Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.

Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.

Management Strategies for Malignant Left-Sided Colonic Obstruction: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials and Propensity Score Matching Studies.

BACKGROUND: The optimal treatment strategy for left-sided malignant colonic obstruction remains controversial. Emergency colonic resection has been the standard of care; however, self-expanding metallic stenting as a bridge to surgery may offer short-term advantages, although oncological concerns exist. Decompressing stoma may provide a valid alternative, with limited evidence. OBJECTIVE: To perform a systematic review and Bayesian arm random effects model network meta-analysis comparing the approaches for management of malignant left-sided colonic obstruction. DATA SOURCES: A systematic review was conducted from inception to August 22, 2023, of PubMed, Embase, Cochrane Library, and Google Scholar databases. STUDY SELECTION: Randomized controlled trials and propensity score matched studies. INTERVENTIONS: Emergency colonic resection, self-expanding metallic stent, decompressing stoma. MAIN OUTCOME MEASURES: Oncologic efficacy, morbidity, successful minimally invasive surgery, primary anastomosis, and permanent stoma rates. RESULTS: Nineteen articles from 5225 identified met our inclusion criteria. Stenting (risk ratio 0.57, 95% credible interval: 0.33, 0.79) and decompressing stomas (risk ratio 0.46, 95% credible interval: 0.18, 0.92) both resulted in a significant reduction in the permanent stoma rate. Stenting facilitated minimally invasive surgery more frequently (risk ratio 4.10, 95% credible interval: 1.45, 13.13) and had lower overall morbidity (risk ratio 0.58, 95% credible interval: 0.35, 0.86). A pairwise analysis of primary anastomosis rates showed an increase in stenting (risk ratio 1.40, 95% credible interval: 1.31, 1.49) as compared with emergency resection. There was a significant decrease in the 90-day mortality with stenting (risk ratio 0.63, 95% credible interval: 0.41, 0.95) when compared with resection. There were no differences in disease-free and overall survival rates, respectively. LIMITATIONS: There is a lack of randomized controlled trial and propensity score matching data comparing short and long-term outcomes for diverting stomas compared to self-expanding metallic stents. Two trials compared self-expanding metallic stents and diverting stomas in left-sided malignant colonic obstruction. CONCLUSION: This study provides high-level evidence that bridge-to-surgery strategy is safe for the management of left-sided malignant colonic obstruction, and may facilitate minimally invasive surgery, increase primary anastomosis rates, and reduce permanent stoma rates and postoperative morbidity as compared to emergency colonic resection.

Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Evaluating analgesia strategies in patients who have undergone oesophagectomy-a systematic review and network meta-analysis of randomised clinical trials.

Optimal pain control following esophagectomy remains a topic of contention. The aim was to perform a systematic review and network meta-analysis (NMA) of randomized clinical trials (RCTs) evaluating the analgesia strategies post-esophagectomy. A NMA was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-NMA guidelines. Statistical analysis was performed using Shiny and R. Fourteen RCTs which included 565 patients and assessed nine analgesia techniques were included. Relative to systemic opioids, thoracic epidural analgesia (TEA) significantly reduced static pain scores at 24 hours post-operatively (mean difference (MD): -13.73, 95% Confidence Interval (CI): -27.01-0.45) (n = 424, 12 RCTs). Intrapleural analgesia (IPA) demonstrated the best efficacy for static (MD: -36.2, 95% CI: -61.44-10.96) (n = 569, 15 RCTs) and dynamic (MD: -42.90, 95% CI: -68.42-17.38) (n = 444, 11 RCTs) pain scores at 48 hours. TEA also significantly reduced static (MD: -13.05, 95% CI: -22.74-3.36) and dynamic (MD: -18.08, 95% CI: -31.70-4.40) pain scores at 48 hours post-operatively, as well as reducing opioid consumption at 24 hours (MD: -33.20, 95% CI: -60.57-5.83) and 48 hours (MD: -42.66, 95% CI: -59.45-25.88). Moreover, TEA significantly shortened intensive care unit (ICU) stays (MD: -5.00, 95% CI: -6.82-3.18) and time to extubation (MD: -4.40, 95% CI: -5.91-2.89) while increased post-operative forced vital capacity (MD: 9.89, 95% CI: 0.91-18.87) and forced expiratory volume (MD: 13.87, 95% CI: 0.87-26.87). TEA provides optimal pain control and improved post-operative respiratory function in patients post-esophagectomy, reducing ICU stays, one of the benchmarks of improved post-operative recovery. IPA demonstrates promising results for potential implementation in the future following esophagectomy.

Evaluating mesh fixation techniques for ventral hernia repair: A systematic review and network meta-analysis of randomised control trials.

INTRODUCTION: There is uncertainty regarding the optimal mesh fixation techniques for laparoscopic ventral and incisional hernia repair. AIM: To perform a systematic review and network meta-analysis of randomised control trials (RCTs) to investigate the advantages and disadvantages associated with absorbable tacks, non-absorbable tacks, non-absorbable sutures, non-absorbable staples, absorbable synthetic glue, absorbable sutures and non-absorbable tacks, and non-absorbable sutures and non-absorbable tacks. METHODS: A systematic review was performed as per PRISMA-NMA guidelines. Odds ratios (ORs) and mean differences (MDs) were extracted to compare the efficacy of the surgical approaches. RESULTS: Nine RCTs were included with 707 patients. Short-term pain was significantly reduced in non-absorbable staples (MD; -1.56, confidence interval (CI); -2.93 to -0.19) and non-absorbable sutures (MD; -1.00, CI; -1.60 to -0.40) relative to absorbable tacks. Recurrence, length of stay, operative time, conversion to open surgery, seroma and haematoma formation were unaffected by mesh fixation technique. CONCLUSION: Short-term post-operative pain maybe reduced by the use of non-absorbable sutures and non-absorbable staples. There is clinical equipoise between each modality in relation to recurrence, length of stay, and operative time.

Surgical Approach for Partial Nephrectomy in the Management of Small Renal Masses: A Systematic Review and Network Meta-Analysis.

Background: A variety of surgical and nonsurgical management options for small renal masses (SRMs) now exist. Surgery in the form of partial nephrectomy (PN) has three different approaches. It is unclear which PN approach, if any, offers superior clinical outcomes. Aim: The aim of this study is to compare outcomes in patients with SRMs <4 cm undergoing PN through the open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN), or robotic partial nephrectomy (RPN) approach and to establish the advantages and disadvantages of the various approaches. Methods: A systematic literature search was conducted for studies comparing at least two of the above techniques. Eighteen studies and 17,013 patients were included in our study. A network meta-analysis with a frequentist framework was performed. OPN was used as the baseline comparator. The prespecified primary outcome was R0 resection rates. Secondary outcomes included operating time, ischemia time, blood loss, transfusion rates, urine leak rates, significant morbidity, length of stay, and recurrence. Results: There was no significant difference between the techniques in terms of R0 rates, tumor recurrence, urine leak rates, renal function, and >3a Clavien-Dindo complications. LPN had a longer ischemic time and operating time. OPN had a longer length of stay and higher average intraoperative blood loss. RPN had lower blood transfusion rates. Discussion: All approaches are acceptable from an oncological perspective. The minimally invasive approaches (i.e., RPN and LPN) offer advantages in terms of morbidity; however, LPN may increase ischemic time and operative duration. Variations between perioperative outcomes may influence the choice of approach on a case-by-case and institutional basis.

Comparing neoadjuvant therapy followed by local excision to total mesorectal excision in the treatment of early stage rectal cancer: a systematic review and meta-analysis of randomised clinical trials.

INTRODUCTION: Total mesorectal excision (TME) is the standard-of-care in early, clinical stage (cT2-3 N0 M0) rectal cancer. Local excision (LE) may be an alternative after adequate response to neoadjuvant therapy (NAT), with either long-course chemoradiotherapy (nCRT) or short-course radiotherapy (SCRT), as a means of preserving the rectum and potentially obviating the morbidity of TME. METHODS: A systematic review was performed according to PRISMA guidelines for studies that randomly assigned patients with cT2-3 N0 M0 rectal cancer to either NAT + LE or TME that reported radiologic, oncologic, surgical, and morbidity outcomes. RESULTS: A total of 4 RCTs comprise 462 patients (232 patients receiving NAT + LE; nCRT n = 205; SCRT n = 27) and 230 undergoing TME, respectively. NAT compliance was 98.86%. The rate of early completion TME in the NAT + LE group was 22.3%, while the proportion of patients achieving durable organ preservation was 75.4% at mean follow-up of 5.6 years. There was no difference in disease-free survival (DFS) (HR [hazard ratio] 1.19; 95% CI 0.95, 1.49; p = 0.13) or overall survival (OS) (HR 0.94; 95% CI 0.72, 1.23; p = 0.63]) according to the assigned treatment arm. The local recurrence rate (LRR) (HR 1.22; 95% CI 0.5-3.02; p = 0.66) and distant metastases (HR 0.92; 95% CI 0.45, 1.90; p = 0.82) were also comparable between the groups. There was a significant reduction in major (OR 0.45; 95% CI 0.21, 0.95; p = 0.04) and minor morbidity (OR 0.45; 95% CI 0.24, 0.85; p = 0.01) for patients undergoing NAT + LE. Overall stoma formation was decreased in the NAT + LE group (OR 0.03; 95% CI 0.0, 0.23; p ≤ 0.00001). CONCLUSION: NAT + LE reduces adverse effects of TME, without any compromise in oncological outcomes, and the potential for an organ preserving strategy should be discussed with patients with T2-3N0 rectal cancers prior to treatment.

Surgical management strategies for colorectal malignancies of the splenic flexure - A systematic review and network meta-analysis.

BACKGROUND: Extended right hemicolectomy (ERHC) or left hemicolectomy (LHC) are accepted as the standard-of-care for colonic tumours of the splenic flexure. Lymphatic drainage at this site is poorly defined and subject to significant heterogeneity. Nevertheless, emerging evidence demonstrates the potential oncological safety of segmental splenic flexure colectomy (SFC). AIM: To perform a systematic review and network meta-analysis (NMA) to compare outcomes following ERHC, LHC and SFC for splenic flexure tumours (SFTs). METHODS: A systematic review was performed as per PRISMA guidelines. NMA was performed using R Shiny and Netmeta packages. RESULTS: A total of 13 studies, involving 6176 patients (ERHC n = 785; LHC n = 1527; SFC n = 3864) were included in the NMA. There was no difference in overall survival (OS) (SFC vs LHC Hazard Ratio [HR] 1.0, 95% Credible Interval [CrI] 0.76,1.34; SFC vs ERHC HR 1.18, 95% CrI 0.85,1.58) between the groups. SFC had a shorter operation time (Mean 176.37 min; Mean Difference [MD] SFC vs LHC 20.34 min 95% CrI 10.9, 29.97; SFC vs ERHC MD 22.19 95% CrI 11.09, 33.29) but also had a lower average lymph node yield (LNY) compared with ERHC (MD 7.15, 95% CrI 5.71, 8.60). ERHC had a significantly higher incidence of post-operative ileus (Odds Ratio [OR] 3.47, 95% CrI 1.11, 10.84). There was also no difference observed for minimally invasive approaches, anastomotic leak rate, perioperative mortality, reoperation rates or length of stay. CONCLUSIONS: While SFC may allow for reduced operative duration and improved bowel function postoperatively. SFC, LHC, ERHC are all acceptable approaches for curative resection of cancers of the splenic flexure, with no difference in OS observed. Thus, surgeon preference and candidate-specific factors will likely determine the management of SFTs.

Obesity, Sarcopenia and Myosteatosis: Impact on Clinical Outcomes in the Operative Management of Crohn's Disease.

BACKGROUND: Obesity, sarcopenia, and myosteatosis in inflammatory bowel disease may confer negative outcomes, but their prevalence and impact among patients with Crohn's disease (CD) have not been systematically studied. The aim of this study was to assess nutritional status and body composition among patients undergoing resectional surgery for CD and determine impact on operative outcomes. METHODS: Consecutive patients with CD undergoing resection from 2000 to 2018 were studied. Total, subcutaneous, and visceral fat areas and lean tissue area (LTA) and intramuscular adipose tissue (IMAT) were determined preoperatively by computed tomography at L3 using SliceOmatic (Tomovision, Canada). Univariable and multivariable linear, logistic, and Cox proportional hazards regression were performed. RESULTS: One hundred twenty-four consecutive patients were studied (ileocolonic disease 53%, n = 62, biologic therapy 34.4% n = 43). Mean fat mass was 22.7 kg, with visceral obesity evident in 23.9% (n = 27). Increased fat stores were associated with reduced risk of emergency presentation but increased corticosteroid use (ß 9.09, standard error 3.49; P = .011). Mean LBM was 9.9 kg. Sarcopenia and myosteatosis were associated with impaired baseline nutritional markers. Myosteatosis markers IMAT (P = .002) and muscle attenuation (P = .0003) were associated with increased grade of complication. On multivariable analysis, IMAT was independently associated with increased postoperative morbidity (odds ratio [OR], 1.08; 95% confidence interval (CI), 1.01-1.16; P = .037) and comprehensive complications index (P = .029). Measures of adiposity were not associated with overall morbidity; however, increased visceral fat area independently predicted venous thromboembolism (OR, 1.02; 95% CI, 1.00-1.05; P = .028), and TFA was associated with increased wound infection (OR, 1.00; 95% CI, 1.00-1.01; P = .042) on multivariable analysis. CONCLUSION: Myosteatosis is associated with nutritional impairment and predicts increased overall postoperative morbidity following resection for CD. Despite its association with specific increased postoperative risks, increased adiposity does not increase overall morbidity, reflecting preservation of nutritional status and relatively more quiescent disease phenotype. Impaired muscle mass and function represent an appealing target for patient optimization to improve outcomes in the surgical management of CD.

Myosteatosis was predictive of postoperative morbidity following surgery for Crohn's Disease. Increased adiposity does not increase overall morbidity, reflecting a more quiescent disease phenotype. Obesity, myosteatosis, and sarcopenia represent appealing targets for patient optimization to improve outcomes surgical outcomes in Crohn's Disease.

Redo Pelvic Surgery and Combined Metastectomy for Locally Recurrent Rectal Cancer with Known Oligometastatic Disease: A Multicentre Review.

INTRODUCTION: Historically, surgical resection for patients with locally recurrent rectal cancer (LRRC) had been reserved for those without metastatic disease. 'Selective' patients with limited oligometastatic disease (OMD) (involving the liver and/or lung) are now increasingly being considered for resection, with favourable five-year survival rates. METHODS: A retrospective analysis of consecutive patients undergoing multi-visceral pelvic resection of LRRC with their oligometastatic disease between 1 January 2015 and 31 August 2021 across four centres worldwide was performed. The data collected included disease characteristics, neoadjuvant therapy details, perioperative and oncological outcomes. RESULTS: Fourteen participants with a mean age of 59 years were included. There was a female preponderance (n = 9). Nine patients had liver metastases, four had lung metastases and one had both lung and liver disease. The mean number of metastatic tumours was 1.5 +/- 0.85. R0 margins were obtained in 71.4% (n = 10) and 100% (n = 14) of pelvic exenteration and oligometastatic disease surgeries, respectively. Mean lymph node yield was 11.6 +/- 6.9 nodes, with positive nodes being found in 28.6% (n = 4) of cases. A single major morbidity was reported, with no perioperative deaths. At follow-up, the median disease-free survival and overall survival were 12.3 months (IQR 4.5-17.5 months) and 25.9 months (IQR 6.2-39.7 months), respectively. CONCLUSIONS: Performing radical multi-visceral surgery for LRRC and distant oligometastatic disease appears to be feasible in appropriately selected patients that underwent good perioperative counselling.

Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

Total neoadjuvant therapy versus standard neoadjuvant treatment strategies for the management of locally advanced rectal cancer: network meta-analysis of randomized clinical trials.

BACKGROUND: This study compared the advantages and disadvantages of total neoadjuvant therapy (TNT) strategies for patients with locally advanced rectal cancer, compared with the more traditional multimodal neoadjuvant management strategies of long-course chemoradiotherapy (LCRT) or short-course radiotherapy (SCRT). METHODS: A systematic review and network meta-analysis of exclusively RCTs was undertaken, comparing survival, recurrence, pathological, radiological, and oncological outcomes. The last date of the search was 14 December 2022. RESULTS: In total, 15 RCTs involving 4602 patients with locally advanced rectal cancer, conducted between 2004 and 2022, were included. TNT improved overall survival compared with LCRT (HR 0.73, 95 per cent credible interval 0.60 to 0.92) and SCRT (HR 0.67, 0.47 to 0.95). TNT also improved rates of distant metastasis compared with LCRT (HR 0.81, 0.69 to 0.97). Reduced overall recurrence was observed for TNT compared with LCRT (HR 0.87, 0.76 to 0.99). TNT showed an improved pCR compared with both LCRT (risk ratio (RR) 1.60, 1.36 to 1.90) and SCRT (RR 11.32, 5.00 to 30.73). TNT also showed an improvement in cCR compared with LCRT (RR 1.68, 1.08 to 2.64). There was no difference between treatments in disease-free survival, local recurrence, R0 resection, treatment toxicity or treatment compliance. CONCLUSION: This study provides further evidence that TNT has improved survival and recurrence benefits compared with current standards of care, and may increase the number of patients suitable for organ preservation, without negatively influencing treatment toxicity or compliance.

Minimally Invasive and Open Gastrectomy for Gastric Cancer: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials.

BACKGROUND AND OBJECTIVES: Optimal surgical management for gastric cancer remains controversial. We aimed to perform a network meta-analysis (NMA) of randomized clinical trials (RCTs) comparing outcomes after open gastrectomy (OG), laparoscopic-assisted gastrectomy (LAG), and robotic gastrectomy (RG) for gastric cancer. METHODS: A systematic search of electronic databases was undertaken. An NMA was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-NMA guidelines. Statistical analysis was performed using R and Shiny. RESULTS: Twenty-two RCTs including 6890 patients were included. Overall, 49.6% of patients underwent LAG (3420/6890), 46.6% underwent OG (3212/6890), and 3.7% underwent RG (258/6890). At NMA, there was a no significant difference in recurrence rates following LAG (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.77-1.49) compared with OG. Similarly, overall survival (OS) outcomes were identical following OG and LAG (OS: OG, 87.0% [1652/1898] vs. LAG: OG, 87.0% [1650/1896]), with no differences in OS in meta-analysis (OR 1.02, 95% CI 0.77-1.52). Importantly, patients undergoing LAG experienced reduced intraoperative blood loss, surgical incisions, distance from proximal margins, postoperative hospital stays, and morbidity post-resection. CONCLUSIONS: LAG was associated with non-inferior oncological and surgical outcomes compared with OG. Surgical outcomes following LAG and RG superseded OG, with similar outcomes observed for both LAG and RG. Given these findings, minimally invasive approaches should be considered for the resection of local gastric cancer, once surgeon and institutional expertise allows.

The Impact of Bariatric Surgery on the Incidence of Colorectal Cancer in Patients with Obesity-a Systematic Review and Meta-analysis of Registry Data.

PURPOSE: Cancer and obesity represent two of the most significant global health concerns. The risk of malignancy, including colorectal cancer (CRC), increases with obesity. The aim of this study was to perform a systematic review and meta-analysis to determine the value of bariatric surgery in reducing CRC risk in patients with obesity using registry data. MATERIALS AND METHODS: A systematic review and meta-analysis were performed as per PRISMA guidelines. The risk of CRC was expressed as a dichotomous variable and reported as odds ratios (OR) with 95% confidence intervals (CIs) using the Mantel-Haenszel method. A multi-treatment comparison was performed, examining the risk reduction associated with existing bariatric surgery techniques. Analysis was performed using RevMan, R packages, and Shiny. RESULTS: Data from 11 registries including 6,214,682 patients with obesity were analyzed. Of these, 14.0% underwent bariatric surgery (872,499/6,214,682), and 86.0% did not undergo surgery (5,432,183/6,214,682). The mean age was 49.8 years, and mean follow-up was 5.1 years. In total, 0.6% of patients who underwent bariatric surgery developed CRC (4,843/872,499), as did 1.0% of unoperated patients with obesity (54,721/5,432,183). Patients with obesity who underwent bariatric surgery were less likely to develop CRC (OR: 0.53, 95% CI: 0.36-0.77, P < 0.001, I2 = 99%). Patients with obesity undergoing gastric bypass surgery (GB) (OR: 0.513, 95% CI: 0.336-0.818) and sleeve gastrectomy (SG) (OR: 0.484, 95% CI: 0.307-0.763) were less likely to develop CRC than unoperated patients. CONCLUSION: At a population level, bariatric surgery is associated with reduced CRC risk in patients with obesity. GB and SG are associated with the most significant reduction in CRC risk. PROSPERO REGISTRATION: CRD42022313280.

PD-1 blockade attenuates surgery-mediated immunosuppression and boosts Th1 immunity perioperatively in oesophagogastric junctional adenocarcinoma.

Introduction: This timely study assesses the immunosuppressive effects of surgery on cytotoxic Th1-like immunity and investigates if immune checkpoint blockade (ICB) can boost Th1-like immunity in the perioperative window in upper gastrointestinal cancer (UGI) patients. Methods: PBMCs were isolated from 11 UGI patients undergoing tumour resection on post-operative days (POD) 0, 1, 7 and 42 and expanded ex vivo using anti-CD3/28 and IL-2 for 5 days in the absence/presence of nivolumab or ipilimumab. T cells were subsequently immunophenotyped via flow cytometry to determine the frequency of T helper (Th)1-like, Th1/17-like, Th17-like and regulatory T cell (Tregs) subsets and their immune checkpoint expression profile. Lymphocyte secretions were also assessed via multiplex ELISA (IFN-γ, granzyme B, IL-17 and IL-10). The 48h cytotoxic ability of vehicle-, nivolumab- and ipilimumab-expanded PBMCs isolated on POD 0, 1, 7 and 42 against radiosensitive and radioresistant oesophageal adenocarcinoma tumour cells (OE33 P and OE33 R) was also examined using a cell counting kit-8 (CCK-8) assay to determine if surgery affected the killing ability of lymphocytes and whether the use of ICB could enhance cytotoxicity. Results: Th1-like immunity was suppressed in expanded PBMCs in the immediate post-operative setting. The frequency of expanded circulating Th1-like cells was significantly decreased post-operatively accompanied by a decrease in IFN-γ production and a concomitant increase in the frequency of expanded regulatory T cells with an increase in circulating levels of IL-10. Interestingly, PD-L1 and CTLA-4 immune checkpoint proteins were also upregulated on expanded Th1-like cells post-operatively. Additionally, the cytotoxic ability of expanded lymphocytes against oesophageal adenocarcinoma tumour cells was abrogated post-surgery. Of note, the addition of nivolumab or ipilimumab attenuated the surgery-mediated suppression of lymphocyte cytotoxicity, demonstrated by a significant increase in tumour cell killing and an increase in the frequency of Th1-like cells and Th1 cytokine production. Conclusion: These findings support the hypothesis of a surgery-mediated suppression in Th1-like cytotoxic immunity and highlights a rationale for the use of ICB within the perioperative setting to abrogate tumour-promoting effects of surgery and ameliorate the risk of recurrence.

Comparing surgical outcomes of approaches to adrenalectomy - a systematic review and network meta-analysis of randomised clinical trials.

BACKGROUND: No randomised clinical trials (RCTs) have simultaneously compared the safety of open (OA), transperitoneal laparoscopic (TLA), posterior retroperitoneal (PRA), and robotic adrenalectomy (RA) for resecting adrenal tumours. AIM: To evaluate outcomes for OA, TLA, PRA, and RA from RCTs. METHODS: A NMA was performed according to PRISMA-NMA guidelines. Analysis was performed using R packages and Shiny. RESULTS: Eight RCTs with 488 patients were included (mean age: 48.9 years). Overall, 44.5% of patients underwent TLA (217/488), 37.3% underwent PRA (182/488), 16.4% underwent RA (80/488), and just 1.8% patients underwent OA (9/488). The mean tumour size was 35 mm in largest diameter with mean sizes of 44.3 mm for RA, 40.9 mm for OA, 35.5 mm for TLA, and 34.4 mm for PRA (P < 0.001). TLA had the lowest blood loss (mean: 50.6 ml), complication rates (12.4%, 14/113), and conversion to open rates (1.3%, 2/157), while PRA had the shortest intra-operative duration (mean: 94 min), length of hospital stay (mean: 3.7 days), lowest visual analogue scale pain scores post-operatively (mean: 3.7), and was most cost-effective (mean: 1728 euros per case). At NMA, there was a significant increase in blood loss for OA (mean difference (MD): 117.00 ml (95% confidence interval (CI): 1.41-230.00)) with similar blood loss observed for PRA (MD: - 10.50 (95% CI: - 83.40-65.90)) compared to TLA. CONCLUSION: LTA and PRA are important contemporary options in achieving favourable outcomes following adrenalectomy. The next generation of RCTs may be more insightful for comparison surgical outcomes following RA, as this approach is likely to play a future role in minimally invasive adrenalectomy. PROSPERO REGISTRATION: CRD42022301005.

Mechanical bowel preparation and antibiotics in elective colorectal surgery: network meta-analysis.

BACKGROUND: The use of intravenous antibiotics at anaesthetic induction in colorectal surgery is the standard of care. However, the role of mechanical bowel preparation, enemas, and oral antibiotics in surgical site infection, anastomotic leak, and other perioperative outcomes remains controversial. The aim of this study was to determine the optimal preoperative bowel preparation strategy in elective colorectal surgery. METHODS: A systematic review and network meta-analysis of RCTs was performed with searches from PubMed/MEDLINE, Scopus, Embase, and the Cochrane Central Register of Controlled Trials from inception to December 2022. Primary outcomes included surgical site infection and anastomotic leak. Secondary outcomes included 30-day mortality rate, ileus, length of stay, return to theatre, other infections, and side effects of antibiotic therapy or bowel preparation. RESULTS: Sixty RCTs involving 16 314 patients were included in the final analysis: 3465 (21.2 per cent) had intravenous antibiotics alone, 5268 (32.3 per cent) had intravenous antibiotics + mechanical bowel preparation, 1710 (10.5 per cent) had intravenous antibiotics + oral antibiotics, 4183 (25.6 per cent) had intravenous antibiotics + oral antibiotics + mechanical bowel preparation, 262 (1.6 per cent) had intravenous antibiotics + enemas, and 1426 (8.7 per cent) had oral antibiotics + mechanical bowel preparation. With intravenous antibiotics as a baseline comparator, network meta-analysis demonstrated a significant reduction in total surgical site infection risk with intravenous antibiotics + oral antibiotics (OR 0.47 (95 per cent c.i. 0.32 to 0.68)) and intravenous antibiotics + oral antibiotics + mechanical bowel preparation (OR 0.55 (95 per cent c.i. 0.40 to 0.76)), whereas oral antibiotics + mechanical bowel preparation resulted in a higher surgical site infection rate compared with intravenous antibiotics alone (OR 1.84 (95 per cent c.i. 1.20 to 2.81)). Anastomotic leak rates were lower with intravenous antibiotics + oral antibiotics (OR 0.63 (95 per cent c.i. 0.44 to 0.90)) and intravenous antibiotics + oral antibiotics + mechanical bowel preparation (OR 0.62 (95 per cent c.i. 0.41 to 0.94)) compared with intravenous antibiotics alone. There was no significant difference in outcomes with mechanical bowel preparation in the absence of intravenous antibiotics and oral antibiotics in the main analysis. CONCLUSION: A bowel preparation strategy with intravenous antibiotics + oral antibiotics, with or without mechanical bowel preparation, should represent the standard of care for patients undergoing elective colorectal surgery.

Comparing minimally invasive surgical and open approaches to pelvic exenteration for locally advanced or recurrent pelvic malignancies - Systematic review and meta-analysis.

INTRODUCTION: Pelvic exenteration (PE) is a complex multivisceral surgical procedure indicated for locally advanced or recurrent pelvic malignancies. It poses significant technical challenges which account for the high risk of morbidity and mortality associated with the procedure. Developments in minimally invasive surgical (MIS) approaches and enhanced peri-operative care have facilitated improved long term outcomes. However, the optimum approach to PE remains controversial. METHODS: A systematic literature search was conducted in accordance with PRISMA guidelines to identify studies comparing MIS (robotic or laparoscopic) approaches for PE versus the open approach for patients with locally advanced or recurrent pelvic malignancies. The methodological quality of the included studies was assessed systematically and a meta-analysis was conducted. RESULTS: 11 studies were identified, including 2009 patients, of whom 264 (13.1%) underwent MIS PE approaches. The MIS group displayed comparable R0 resections (Risk Ratio [RR] 1.02, 95% Confidence Interval [95% CI] 0.98, 1.07, p = 0.35)) and Lymph node yield (Weighted Mean Difference [WMD] 1.42, 95% CI -0.58, 3.43, p = 0.16), and although MIS had a trend towards improved towards improved survival and recurrence outcomes, this did not reach statistical significance. MIS was associated with prolonged operating times (WMD 67.93, 95% CI 4.43, 131.42, p < 0.00001) however, this correlated with less intra-operative blood loss, and a shorter length of post-operative stay (WMD -3.89, 955 CI -6.53, -1.25, p < 0.00001). Readmission rates were higher with MIS (RR 2.11, 95% CI 1.11, 4.02, p = 0.02), however, rates of pelvic abscess/sepsis were decreased (RR 0.45, 95% CI 0.21, 0.95, p = 0.04), and there was no difference in overall, major, or specific morbidity and mortality. CONCLUSION: MIS approaches are a safe and feasible option for PE, with no differences in survival or recurrence outcomes compared to the open approach. MIS also reduced the length of post-operative stay and decreased blood loss, offset by increased operating time.

Comparison of Restorative Proctocolectomy with and Without Defunctioning Loop Ileostomy in Patients with Ulcerative Colitis: A Systematic Review and Meta-analysis.

BACKGROUND: Restorative proctocolectomy [RPC] without a defunctioning loop ileostomy [DLI] in patients with ulcerative colitis [UC] remains controversial. AIM: To compare safety and efficacy of RPC with and without DLI in patients exclusively with UC. METHODS: A systematic review was performed according to PRISMA/MOOSE guidelines. Dichotomous variables were pooled as odds ratios [OR]. Continuous variables were pooled as weighted mean differences [WMD]. Quality assessment was performed using the Newcastle-Ottawa score [NOS]. RESULTS: A total of 20 studies [five paediatric and 15 adult] with 4550 UC patients [without DLI, n = 2370, 52.09%; with DLI, n = 2180, 47.91%] were eligible for inclusion. The median NOS was 8 [range 6-9]. There was no increased risk of anastomotic leak [AL] (OR 1.13, 95% confidence interval [CI]: 0.92, 1.39; p = 0.25), pouch excision [OR 1.01, 95% CI: 0.68, 1.50; p = 0.97], or overall major morbidity [OR 1.44, 95% CI, 0.91, 2.29; p = 0.12] for RPC without DLI, and this technique was associated with fewer anastomotic strictures [OR 0.45, 95% CI: 0.29, 0.68; p = 0.0002] and less bowel obstruction [OR 0.73, 95% CI: 0.57, 0.93; p = 0.01]. However, RPC without DLI increased the likelihood of pelvic sepsis [OR 1.68, 95% CI: 1.03, 2.75; p = 0.04] and emergency reoperation [OR 1.74, 95% CI: 1.22, 2.50; p = 0.002]. CONCLUSION: RPC without DLI is not associated with increased clinically overt AL or pouch excision rates. However, it is associated with increased risk of pelvic sepsis and emergency reoperation. RPC without DLI is feasible, but should only be performed judiciously in select UC patient cohorts in high-volume, specialist, tertiary centres.