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.

Ulcerative colitis is a chronic inflammatory bowel disease with rising global prevalence. Despite therapeutic advances including biologic agents targeting tumor necrosis factor-alpha, integrins, and interleukin pathways, alongside Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators, substantial unmet needs persist in moderate to severe disease. Current advanced therapies achieve clinical response rates of only 30-60% in trials, with approximately 20% of patients requiring hospitalization and 7% undergoing colectomy within five years of diagnosis. The therapeutic pipeline for moderate to severe ulcerative colitis currently encompasses over 100 investigational agents in Phase II and III clinical development. Emerging mechanisms include next-generation Janus kinase and tyrosine kinase 2 inhibitors with enhanced selectivity, novel cell trafficking modulators, advanced tumor necrosis factor-alpha inhibition strategies, and selective interleukin-23 pathway antagonists. Tumor necrosis factor-like ligand 1A pathway inhibitors demonstrate particularly robust efficacy in early trials, with clinical remission rates exceeding 25% compared to less than 2% for placebo. Additional promising approaches target immune checkpoint pathways, receptor-interacting protein kinase 1, and intracellular signaling cascades. innovative combination therapy approaches demonstrated to achieve superior response rates compared to monotherapy. The convergence of novel therapeutic targets, gut-selective compounds minimizing systemic immunosuppression, and biomarker-guided therapy selection represents a paradigm shift toward precision medicine. These advances hold genuine promise for transforming moderate to severe ulcerative colitis management.

Introduction: Most rectal cancers are microsatellite-stable (MSS) and derive limited benefit from immune checkpoint inhibition. We assessed whether familial colorectal cancer aggregation defines a distinct biological context within MSS rectal cancer.Materials and Methods: We performed a prespecified analysis of two prospective multicentre cohorts conducted between 2018 and 2024. Patients with MSS rectal adenocarcinoma were classified as familial (FH⁺) or sporadic (FH⁻), with a predefined subgroup of patients with an affected first-degree relative (FDR⁺). Known hereditary colorectal cancer syndromes were excluded. Immune profiling, transcriptomic analysis and targeted sequencing were performed on tumour-adjacent histologically normal rectal mucosa and, when appropriate, tumour tissue. Analyses were stratified by neoadjuvant treatment status.Results: Among 374 patients, 92 were FH⁺ and 65 were FDR⁺. In NAT-naïve patients, FDR⁺ cases showed higher epithelial CD80⁺ cell density than FH⁻ cases. After neoadjuvant therapy, FH⁺ patients had increased activated CD8⁺CD28⁺ T cells and reduced epithelial HLA-ABC expression, whereas FDR⁺ cases showed lower CD3⁺ T-cell density. Transcriptomic analysis indicated a quiescent mucosal phenotype in FH⁺ patients, with reduced DNA repair, proliferative, metabolic, angiogenic, and immune pathway activity. Post-NAT FH⁺ and FDR⁺ patients showed higher mutational ratios. In FH⁻, but not FH⁺, higher mutational ratio was associated with improved disease-free survival and immune activation.Discussion: Familial aggregation may define a biologically distinct MSS rectal cancer subgroup, characterised by altered epithelial–immune coordination and dissociation between therapy-induced genomic stress and immune surveillance.​

Background . Pelvic exenteration (PE) and multivisceral resection are complex surgical procedures indicated for highly selected patients with locally advanced primary and recurrent pelvic malignancies. This study aimed to evaluate the actual short-term outcomes of patients undergoing PE in two coordinating centers for the Pelv-ITA project. Methods . Patients who underwent curative-intent PE for locally advanced colorectal and anal cancers between 2018 and 2024 were included in the study. The outcomes were major postoperative complications (Clavien–Dindo grade ≥ 3), length of hospital stay (LOS), 30-day readmission, 30-day mortality, and 2-year overall- (OS), recurrence-free- (RFS), local recurrence-free- (LRFS), and distant recurrence-free survival (DRFS). Results . Among the 78 patients who underwent PE, median age was 62.0 (IQR 56.0–72.0) years. Indications for PE were locally advanced rectal cancer (n = 48, 61.5%), followed by colon (n = 19, 24.4%) and anal malignancies (n = 11, 14.1%). Among these, 34 (43.6%) had a recurrent disease. An R0 resection was achieved in 59 (77.6%) patients. Major postoperative complications occurred in 20 (25.6%) of patients. The 2-year OS was 93.0% for rectal cancers, 84.6% for colon cancers, and 76.2% for anal cancers. The 2-year RFS was 54.9%, 81.5%, and 30.0%, respectively. The 2-year LRFS was 49.2% for rectal cancers, 72.7% for colon cancers, and 50.0% for anal cancers, while the 2-year DRFS was 65.6%, 81.5%, and 65.6%, respectively. Conclusion. PE is a surgical option for selected locally advanced pelvic malignancies. The establishment of multi-institutional networks such as Pelv-ITA supports the centralization of care and facilitates standardized decision-making.

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.

Postoperative recurrence (POR) remains a significant challenge in Crohn's disease (CD) management despite therapeutic advances. Contemporary data show ileocecal resection rates of 18.7%, 28.0%, and 39.5% at one, five, and ten years after diagnosis, with endoscopic recurrence occurring in 22.4-53% of patients within 18-36 months postoperatively. Current understanding of POR pathophysiology includes microbiota dysbiosis, mesenteric inflammation, immune dysregulation, and genetic factors, particularly NOD2 variants. Key risk factors comprehend smoking, penetrating or perianal disease, prior surgeries, and extensive small bowel involvement. The Rutgeerts score remains the endoscopic gold standard for assessing recurrence, though it has never been validated and modifications addressing modern anastomotic techniques have been proposed. Non-invasive monitoring strategies using fecal calprotectin, intestinal ultrasound, and magnetic resonance enterography demonstrate promising diagnostic performance and may reduce the burden of routine endoscopy. Anti-TNF agents and Vedolizumab show superior efficacy in preventing endoscopic recurrence compared to conventional therapies, while other advanced therapies like anti-JAKs, risankizumab and ustekinumab demonstrate potential benefit in postoperative prophylaxis. Management approaches have evolved toward risk-stratified strategies balancing systematic prophylaxis against endoscopy-driven therapy. While medical prophylaxis remains first-line for high-risk patients, the expanding therapeutic armamentarium and improved understanding of pathophysiologic mechanisms enable increasingly personalized postoperative care. Further research is needed to validate risk assessment tools, optimize timing and selection of prophylactic therapies, and define the role of emerging agents in reducing long-term disease burden.

Background: Transanal excision of rectal cancer can be considered the definitive surgical treatment if the depth spread is T1 or lower, and the lesion is completely included within the resection margin. This study aims to analyze the immune microenvironment in healthy rectal mucosa as a possible predictor of tumor infiltration depth, lateral tumor spread, and recurrence of rectal cancer after transanal local excision. Methods: This study is a subanalysis of data from the IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263, respectively) including all the patients who underwent transanal excision of rectal cancer. This multicentric study collected healthy mucosa surrounding the neoplasms of patients with rectal cancer. A panel of immune markers was investigated at immunohistochemistry: CD3, CD4, CD8, CD8(3, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. Flow cytometry determined the proportion of epithelial cells expressing CD80, CD86, CD40, HLA ABC or HLA DR and the proportion of activated CD8+ T cells, CD4+ Th1 cells, and Treg. Results: Receiver operating characteristic curve analysis for predicting deep tumor spread showed an area under the curve of 0.70 (95% confidence interval: 0.60-0.80) for CD25+FoxP3+ cell rate and 0.74 (95% confidence interval: 0.53-0.92) for CK+CD86+ cell rate. Receiver operating characteristic curve analysis for predicting lateral tumor spread showed an area under the curve of 0.82 (95% confidence interval: 0.61-0.99) for CD8+CD38+ MFI, 0.96(95% confidence interval: 0.85-0.99) for CD8(3 infiltration, and 0.97 (95% confidence interval: 0.87-0.99) for CK+HLAabc+ cell rate. Receiver operating characteristic curve analysis for predicting recurrence showed an area under the curve of 0.93 (95% confidence interval: 0.76-0.99) for CD8+CD38+ MFI and 0.94 (95% confidence interval: 0.78-0.99) for CD8+CD28+ MFI. Low CD8+CD38+ MFI and low CD8+CD28+ MFI were associated with shorter disease-free survival (P = .025 and P = .021, respectively). Conclusion: Our study showed that the association between the high proportion of epithelial cells acting as presenting cells and deep or lateral tumor spread may be explained by the presence of a greater tumor load at the site. Moreover, it showed that weak activation of CD8+ T cells within the rectal mucosa is associated with lateral tumor spread and eventually a higher recurrence rate. The mucosal level of CD8(3 infiltration detected at immunohistochemistry might be tested as a marker of lateral tumor spread and potentially translated into clinical practice. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

INTRODUCTION:Women with HIV face a significantly elevated risk of developing anal cancer (AC). However, data about screening (S) implementation in clinical practice and women's acceptability are still scarce. METHODS:Since October 2022 our clinic implemented anal cancer screening (ACS) using anal HPV-DNA/cytology for women with HIV. Women with at least one positive result from these tests were referred for a high-resolution anoscopy (HRA). We collected demographic and clinical data, ACS adherence rates and reasons for refusal. Multivariable analyses were conducted to identify factors associated with ACS refusal and the presence of high-risk human papilloma virus (HPV) genotypes, HSIL and AC. RESULTS:ACS was offered to 331 women with HIV, but 150 (45.3%) refused testing: main reasons for refusal included lack of specific concerns, no history of anal sex and a perception of not being at risk of having AC. One hundredmeightyone women underwent ACS. Cytology and HPV-DNA were positive in 54 (29.8%) and 139 (76.8%) cases. High-risk HPV genotypes were detected in 94 (67.6%) women with HIV. HSIL, LSIL and ASC-US were detected in 8 (4.4%), 43 (23.7%) and 3 (1.6%) women with HIV, respectively. Of the 135 women (93.7%) who underwent HRA, 19 (14.1%) had lesions requiring biopsies: 6 were negative, 5 were positive for dysplastic polyps, and 8 (5.5%) were diagnosed with AC. Older age, lower nadir CD4 counts, and a previous history of cervical HPV-related disease were significant risk factors for HSIL and AC. Conversely, partial or complete HPV vaccination were protective factors against high-risk HPV infection. CONCLUSIONS:Despite the high prevalence of anal HR-HPV genotypes and the high risk of AC among women with HIV, the uptake of ACS in our cohort was notably low. Among those who participated, a high prevalence of HPV infection and associated cytological abnormalities was observed, indicating an urgent need for increased awareness and education regarding AC in this population. The findings identify crucial risk factors, such as older age and lower CD4 counts, while also suggesting that HPV vaccination may offer protective benefits against high-risk HPV infections. These insights emphasize the importance of targeted screening programmes and interventions to improve health outcomes for women with HIV.

Appendectomy has been associated with reduced risk of developing ulcerative colitis (UC) or experiencing flares after diagnosis, suggesting the appendix may play a role in UC pathogenesis. Given its function in microbial homeostasis and gut immunity, we investigated the relationship between mucosal microbiota and immune environment of the appendix in UC. Appendix tissue was collected from 85 patients undergoing surgery for UC, acute appendicitis (APA) or colon cancer (CC). Immunophenotyping of dendritic cells (DC), macrophages and T lymphocytes was performed using flow cytometry. Microbiota composition was analyzed via 16S rRNA gene amplicon sequencing. Although alpha diversity did not differ between UC and non-UC appendices, beta diversity indicated significant compositional differences. Five bacterial species (Actinomyces hyovaginalis, Mogibacterium sp. Fusobacterium sp. Pseudoramibacter eubacterium, and Streptococcus anginosus) were significantly reduced in the UC appendix compared to APA. However, no species were associated with UC disease activity. In contrast, UC patients showed a significantly higher frequency of activated DCs (CD1a+ HLAdr+ CD86+). DC activation levels correlated with daily stool frequency and T-cell activation. These findings suggest that the appendix may contribute to UC pathogenesis through immune, rather than microbial, mechanisms - supporting a role for dendritic cell-mediated T-cell priming in colonic inflammation.