examination and imaging according to the M-ANNHEIM classification of CP . PatientThe treatment strategy for CP at our centre was similar to the standard step-up approach with initial medical therapy, followed by endoscopic intervention and lastly surgery. Hence, surgical treatment was reserved for patients with intractable abdominal pain after failure of medical and/or endoscopic intervention. Other indications comprised suspicion of malignancy, locoregional complications, such as biliary and duodenal obstruction due to an inflammatory mass of the pancreatic head, and symptomatic pseudocysts. The decision for surgical treatment was taken following multidisciplinary meetings with surgeons, radiologists, endoscopists and pancreatologists. The type of surgery performed was decided, based on the specific pancreatic morphological features.The following parameters were collected: sex; age; aetiology of CP; history of smoking; time between CP diagnosis and surgery (months); number of endoscopic retrograde cholangiopancreatography (ERCP) procedures performed prior to surgery; presence of calcification on radiology; indication for surgery; presence of pancreatic exocrine insufficiency (PEI); dosage of pancreatic enzyme replacement therapy (PERT); body mass index (BMI); stool consistency; diabetes mellitus (DM); pain treatment and pain intensity.The following parameters were collected: intraoperative blood loss (millilitres); operative time (minutes); hospital length of stay ; LOS at the high-dependency unit ; intensive care unit (ICU) admission and ICU LOS; duration of epidural anaesthesia usage (days); duration of patient-controlled analgesia usage (days); postoperative morbidity; delayed gastric emptying (DGE); postoperative pancreatic fistula (POPF); Postpancreatectomy haemorrhage (PPH) and bile leakage.The outpatient follow-up at our centre was scheduled at 3 and 6 months postoperatively. Thus, data at the 6-month follow-up were retrieved and evaluated for medium-term outcomes, including PEI, BMI, stool consistency, DM treatment, pain medication and pain intensity. The 6-month cut-off ensured an adequate time for patients to recover from surgery and adapt to their insufficiencies, thus improving the homogeneity of the cohort, and also reduced the amount of missing data.For the purposes of the analysis of trends in surgical procedures, the study period was arbitrarily sub-classified into two periods (2000 to 2010 and 2011 to 2019). The surgical procedures evaluated were DPPHR, PD, DP and TP.PEI was defined as faecal elastase-1 values <200 µg/g or steatorrhea . Stool ct-test or Mann–Whitney U test, depending on the distribution of the data. Categorical variables were compared using Pearson’s chi-squared test or Fisher’s exact test, when appropriate. Comparisons of pre- and postoperative data were performed using McNemar’s test and the Wilcoxon signed-rank test on nominal and non-parametric data, respectively. A normality was tested using the Shapiro–Wilk test. Statistical significance was assumed for a 2-sided p-value < 0.05. Statistical analysis was performed using the software SPSS Statistical Package for the Social Sciences .Descriptive results for numerical variables were presented as the means with standard deviation (±SD) in normally distributed data and as the median with interquartile range (IQR) in non-normally distributed data. Frequency distributions and percentages were used to summarise the categorical variables. Comparisons of numerical data were performed using the independent There were 162 patients included in the study. Pancreatic resection was the most common procedure (70%), the majority being PD, 65 out of 162 (40%). A total of 35 patients (22%) underwent DPPHR. Of these, 23 patients (14%) underwent the Beger procedure and 3 patients (2%), the Frey procedure. Surgical drainage procedures were performed on 2 patients (1%), according to Partington–Rochelle. See Clinical characteristics are presented in p < 0.001) than the PD group, and underwent a greater number of endoscopic interventions (ERCP) prior to surgery (p = 0.005). The indications for surgery were different between the 2 groups, in which CP complications accounted for 74% of all indications in the DPPHR group compared to 18% in the PD group (p < 0.001). There was also a higher rate of radiologically confirmed pancreatic calcification in patients who underwent DPPHR, compared to PD, 71% vs. 42%, (p = 0.006).Patients in the DPPHR group were younger . The 90-day mortality was 1% (n = 2).The short-term outcomes are summarised in p < 0.001) compared to PD, in adjunct to epidural analgesia, which was used in 97% of all cases.There was no difference in hospital or ICU LOS between the DPPHR and PD groups. Regarding morbidity  and mortality , the two groups did not differ. Patient-controlled analgesia was required more frequently in the DPPHR group  prior to surgery. A total of 72 patients (46%) developed new-onset PEI, resulting in a total of 142 patients (90%) with PEI at the 6-month postoperative evaluation.p < 0.001, respectively). New-onset PEI developed in 12 patients (34%) in the DPPHR group compared to 37 patients (59%) who underwent PD, which differed significantly between the 2 groups (p = 0.020).There was an increase in the number of PEI cases postoperatively in both the DPPHR and PD groups, compared to preoperatively  had DM prior to surgery. A total of 29 of 105 patients (28%) (9 missing cases) developed new-onset DM. DM was thus present in 77 cases (50%) at follow-up.p = 0.063) in the DPPHR group. A similar relation was observed after PD, from 38% to 48%, (p = 0.031), this time significant. There was, however, no difference in the proportion of new-onset DM nor total proportion of DM between the two procedures .The proportion of patients with DM increased postoperatively, although not significantly, from 29% to 44% (p < 0.001).For the entire cohort, 69 out of 121 patients  reported having abdominal pain of varying severity before surgery. Complete or partial pain relief was achieved in 45 out of the 69 patients (65%). In total, 42 out of 121 patients  experienced pain after surgery, thus resulting in a reduction in overall pain when comparing pain before and after surgery . Additionally, the DPPHR group had higher pain levels (mild/moderate and severe pain) at follow-up compared with the PD group . For the DPPHR group, there was no difference between pre- and postoperative opioid consumption. In the PD group, however, there was a tendency toward less opioid consumption at postoperative follow-up compared to preoperatively .Opioid consumption was higher at 6-month follow-up among patients who underwent DPPHR, compared to PD . For the PD group, 22 patients (44%) experienced abdominal pain prior to surgery, and, of these, complete or partial pain relief was noted in 16 patients (73%) (p = 0.022). Moreover, the overall difference between subjectively reported pain levels before and after DPPHR and PD interventions was significantly lower . However, the differences in pain relief between the two groups was not statistically significant (p = 0.142).Regarding pain relief, 21 patients (81%) in the DPPHR group experienced abdominal pain (mild/moderate or severe pain) prior to surgery, and, of these, complete or partial pain relief was achieved in 13 patients (62%) (p < 0.001). The frequency of DPPHR decreased from 41% during the first decade to 5% in the following years. In fact, no patient underwent DPPHR in the last seven years of the study period. Conversely, the rates of DP and TP increased from 8% to 31% and from 4% to 14%, respectively, during the same time period. The rate of PD remained largely unaltered throughout the years.To evaluate the safety and efficacy of surgical treatment for CP, we conducted a retrospective cohort study of 162 CP patients undergoing surgery. The results suggest that surgical treatment for CP can be carried out safely with acceptable pain relief. Furthermore, both DPPHR and PD were found to be equally safe. In addition, the two procedures did not differ in terms of pain relief or endocrine insufficiency, although the DPPHR group experienced higher pain levels and opioid consumption at the 6-month follow-up. Trends over time revealed pancreatic resections  as more commonly performed at our centre compared to DPPHR.The current study revealed low overall rates of major morbidity (17%) and 90-day mortality (1%). The results are in line with pervious series  ,36,37. TThe incidence of endocrine and exocrine insufficiency is common in long-term follow-up series, ranging between 0–34% and 27–37%, respectively ,39. SimiThe main criterion of success in the surgical management for CP is the achievement of pain relief ,41,42. IOur study is unusual in its short median duration 14 months) between CP diagnosis and surgical intervention. Several studies reported a median duration of 40 months or more ,37. This months bIn our comparison of DPPHR with PD, we found that both procedures were equally safe concerning morbidity 17% vs. 20%) and 90-day mortality (0% vs. 3%). These findings are in concordance with the previously published data % vs. 20%,46. Howep = 0.142). Thus, our results provide further evidence that DPPHR and PD interventions are equally effective concerning pain relief. Nevertheless, regarding the discrepancy in postoperative pain levels, one should consider that patients who underwent DPPHR had a higher number of ERCP procedures prior to surgery, a significantly higher rate of pancreatic calcifications, higher opioid consumption, and a longer duration of symptoms. Therefore, it is reasonable that these preoperative characteristics might reflect a more advanced disease in this group, which could explain the slightly higher pain levels observed at follow-up. Concerning the difference in opioid consumption between the groups, it should be noted that there was a significantly higher proportion of patients in the DPPHR group who required opioids prior to surgery, 56% vs. 39%. More importantly, we found no significant difference in opioid consumption between preoperative and postoperative values in either group.In the current study, patients who underwent DPPHR procedures had continued pain and higher amounts of opioid consumption at follow-up, compared to the PD group. However, the two groups did not differ significantly regarding complete or partial pain relief . Secondly, even though those with primary suspicion of malignancy as an indication for surgery also had CP complications, the two treatment groups (DPPHR vs. PD) were not entirely comparable in terms of surgical indications and pancreatic morphology. Thirdly, our 6-month follow-up period is relatively short compared to other similar studies. Although there is high-quality literature examining this field, the main strength of our study is its status as the first in-depth analysis of a Scandinavian population. Additionally, a relatively large number of patients from a single centre were included in the final analysis. Thus, detailed surgical and non-surgical results could be obtained. Finally, the long study period provided the opportunity to study the trends in pancreatic surgery for CP patients over time.Surgical treatment for chronic pancreatitis is safe and effective when performed at a high-volume centre. In properly selected patients, surgical intervention is associated with acceptable low perioperative morbidity and mortality and provides adequate pain relief. Furthermore, DPPHR and PD procedures seemed to be equally effective with regard to morbidity, mortality, pain relief and endocrine preservation. These findings must be carefully interpreted considering the limited sample sizes and the retrospective nature of the study making new prospective studies warranted. Trends over time revealed pancreatic resection as more commonly performed compared to DPPHR, which may be due to increased malignant indications for pancreatic surgery.