RORγt inverse agonist TF-S14 inhibits Th17 cytokines and prolongs skin allograft survival in sensitized mice.

Chronic antibody mediated rejection (AMR) is the major cause of solid organ graft rejection. Th17 contributes to AMR through the secretion of IL17A, IL21 and IL22. These cytokines promote neutrophilic infiltration, B cell proliferation and donor specific antibodies (DSAs) production. In the current study we investigated the role of Th17 in transplant sensitization. Additionally, we investigated the therapeutic potential of novel inverse agonists of the retinoic acid receptor-related orphan receptor gamma t (RORγt) in the treatment of skin allograft rejection in sensitized mice. Our results show that RORγt inverse agonists reduce cytokine production in human Th17 cells in vitro. In mice, we demonstrate that the RORγt inverse agonist TF-S14 reduces Th17 signature cytokines in vitro and in vivo and leads to blocking neutrophilic infiltration to skin allografts, inhibition of the B-cell differentiation, and the reduction of de novo IgG3 DSAs production. Finally, we show that TF-S14 prolongs the survival of a total mismatch grafts in sensitized mice. In conclusion, RORγt inverse agonists offer a therapeutic intervention through a novel mechanism to treat rejection in highly sensitized patients.

Enhanced recovery protocols in trauma and emergency abdominal surgery: a scoping review.

PURPOSE: Enhanced recovery protocols (ERP) have been shown to improve patient outcomes and is now regarded as standard of care in elective surgical setting. However, the literature addressing the use of ERP in trauma and emergency abdominal surgery (EAS) is limited and heterogenous. A scoping review was conducted to comprehensively assess the literature on ERP in trauma laparotomy and EAS. METHODS: Three bibliographic databases were searched for studies addressing ERP in trauma laparotomy and EAS. We extracted the study characteristics including study design, country, year, surgical procedures, ERP components used, and outcomes. Reporting was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews. RESULTS: After screening of 1631 articles for eligibility, 39 studies were included in the review. There has been an increase in the number of articles in the field, with 44% of the identified studies published between 2020 and 2022. Fourteen different protocols were identified, with varying components for each operative phase (preoperative; 29, intraoperative; 20, postoperative; 27). The majority of the studies addressed the effectiveness of ERP on clinical outcomes (31/39: 79%). Only two studies (5%) included purely trauma populations. CONCLUSIONS: Studies on ERP implementations in the EAS populations were published across a range of countries, with improved outcomes. However, a clear gap in ERP research on trauma laparotomy was identified. This scoping review indicates that standardization of care through ERP implementation has potential to improve the quality of care in both EAS and trauma laparotomy.

Impact of enhanced recovery pathways on patient-reported outcomes after abdominal surgery: a systematic review.

INTRODUCTION: Evidence supports that enhanced recovery pathways (ERPs) reduce length of stay and complications; however, these measures may not reflect the perspective of patients who are the main stakeholders in the recovery process. This systematic review aimed to appraise the evidence regarding the impact of ERPs on patient-reported outcomes (PROs) after abdominal surgery. METHODS: Five databases (Medline, Embase, Biosis, Cochrane, and Web of Science) were searched for randomized controlled trials (RCTs) addressing the impact of ERPs on PROs after abdominal surgery. We focused on distinct periods of recovery: early (within 7 days postoperatively) and late (beyond 7 days). Risk of bias was assessed using Cochrane's RoB 2.0. Results were appraised descriptively as heterogeneity hindered meta-analysis. Certainty of evidence was evaluated using GRADE. RESULTS: Fifty-six RCTs were identified [colorectal (n = 18), hepatopancreaticobiliary (HPB) (n = 11), upper gastrointestinal (UGI) (n = 10), gynecological (n = 7), urological (n = 7), general surgery (n = 3)]. Most trials had 'some concerns' (n = 30) or 'high' (n = 25) risk of bias. In the early postoperative period, ERPs improved patient-reported general health (colorectal, HPB, UGI, urological; very low to low certainty), physical health (colorectal, gynecological; very low to low certainty), mental health (colorectal, gynecological; very low certainty), pain (all specialties; very low to moderate certainty), and fatigue (colorectal; low certainty). In the late postoperative period, ERPs improved general health (HPB, UGI, urological; very low certainty), physical health (UGI, gynecological, urological; very low to low certainty), mental health (UGI, gynecological, urological; very low certainty), social health (gynecological; very low certainty), pain (gynecological, urological; very low certainty), and fatigue (gynecological; very low certainty). CONCLUSION: This review supports that ERPs may have a positive impact on patient-reported postoperative health status (i.e., general, physical, mental, and social health) and symptom experience (i.e., pain and fatigue) after abdominal surgery; however, data were largely derived from low-quality trials. Although these findings contribute important knowledge to inform evidence-based ERP implementation, there remains a great need to improve PRO assessment in studies focused on postoperative recovery.

TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation.

Tumor necrosis factor receptor 2 (TNFR2) has been shown to play a crucial role in CD4+ T regulatory cells (CD4+Tregs) expansion and suppressive function. Increasing evidence has also demonstrated its role in a variety of immune regulatory cell subtypes such as CD8+ T regulatory cells (CD8+ Tregs), B regulatory cells (Bregs), and myeloid-derived suppressor cells (MDSCs). In solid organ transplantation, regulatory immune cells have been associated with decreased ischemia-reperfusion injury (IRI), improved graft survival, and improved overall outcomes. However, despite TNFR2 being studied in the context of autoimmune diseases, cancer, and hematopoietic stem cell transplantation, there remains paucity of data in the context of solid organ transplantation and islet cell transplantation. Interestingly, TNFR2 signaling has found a clinical application in islet transplantation which could guide its wider use. This article reviews the current literature on TNFR2 expression in immune modulatory cells as well as IRI, cell, and solid organ transplantation. Our results highlighted the positive impact of TNFR2 signaling especially in kidney and islet transplantation. However, further investigation of TNFR2 in all types of solid organ transplantation are required as well as dedicated studies on its therapeutic use during induction therapy or treatment of rejection.

Opioid versus opioid-free analgesia after surgical discharge: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Excessive opioid prescribing after surgery has contributed to the current opioid crisis; however, the value of prescribing opioids at surgical discharge remains uncertain. We aimed to estimate the extent to which opioid prescribing after discharge affects self-reported pain intensity and adverse events in comparison with an opioid-free analgesic regimen. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, Scopus, AMED, Biosis, and CINAHL from Jan 1, 1990, until July 8, 2021. We included multidose randomised controlled trials comparing opioid versus opioid-free analgesia in patients aged 15 years or older, discharged after undergoing a surgical procedure according to the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity definition (minor, moderate, major, and major complex). We screened articles, extracted data, and assessed risk of bias (Cochrane's risk-of-bias tool for randomised trials) in duplicate. The primary outcomes of interest were self-reported pain intensity on day 1 after discharge (standardised to 0-10 cm visual analogue scale) and vomiting up to 30 days. Pain intensity at further timepoints, pain interference, other adverse events, risk of dissatisfaction, and health-care reutilisation were also assessed. We did random-effects meta-analyses and appraised evidence certainty using the Grading of Recommendations, Assessment, Development, and Evaluations scoring system. The review was registered with PROSPERO (ID CRD42020153050). FINDINGS: 47 trials (n=6607 patients) were included. 30 (64%) trials involved elective minor procedures (63% dental procedures) and 17 (36%) trials involved procedures of moderate extent (47% orthopaedic and 29% general surgery procedures). Compared with opioid-free analgesia, opioid prescribing did not reduce pain on the first day after discharge (weighted mean difference 0·01cm, 95% CI -0·26 to 0·27; moderate certainty) or at other postoperative timepoints (moderate-to-very-low certainty). Opioid prescribing was associated with increased risk of vomiting (relative risk 4·50, 95% CI 1·93 to 10·51; high certainty) and other adverse events, including nausea, constipation, dizziness, and drowsiness (high-to-moderate certainty). Opioids did not affect other outcomes. INTERPRETATION: Findings from this meta-analysis support that opioid prescribing at surgical discharge does not reduce pain intensity but does increase adverse events. Evidence relied on trials focused on elective surgeries of minor and moderate extent, suggesting that clinicians can consider prescribing opioid-free analgesia in these surgical settings. Data were largely derived from low-quality trials, and none involved patients having major or major-complex procedures. Given these limitations, there is a great need to advance the quality and scope of research in this field. FUNDING: The Canadian Institutes of Health Research.

The Effect of Preoperative Anemia and Perioperative Transfusion on Surgical Outcomes After Gastrectomy for Gastric Cancer.

BACKGROUND: The aim of this study is to examine the interaction between preoperative anemia and perioperative transfusions with postoperative morbidity and mortality among patients undergoing gastrectomy for cancer. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2016. Restricted cubic splines modeled the nonlinear relationship between preoperative hematocrit (Hct) and 30-day overall morbidity, sepsis, and mortality. Preoperative Hct was categorized based on cut points for the three models. Multiple regression modeling examined the interactive effect of preoperative anemia and postoperative transfusion on surgical outcomes. RESULTS: Among 9936 included patients, complication incidence was 38.9% (sepsis 12.7%; mortality 6.0%). Preoperative Hct cut points were identified at 29 and 42. Hct <29 was associated with higher risk of morbidity (OR 2.47, 95%CI 2.10-2.93). Postoperative transfusion was associated with lower risk of morbidity for Hct <29 (OR 0.56, 95%CI 0.43-0.73) but increased risk between 29 and 42 (OR 1.59, 95%CI 1.21-2.08). Similar relationships were found for sepsis and mortality. CONCLUSIONS: Preoperative Hct <29 is associated with an increased risk of surgical complications after gastrectomy for cancer and perioperative transfusions appear to be beneficial for Hct <29 only. There may be a role for better optimization of red cell mass among high-risk patients before gastrectomy for cancer.

Opioid versus opioid-free analgesia after surgical discharge: protocol for a systematic review and meta-analysis.

INTRODUCTION: Excessive prescribing after surgery has contributed to a public health crisis of opioid addiction and overdose in North America. However, the value of prescribing opioids to manage postoperative pain after surgical discharge remains unclear. We propose a systematic review and meta-analysis to assess the extent to which opioid analgesia impact postoperative pain intensity and adverse events in comparison to opioid-free analgesia in patients discharged after surgery. METHODS AND ANALYSIS: Major electronic databases (MEDLINE, Embase, Cochrane Library, Scopus, AMED, BIOSIS, CINAHL and PsycINFO) will be searched for multi-dose randomised-trials examining the comparative effectiveness of opioid versus opioid-free analgesia after surgical discharge. Studies published from January 1990 to July 2019 will be targeted, with no language restrictions. The search will be re-run before manuscript submission to include most recent literature. We will consider studies involving patients undergoing minor and major surgery. Teams of reviewers will, independently and in duplicate, assess eligibility, extract data and evaluate risk of bias. Our main outcomes of interest are pain intensity and postoperative vomiting. Study results will be pooled using random effects models. When trials report outcomes for a common domain (eg, pain intensity) using different scales, we will convert effect sizes to a common standard metric (eg, Visual Analogue Scale). Minimally important clinical differences reported in previous literature will be considered when interpreting results. Subgroup analyses defined a priori will be conducted to explore heterogeneity. Risk of bias will be assessed according to the Cochrane Collaboration's Risk of Bias Tool 2.0. The quality of evidence for all outcomes will be evaluated using the GRADE rating system. ETHICS AND DISSEMINATION: Ethical approval is not required since this is a systematic review of published studies. Our results will be published in a peer-reviewed journal and presented at relevant conferences. Further knowledge dissemination will be sought via public and patient organisations focussed on pain and opioid-related harms.

Intracorporeal versus extracorporeal anastomosis for right colectomy does not affect gastrointestinal recovery within an enhanced recovery after surgery program.

INTRODUCTION: Delayed gastrointestinal (GI) recovery remains a significant morbidity after colorectal surgery. Intracorporeal anastomosis for right colectomy may hasten GI recovery. Therefore, the objective of this study was to determine the effect of intracorporeal versus extracorporeal anastomosis on GI recovery after elective laparoscopic right colectomy within an established ERAS program. METHODS: Adult patients undergoing elective laparoscopic right colectomy at a single high-volume institution from 07/2014 to 12/2018 were reviewed. Patients were divided into two groups: intracorporeal (IC) and extracorporeal (EC). The primary outcome was time to GI-3 defined as days to tolerance of solid diet and first flatus/bowel movement. Prolonged postoperative ileus (PPOI) was defined as GI-3 not met by postoperative day 4. Secondary outcomes were length of stay (LOS) and overall 30-day complications. Sensitivity analysis was performed using coarsened exact matching to account for unmeasured confounding. Multiple regression was performed using a Cox proportional hazard model to identify predictors of GI recovery. RESULTS: A total of 346 patients were reviewed, of which 226 were included (71IC, 155EC). Patient characteristics were well balanced between groups: mean age was 64.9 years (SD 15.9), BMI was 26.3 (SD 5.7), 38.1% of patients had ASA ≥ 3, and 78.3% underwent surgery for neoplasms. IC anastomosis was associated with longer operative duration (165 min (SD 40); 144 min (SD 48), p = 0.002). There was no difference in the median time to GI-3 (IC 2 days [IQR1-2]; EC 2 days [IQR2-3], p = 0.135). The incidence of PPOI (IC 8.5%; EC 10.3%, p = 0.659), superficial SSI (4.2% vs. 5.8%, p = 0.757), deep SSI (2.8% vs. 5.2%, p = 0.729), and median LOS (3 days [IQR 2-4] vs. 3 [IQR 3-5], p = 0.059) were also similar. On multivariate analysis, IC anastomosis did not independently predict faster GI recovery (HR 0.98, 95% CI 0.71-1.34). Similar results were observed in the matched cohort (185 patients (61IC, 124EC)). CONCLUSION: In this study, IC anastomosis was not associated with faster GI recovery or reduced complication rate compared to EC anastomosis. Longer term studies may be required to determine the potential benefits of IC anastomosis.

The Impact of Delays to Definitive Surgical Care on Survival in Colorectal Cancer Patients.

INTRODUCTION: Treatment delay may have detrimental effects on cancer outcomes. The impact of longer delays on colorectal cancer outcomes remains poorly described. The objective of this study was to determine the effect of delays to curative-intent surgical resection on survival in colorectal cancer patients. METHODS: All adult patients undergoing elective resection of primary non-metastatic colorectal adenocarcinoma from January 2009 to December 2014 were reviewed. Treatment delays were defined as the time from tissue diagnosis to definitive surgery, categorized as < 4, 4 to < 8, and ≥ 8 weeks. Primary outcomes were 5-year disease-free (DFS) and overall survival (OS). Statistical analysis included Kaplan-Meier curves and Cox regression models. RESULTS: A total of 408 patients were included (83.2% colon;15.8% rectal) with a mean follow-up of 58.4 months (SD29.9). Fourteen percent (14.0%) of patients underwent resection < 4 weeks, 40.0% 4 to < 8 weeks, and 46.1% ≥ 8 weeks. More rectal cancer patients had treatment delay ≥ 8 weeks compared with colonic tumors (69.8% vs. 41.4%, p < 0.001). Cumulative 5-year DFS and OS were similar between groups (p = 0.558; p = 0.572). After adjusting for confounders, surgical delays were not independently associated with DFS and OS. CONCLUSIONS: Treatment delays > 4 weeks were not associated with worse oncologic outcomes. Delaying surgery to optimize patients can safely be considered without compromising survival.

Preventing opioid prescription after major surgery: a scoping review of opioid-free analgesia.

BACKGROUND: Excessive opioid prescribing after surgery has been recognised as a contributor to the current crisis of opioid addiction and overdose. Clinicians may potentially tackle this crisis by using opioid-free postoperative analgesia; however, the scientific literature addressing this approach is sparse and heterogeneous, thereby limiting robust conclusions. A scoping review was conducted to systematically map the extent, range, and nature of the literature addressing postoperative opioid-free analgesia. METHODS: Eight bibliographic databases were searched for studies addressing opioid-free analgesia after a major surgery. We extracted the study characteristics, including design, country, year, surgical procedure(s), and interventions. Results were organised thematically according to surgical specialty and targeted phase of recovery: in hospital (early recovery, ≤24 h after operation; intermediate recovery, >24 h) and post-discharge (late recovery). Reporting was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for scoping reviews. RESULTS: We identified 424 studies addressing postoperative opioid-free analgesia. The number of studies conducted in countries where the opioid crisis is primarily focused was remarkably low (USA, n=11 [3%]; Canada, n=5 [1%]). Many RCTs compared opioid-free vs opioid analgesia during hospital stay (n=117), but few targeted analgesia post-discharge (n=8). Studies were predominantly focused on procedures in orthopaedic, general, and gynaecological/obstetric surgery. Limited attention has been directed towards non-pharmacological pain interventions. We did not identify knowledge synthesis studies (i.e. systematic reviews and meta-analyses) focused on the comparative effectiveness of opioid-free vs opioid analgesia. CONCLUSIONS: Opioids remain a mainstay analgesic for managing pain after surgery, but alternative analgesia strategies should not be overlooked. This scoping review indicates numerous opportunities for future research targeting opioid-free postoperative analgesia. REVIEW REGISTRATION: http://www.researchregistry.com; ID: reviewregistry576.

Examining the relationship between lymph node harvest and survival in patients undergoing colectomy for colon adenocarcinoma.

BACKGROUND: Current standards for lymph node harvest in colorectal cancer surgery may be inadequate. Higher lymph node yield may improve survival, but the number of lymph nodes needed to optimize survival is unknown. The objective of this study was to examine the relationship between lymph node yield and overall survival in patients undergoing colectomy for nonmetastatic colon adenocarcinoma. METHODS: The 2010 to 2014 National Cancer Database was queried for patients undergoing colectomy for nonmetastatic colon adenocarcinoma. Adjusted restricted cubic splines were used to model the nonlinear relationship between lymph node harvest and overall survival. Cox proportional hazard determined independent predictors of overall survival. RESULTS: A total of 261,423 patients were included. Restricted cubic splines demonstrated that the adjusted improvements in overall survival stabilized after 24 nodes. Patients were divided into: <12, 12 to 23, and ≥24 nodes. On survival analysis, patients with ≥24 nodes had better survival across all N stages compared to other groups (P < .001). Lymph node harvest ≥24 nodes was independently associated with improved overall survival compared to 12 to 23 nodes (hazard ratio 0.82; 95% confidence interval, 0.80-0.85). CONCLUSION: Lymph node harvest ≥24 nodes is associated with improved survival in colorectal cancer patients. These data may provide indirect evidence for a more extensive lymphadenectomy for colon cancer.