Background: the improved survival rates achieved using new polychemotherapy regimens in patients with metastatic pancreatic cancer (mPDAC) have suggested a potential role for surgery following a favorable response to initial chemotherapy (IC). The purpose of this systematic review is to summarize the available evidence on the role of surgery following IC in mPDAC, focusing on oligometastatic disease to the liver (lmPDAC). Methods: studies reporting on patients with lmPDAC undergoing surgery after IC were included. The main outcome was overall survival (OS). Results: six observational retrospective studies were included in the qualitative analysis. Data were retrieved on 2087 patients. The most common IC regimen in patients undergoing surgery was FOLFIRINOX (N 84, 73%). Only three studies reported survival comparison among patients treated with IC+surgery vs. IC alone. Median OS varied from 23 to 56 months after conversion surgery vs. 11 to 16.4 months after IC alone. Conclusions: despite wide heterogeneity of chemotherapy regimens, different downstaging criteria and potential selection biases, patients with oligometastatic lmPDAC undergoing surgery after IC have significantly higher survival rates compared to patients treated with IC alone. Future trials are needed for definition of univocal criteria of downstaging, oligometastatic definition and indications for surgery.

Background. Total neoadjuvant therapy (TNT), intended as induction chemotherapy (IC) followed by radio-chemotherapy (RCT), has been taking hold in the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to summarize the available evidence on the role of TNT followed by curative surgery. Methods. Eligible studies were those reporting on patients with PDAC undergoing curative surgery after TNT. The primary endpoint was overall survival (OS). Results. A total of 1080 patients with PDAC who had undergone TNT were analyzed. The most common IC regimen was Gemcitabine (N 620, 57%). Toxicity during IC varied from 14% to 51%. Disease progression during IC varied from 3% to 25%. 607 (62%) patients underwent curative surgery after IC + CRT. In meta-analysis, the available data on lymph node metastases radicality and 2 years OS had better results in favor of TNT groups (OR 1.77, 95% CI 1.20–2.60, p = 0.004 and OR 2.03, 95% CI 1.19–3.47, p = 0.01 and OR 1.64, CI 1.09–2.47, p = 0.02, respectively). Conclusions. Despite the heterogeneity of the studies, different selection criteria, and non-negligible drop-out rate, TNT demonstrated a potential superiority to NAT without CRT in oncological and pathological outcomes, even if the main differences seem to depend on the IC regimen.

Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas (‘TCGA’) were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 (‘IMMUNOREACT’) series. In the authors’ series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8β expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

Ampullary lesions, neoplasms originating in the papilla of Vater, represent a rare yet clinically significant group of tumors with diverse etiologies and management challenges. This comprehensive review aims to elucidate the pivotal role of endoscopic ultrasound (EUS) in the diagnosis, staging, and management of ampullary lesions. This review begins by providing an overview of ampullary lesions, their epidemiology, and associated risk factors. We delve into their clinical presentation, emphasizing the importance of early and accurate diagnosis. Furthermore, we explore the limitations of traditional diagnostic modalities and highlight the growing relevance of EUS in ampullary lesion evaluation. We discuss the superior spatial resolution of EUS in comparison with other imaging methods, and we present an in-depth analysis of EUS-guided sampling and its pivotal role in obtaining histological samples for accurate diagnosis. In addition to diagnosis, we examine the indispensable role of EUS in ampullary lesion staging and its clinical implications. Furthermore, we discuss the potential of EUS in the surveillance and follow-up of ampullary lesions, ensuring timely detection of recurrence and monitoring treatment response in sporadic cases and in the context of familial syndromes, such as familial adenomatous polyposis (FAP). In conclusion, this review underscores the indispensable role of endoscopic ultrasound in the multifaceted approach to ampullary lesion evaluation. EUS not only enhances diagnostic accuracy but also informs treatment decisions and minimally invasive therapeutic interventions. As our understanding of ampullary lesions continues to evolve, EUS remains an invaluable tool for the improvement of patient outcomes and quality of life.

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: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. Methods: We retrospectively included patients with a diagnosis of resectable PDAC having undergone upfront surgery. Immunohistochemical (IHC) staining using tissue microarray for PD-L1, CD3, CD4, CD8, FOXP3, CD20, iNOS and CD163 was performed in order to characterize the TME. The primary endpoint was long-term survival, defined as the Overall Survival > 24 months from surgery. Results: A total of 38 consecutive patients were included, and 14 (36%) of them were long-term survivors. Long-term survivors showed a higher density of CD8+ lymphocytes intra- and peri-acinar (p = 0.08), and a higher CD8/FOXP3 intra- and peri-tumoral ratio (p = 0.05). A low density of intra- and peri-tumoral FOXP3 infiltration is a good predictor of long-term survival (p = 0.04). A significant association of the low density of intra- and peri-tumoral tumor-associated macrophages (TAMs) iNOS+ with long-term survival was detected (p = 0.04). Conclusions: Despite the retrospective nature and small sample size, our study showed that the high infiltration of CD8+ lymphocytes and low infiltration of FOXP3+ and TAMs iNOS+ are predictors of good prognosis. A preoperative assessment of these potential immune markers could be useful and determinant in the staging process and in PDAC management.