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Aim: To evaluate the use of low-dose naltrexone (LDN) as a broad-spectrum analgesic. Methods: Retrospective cohort study from a single pain management practice using data from 2014 to 2020. Thirty-six patients using LDN for ≥2 months were matched to 42 controls. Pain scores were assessed at initial visit and at most recent/final documented visit using a 10-point scale. Results: Cases reported significantly greater pain reduction (-37.8%) than controls (-4.3%; p < 0.001). Whole sample multivariate modeling predicts 33% pain reduction with LDN, with number needed to treat (for 50% pain reduction) of 3.2. Patients with neuropathic pain appeared to benefit even more than those with 'nociceptive'/inflammatory pain. Conclusion: LDN is effective in a variety of chronic pain states, likely mediated by TLR-4 antagonism.

Background: There is growing evidence that failure to rescue (FTR) is an important factor of postoperative mortality (POM) after rectal cancer surgery and surgical approach modified post-operative outcomes. However, the impact of laparoscopy on FTR after proctectomy for rectal cancer remains unknown. The aim of this study was to compare the rates of postoperative complications and FTR after laparoscopy vs open proctectomy for cancer., Methods: All patients who underwent proctectomy for rectal cancer between 2012 and 2016 were included. FTR was defined as the 90-day POM rate among patients with major complications. Outcomes of patients undergoing open or laparoscopic rectal cancer surgery were compared after 1:1 propensity score matching by year of surgery, hospital volume, sex, age, Charlson score, neoadjuvant chemotherapy, tumor localization and type of anastomosis., Results: Overall, 44,536 patients who underwent proctectomy were included, 7043 of whom (15.8%) developed major complications. The rates of major complications, POM and FTR were significantly higher in open compared to laparoscopic procedure (major complications: 19.2% vs 13.7%, p < 0.001; POM: 5.4% vs 2.3%, p < 0.001; FTR: 13.6% vs 8.3%, p < 0.001; respectively). After matching, open and laparoscopic groups were comparable. Multivariate analysis showed that age, Charlson score, sphincter-preserving procedure and surgical approach were predictive factors for FTR. Open proctectomy was found to be a risk factor for FTR (OR 1.342, IC95% [1.066; 1.689], p = 0.012) compared to laparoscopic procedure., Conclusion: When complications occurred, patients operated on by open proctectomy were more likely to die., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of this study was to evaluate the benefit of diverting enterostomy (DE) in patients with severe steroid-refractory (SR) gastrointestinal acute graft-versus-host-disease (GI-aGVHD) following allogeneic hematopoietic stem-cell transplantation (ASCT)., Summary and Background Data: Severe GI-aGVHD refractory to the first-line steroid therapy is a rare but dramatic life-threatening complication. Second lines of immunosuppressors have limited effects and increase the risk of sepsis. Data suggest that limiting GI bacterial translocation by DE could restrain severe GI-aGVHD., Methods: From 2004 to 2018, we retrospectively reviewed all consecutive patients undergoing ASCT for hematologic malignancies who developed severe SR GI-aGVHD. We compared patients in whom a proximal DE was performed (Enterostomy group) with those not subjected to DE (Medical group). The primary endpoint was the 1-year overall survival (OS) measured from the onset of GI-aGVHD. Secondary endpoints were the 2-year OS and causes of death., Results: Of the 1295 patients who underwent ASCT, 51 patients with severe SR GI-aGVHD were analyzed (13 in Enterostomy group and 38 in Medical group). Characteristics of patients, transplantation modalities, and aGVHD severity were similar in both groups. The 1-year OS was better after DE (54% vs 5%, P = 0.0004). The 2-year OS was also better in "Enterostomy group" (31% vs 2.5%; P = 0.0015), with a trend to lower death by sepsis (30.8% vs 57.9%; P = 0.091)., Conclusion: DE should be considered for severe GI-aGVHD as soon as resistance to the corticosteroid is identified., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-κB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP's potential therapeutic importance as a drug of choice in managing COVID-19 cases.

Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs., Competing Interests: Conflicts of Interest: None declared., (©Moshe Rogosnitzky, Esther Berkowitz, Alejandro R Jadad. Originally published in JMIRx Med (https://med.jmirx.org), 30.09.2020.)

Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is a widely overlooked opportunity. Off-label prescribing (ie, for a nonapproved indication) is legal in most countries and tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, health crises may mean that real-world repurposing is the only realistic source for solutions. Optimal real-world repurposing requires a track record of safety, affordability, and access for drug candidates. Although thousands of such drugs are already available, there is no central repository of off-label uses to facilitate immediate identification and selection of potentially useful interventions during public health crises. Using the current coronavirus disease (COVID-19) pandemic as an example, we provide a glimpse of the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and targeted toward the underlying pathophysiology that makes COVID-19 so deadly. This paper briefly summarizes why cimetidine or famotidine, dipyridamole, fenofibrate or bezafibrate, and sildenafil citrate are worth considering for patients with COVID-19. Clinical trials to assess efficacy are already underway for famotidine, dipyridamole, and sildenafil, and further trials of all these agents will be important in due course. These examples also reveal the unlimited opportunity to future-proof our health care systems by proactively mining, synthesizing, cataloging, and evaluating the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs., (©Moshe Rogosnitzky, Esther Berkowitz, Alejandro R Jadad. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 13.05.2020.)

Objective: To identify the impact of hospital volume according to Charlson Comorbidity Index (ChCI) on postoperative mortality (POM) after rectal cancer surgery., Background: A volume-outcome relationship has been established in complex surgical procedures. However, little is known regarding the impact of hospital volume on POM according to patients' comorbidities after rectal cancer surgery., Methods: All patients undergoing proctectomy for cancer from 2012 to 2016 were identified in the French nationwide database. Patient condition was assessed on the basis of the validated ChCl and was stratified into 3 groups according to the score (0-2, 3, and ≥4). Chi-square automatic interaction detector (CHAID) was used to identify the cut-off values of the annual proctectomy caseload affecting the 90-day POM. The 90-day POM was analyzed according to hospital volume (low: <10, intermediate: 10-40, and high: ≥41 cases/yr) and ChCI., Results: Among 45,569 rectal cancer resections, the 90-day POM was 3.5% and correlated to ChCI (ChCI 0-2: 1.9%, ChCI 3: 4.9%, ChCI ≥4: 5.8%; P < 0.001). There was a linear decrease in POM with increasing hospital volume (low: 5.6%, intermediate: 3.5%, high: 1.9%; P < 0.001). For low-risk patients (ChCl 0-2), 90-day POM was significantly higher in low and intermediate hospital volume compared with high hospital volume centers (3.2% and 1.8% vs 1.1%; P < 0.001). A significant decrease in postoperative hemorrhage complication rates was observed with increasing center volume (low: 13.3%, intermediate: 11.9%, and high: 9.4%; P < 0.001). After multivariable analysis, proctectomy in low [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.71-2.58, P < 0.001] and intermediate (OR 1.45, 95% CI 1.2-1.75, P < 0.001) hospital volume centers were independently associated with higher risk of mortality., Conclusion: The POM after proctectomy for rectal cancer is strongly associated with hospital volume independent of patients' comorbidities. To improve postoperative outcomes, rectal surgery should be centralized.

Background/aim: Colorectal cancer (CRC) is associated with high incidence and mortality rates. Carcinoembryonic antigen (CEA), a prognostic biomarker for recurrent CRC following curative resection, suffers from low sensitivity, especially in early-stage screening. Intraplatelet angiogenesis regulators (IPAR), such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), have been identified as important regulators of tumor growth in CRC. The aim of this study was to confirm the higher preoperative level of IPAR (VEGF and PDGF) in CRC patients compared to controls and to measure IPAR in CEA-negative CRC patients., Methods: The data and blood of 30 CRC patients and 30 presumably healthy controls were prospectively analyzed and compared., Results: We confirmed elevated preoperative intraplatelet VEGF and PDGF levels in CRC patients compared to controls. Importantly, IPAR were significantly elevated even in CEA-negative CRC patients., Conclusion: Elevated preoperative intraplatelet VEGF and PDGF levels in CRC patients suggest new possibilities for postoperative monitoring in CRC patients, especially when CEA is negative.

Background and Aims: Persistent perineal sinus (PPS) defined as a perineal wound remaining unhealed more than 6 months after abdominoperineal resection (APR) is a well-known complication. The aim of our study was (1) to evaluate the incidence of PPS after APR for Crohn's disease (CD) in the era of biotherapy, (2) to determine long-term outcome of PPS, (3) to study risk factors associated with delayed perineal healing, and (4) to compare the results in this CD patient group with patients without CD., Methods: From 1997 to 2013, the records of patients who underwent APR for CD and for non-CD rectal cancer with or without radiochemotherapy at two French university hospitals were studied retrospectively. Perineal healing was evaluated by clinical examination at 1, 6, and 12 months after surgery., Results: The cumulative probability of perineal wound unhealed at 6 and 12 months after surgery was 85 and 48%, respectively, for 81 patients who underwent APR for CD patients in contrast to 21 and 13%, respectively, for 25 non-CD patients with rectal cancer. Eight patients with CD (10%) remained with PPS after a median follow up of 4 years and spontaneous perineal healing occurred with time for all non-CD patients. Factors associated with delayed perineal healing in CD included age at surgery < 49 years (p = 0.001) and colonic-only Crohn's disease location (p = 0.045). Medical treatments had no significant impact on perineal healing., Conclusions: PPS beyond 6 months post-APR remains a frequent complication but mostly resolves over time. CD is a risk factor for developing PPS and factors associated with higher incidence of PPS were age at surgery < 49 years and colonic-only Crohn's disease location. Prevention of PPS in this population with muscle flap during APR deserves to be evaluated.

Introduction: Corticosteroids are still the standard first-line treatment for immune thrombocytopenic purpura (ITP). As second-line therapy, splenectomy and Rituximab are both recommended. The aim of our study was to compare the efficacy of Rituximab to splenectomy in persistent or chronic ITP patients., Methods: Between January 1999 and March 2015, we retrospectively selected all consecutive patients who underwent an ITP second-line treatment: Rituximab or splenectomy. The distinction between open (OS) and laparoscopic splenectomy (LS) was analyzed. Primary outcome was composite: hospitalization for bleeding and/or thrombocytopenia and death from hemorrhage or infection. Secondary outcomes were based on response (R) and complete response (CR) rates as defined by the American Society of Hematology., Results: Ninety-six patients were included: 30 patients received Rituximab, 37 underwent OS, and 29 underwent LS. The follow-up was 30, 60, and 120 months in Rituximab, LS, and OS groups, respectively. At 30 month, the primary outcome-free survival rate was higher in splenectomy groups (84% for OS, 86% for LS) than Rituximab group (47%) (P = 0.0002). Similarly, at 30 month, R and CR rates were higher for OS (86.5% and 75.7%, respectively) and LS groups (93.1% and 89.7%) than Rituximab (46.7% and 30%) (P = 0.0001). Moreover, R rates remained elevated at 60 month for OS and LS groups (83.7% and 89.6% respectively) and 78.4% at 120 month for OS group., Conclusion: We observed that splenectomy for ITP second-line treatment was more effective than Rituximab regarding maintenance of R, CR, and overall response rates. OS and LS had similar efficacy.

Gadolinium chelates are widely used as contrast media for magnetic resonance imaging. The approved gadolinium-based contrast agents (GBCAs) have historically been considered safe and well tolerated when used at recommended dosing levels. However, for nearly a decade, an association between GBCA administration and the development of nephrogenic systemic fibrosis (NSF) has been recognized in patients with severe renal impairment. This has led to modifications in clinical practices aimed at reducing the potential and incidence of NSF development. Newer reports have emerged regarding the accumulation of gadolinium in various tissues of patients who do not have renal impairment, including bone, brain, and kidneys. Despite the observations of gadolinium accumulation in tissues regardless of renal function, very limited clinical data regarding the potential for and mechanisms of toxicity is available. This significant gap in knowledge warrants retrospective cohort study efforts, as well as prospective studies that involve gadolinium ion (Gd(3+)) testing in patients exposed to GBCA. This review examines the potential biochemical and molecular basis of gadolinium toxicity, possible clinical significance of gadolinium tissue retention and accumulation, and methods that can limit gadolinium body burden.

Dipyridamole was introduced decades ago as a treatment for angina, subsequently found to inhibit platelet aggregation. It is most commonly used, and approved for use in thromboembolism prevention, following surgery. Some of its recognized effects such as adenosine uptake inhibition, elevation of cAMP and cGMP levels, vasodilation, and tissue perfusion are important in various ocular disorders. For this reason, dipyridamole represents an interesting candidate as a therapeutic target for the treatment of eye disorders affecting different ocular structures. The aim of this article is to review the evidence and current understanding of the mechanisms by which dipyridamole exerts its effects on different ocular tissues, discuss the role of dipyridamole in clinical practice, and highlight areas of use and routes of administration.

A role for CD20 antibodies in treating prostate cancer has not yet been established. We report a case of advanced prostate cancer presenting with generalized lymphadenopathy that expressed CCR7 and CD20. CCR7 expression in prostate cancer has been previously reported only once; the expression of CD20 has not been reported before. Rituximab therapy was initiated in this case and resulted in a significant biochemical response. This unique metastatic and biochemical pattern may signify a distinct subtype of prostate cancer that may be amenable to treatment with anti-CD20 antibodies.