Background: Anastomotic leaks (ALs) remain a critical complication after rectal cancer surgery. Emerging evidence suggests that local immune dysregulation may play a key role in anastomotic healing. We investigated the immune microenvironment of histologically normal, tumor-adjacent rectal mucosa—a tumor-conditioned field—as a potential substrate for AL predisposition. Methods: IMMUNOREACT 4 is a sub-analysis of the IMMUNOREACT project (clinicaltrials.gov NCT04915326 and NCT04915326), a multicenter translational study evaluating immune features of histologically normal, tumor-adjacent rectal mucosa of patients undergoing colorectal anastomosis. A prospective cohort (n = 121) was analyzed using flow cytometry, in addition to a retrospective cohort (n = 262) using immunohistochemistry. Immune markers of epithelial activation and lymphocyte subsets were compared between patients with and without postoperative ALs. Exploratory predictive models combining immune and clinical variables were developed and evaluated using discrimination, calibration and decision curve analyses. Results: At flow cytometry, the CK⁺HLAabc⁺ MFI (AUC 0.66, 95% CI 0.52–0.80), CD8⁺CD38⁺ cell rate (AUC 0.65, 95% CI 0.52–0.78) and CD3⁺CTLA4⁺ cell rate (AUC 0.65, 95% CI 0.51–0.80) showed moderate predictive potential for ALs. In immunohistochemistry, CD3⁺ (AUC 0.57, 95% CI 0.54–0.60), CD8⁺ (AUC 0.57, 95% CI 0.52–0.62), CD8β⁺ (AUC 0.59, 95% CI 0.53–0.65) and Tbet⁺ (AUC 0.60, 95% CI 0.56–0.64) showed some predictive ability for ALs. The model including CD8β⁺, the BMI, neutrophile/lymphocyte ratio and tumor location had an AUC of 0.67 (95% CI 0.62–0.72). Conclusions: Immune activation within histologically normal, tumor-adjacent rectal mucosa—characterized by epithelial HLA upregulation and cytotoxic or Th1 T cell infiltration—is associated with postoperative ALs. Although predictive accuracy is limited, these findings support the concept that a tumor-conditioned immune microenvironment may predispose patients to impaired anastomotic healing. Integration of mucosal immune profiling with clinical variables represents a promising exploratory approach that warrants further prospective validation.

Background and Objectives: Post-Operative Pancreatic Fistula (POPF) is reported among 13% to 64% of cases following a distal/left pancreatectomy (D/LP). Many efforts aim to prevent the onset of POPF or reduce its clinical impact. This meta-analysis sought to provide data by assessing POPF rates among patients undergoing D/LP for benign or malignant pancreatic diseases, with or without pancreatic stump mesh wrapping. Materials and Methods: We undertook a systematic review following the PRISMA guidelines, alongside the Cochrane Handbook for Systematic Reviews of Interventions. We evaluated the certainty in the evidence using the GRADE approach for the following key outcomes: overall POPF and clinically relevant POPF. PubMed/MEDLINE, Web of Science, and Scopus were employed to retrieve relevant papers. Pooled analysis was carried out employing RevMan Version 5.4.1. Results: Among the 8 comparative studies considered (1042 subjects: 430 Wrapping Mesh Group (WMG) versus 612 control group (CG)), seven were retrospective observational studies and one was a randomized controlled trial. Polyglycolic acid (PGA) mesh was used in 7 studies, except for one, who used a polyglactin mesh. Regarding the primary outcomes, meta-analysis showed lower rates of Overall POPF (Ov-POPF) (OR: 0.57, 95% CI: 0.37, 0.88; p = 0.01) and clinically relevant POPF (CR-POPF) (OR: 0.33, 95% CI: 0.21, 0.50; p < 0.00001) in the WMG. Moreover, the WMG also showed a decrease in Estimated Blood Loss (EBL) (MD: −43.11, 95%, CI: −63.20, −23.02, p < 0.0001), a shorter period with surgical drain (MD: −9.66, 95% CI: −17.99, −1.34, p = 0.02) and a decreased length of hospital stay (MD: −4.60, 95%, CI: −7.83, −1.36, p = 0.005). Conclusions: Our meta-analysis showed that wrapping the pancreatic stump with mesh is associated with lower rates of overall POPF and clinically relevant POPF, lower EBL, a shorter period with the surgical drain and reduced hospital stay duration. There is a need for high-quality methodological research to identify the risk factors for the onset of POPF and to evaluate and compare the results of various surgical approaches used to reduce its rate and associated morbidity.

Background/Objectives: Mucinous adenocarcinoma (MAC) is a rare and clinically problematic subtype of rectal cancer, tending to present at an advanced stage and to respond poorly to neoadjuvant therapy. The consistently worse prognosis than that of not-otherwise-specified adenocarcinoma (NOS-AC) is not fully understood, potentially owing to intrinsically more aggressive biology or specific immune evasion mechanisms. We used the IMMUNOREACT multicentre cohort, with external validation in TCGA, to investigate the clinical and immunological features of rectal MAC in detail. Methods: Two hundred patients with rectal adenocarcinoma (16 MAC, 184 NOS-AC) from the IMMUNOREACT 1 (NCT04915326) and IMMUNOREACT 2 (NCT04917263) prospective cohorts were included. To account for the imbalance in baseline characteristics, propensity score matching (PSM) was performed on age, sex, neoadjuvant treatment and TNM stage. The immune microenvironment was characterised using immunohistochemistry (CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, PMS2, CD80), flow cytometry and NanoString PanCancer IO 360™ transcriptomics of adjacent healthy mucosa. Findings were externally validated against TCGA rectal and colon adenocarcinoma datasets. Results: MAC presented at significantly more advanced stage than NOS-AC across all TNM parameters: higher T stage (p = 0.006), N stage (p < 0.001), M stage (p = 0.039) and overall TNM stage (p < 0.001). In the unmatched cohort, MAC was associated with worse overall survival (HR 2.53; 95% CI 1.03–6.23; p = 0.043) and disease-free survival (HR 2.86; 95% CI 1.25–6.55; p = 0.013), but both differences became non-significant after PSM. MAC patients had higher haemoglobin after adjusting for confounders (mean difference [MD] 1.26 g/dL, 95% CI 0.30–2.31, p = 0.012), consistent with a hypothesis of reduced chronic rectal bleeding as a possible mechanism for late presentation. Transcriptomically, MAC showed suppression of HLA class II antigen presentation genes (HLA-DQA1, HLA-DQB1, HLA-DRB1) and myeloid activation genes (S100A8/A9/A12) in adjacent healthy mucosa. Loss of MMR proteins MSH6 and PMS2 in histologically normal mucosa was significantly more frequent in MAC. These findings were replicated in the TCGA cohort, which also showed lower tumour mutational burden and a distinct mucin-associated transcriptomic profile in MAC. Conclusions: The worse outcomes of rectal MAC appear to be driven largely by late-stage presentation, possibly owing to later diagnosis. MAC nonetheless carries a distinct immune phenotype, detectable even in histologically normal surrounding mucosa, that likely contributes to its treatment resistance. These observations provide a basis for developing histotype-specific approaches to both early detection and treatment in this uncommon but clinically challenging tumour subtype.

Background and Objectives: Perforated peptic ulcer (PPU) is an emergent condition managed by surgical intervention. No conclusive evidence has been produced regarding the need for drain placement after primary repair. Our meta-analysis aimed to provide insight into the short-term outcomes by comparing the two strategies of drain omission or intra-operative placement of at least one drain. Materials and Methods: We performed a systematic review following the PRISMA guidelines. PubMed/MEDLINE, Web of Science, Cochrane Library, and Embase databases were utilized to identify articles of interest. Meta-analysis was performed using RevMan Version 5.4. Eligible studies were comparative studies (RCTs and observational studies) enrolling adult patients (≥18 years) undergoing emergency primary repair for PPU, with or without prophylactic intra-abdominal drain placement; case reports and series of fewer than 10 patients were excluded. The literature search covered January 2010 to 22 February 2026. Risk of bias was assessed using the Cochrane RoB 2.0 tool for RCTs, and the ROBINS-I V2 tool for observational studies; certainty of evidence was graded using the GRADE framework. Pooled effect estimates were calculated using a random-effects model and expressed as odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI); statistical heterogeneity was quantified using the I² statistic. Results: Five studies were considered for comparison, for a total of 1354 patients (744 and 610 in the drain and no-drain groups, respectively). Three were randomized controlled trials, and two were retrospective cohort studies, conducted across four countries (India, the USA, Egypt, and Japan). Meta-analysis of the pooled results showed that drain omission was associated with a shorter length of stay (LOS) (MD −2.13, 95% CI [−3.91–−0.35], p < 0.0001) and a lower rate of superficial surgical site infections (SSIs) (16.7% vs. 52.7%, OR 0.24, 95%CI [0.11–0.55], p = 0.0007). No difference was observed regarding the rate of leaks, reoperation, or deep SSIs. Low-certainty evidence suggested higher postoperative mortality in the no-drain group (OR: 1.96; 95% CI: 1.10 to 3.48; p = 0.02; I² = 0%), largely driven by retrospective studies with a high risk of bias. This mortality finding is of very low certainty and is most likely attributable to confounding in the observational studies rather than a true causal effect of drain omission. Several outcomes were based on data from only two to three studies, and the overall certainty of evidence was low to very low. Conclusions: Drain omission after primary repair for PPU may be associated with better outcomes in terms of LOS and superficial SSIs, primarily in lower-acuity patients, as reflected by the inclusion criteria of the contributing RCTs. Pooled analysis showed a higher postoperative mortality in the no-drain group; however, given the significant biases among included studies, our results should be interpreted as non-causal and thus require careful interpretation. Further research encompassing the full clinical spectrum of PPU is needed to confirm our results. Evidence certainty was low to very low across all outcomes, primarily due to a risk of bias, high heterogeneity (I² up to 95% for LOS), indirectness, and imprecision.

The splenic flexure of the colon is one of the least frequently affected sites by colon cancer. However, when diagnosed, it presents a significant surgical challenge primarily due to its vascular anatomical variability. In fact, the splenic flexure of the colon originates from structures embryologically derived from the midgut and hindgut, such that a careful preoperative and intraoperative evaluation of the vascular anatomy is required to perform an adequate lymphadenectomy in cases of splenic flexure colon cancer. The surgical management of splenic flexure colon cancer is currently unstandardized. In addition to the significant lack of a shared definition of splenic flexure colon cancer that would allow for comparison across studies on the topic, there is extreme variability in the type of surgical procedure and lymphadenectomy performed. The few studies in the literature on the surgical management of splenic flexure colon cancer indicate that minimally invasive segmental resection of the splenic flexure of the colon, whether laparoscopic or robotic, and a lymphadenectomy focused on knowledge of the vascular anatomy and the site of the primary colon cancer are safe and effective in ensuring good short- and long-term outcomes. However, further well-designed studies are needed to reach strong conclusions that can be used to develop recommendations regarding the surgical management of splenic flexure colon cancer.