ABSTRACT The role of the human microbiome in cancer development, progression, and response to therapy has moved from correlative curiosity to demonstrated impact on tumor biology. This represents a critical factor for surgical oncologists as they not only resect these tumors, but also direct perioperative antimicrobial exposure and increasingly co‐manage neoadjuvant and surveillance pathways in which microbial state may predict and modify response. This review summarizes the basis for therapeutic modulation of the cancer microbiome and metabolome in a contemporary clinical‐trial landscape across four broad strategies: additive (fecal microbiota transplantation, defined consortia, and live biotherapeutic products), subtractive (targeted antimicrobials), dietary and metabolome‐directed interventions, and engineered or next‐generation platforms. Particular attention is given to subtractive approaches in colon and rectal cancer and to the underexplored perioperative interface between the microbiome and surgical outcomes such as anastomotic leak. We outline the principal methodological and translational obstacles, including low‐biomass contamination, causal inference, unintended antibiotic effects, and product standardization. Looking ahead, we propose roles for surgeons across the care continuum, from biospecimen stewardship and trial referral to integration of microbiome and circulating tumor DNA signals in surveillance.
ABSTRACT Background Microscopic margin involvement (≤ 1 mm) strongly predicts poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Adjuvant chemotherapy (ACT) after upfront resection fails to fully mitigate this risk. It remains uncertain whether neoadjuvant chemotherapy (NACT) can neutralize the adverse prognostic impact of impending ≤ 1 mm margins. Methods Prognostic significance of ≤ 1 mm margins was assessed in an upfront‐resection cohort ( n = 228) using multivariable Cox regression. A separate cohort ( n = 110; 52 NACT, 58 upfront surgery) compared overall survival (OS) by margin status. A CT‐based radiomics model using a Laplacian‐Dirichlet operator was developed to predict ≤ 1 mm margins and externally validated ( n = 230). Results ≤ 1 mm margins independently predicted worse OS vs. > 1 mm (15.0 vs. 24.0 months, p = 0.005). ACT numerically extended OS for ≤ 1 mm patients (16.0 vs. 15.0 months, p = 0.271) but did not close the survival gap. Notably, ≤ 1 mm patients receiving NACT achieved median OS of 29.4 months—comparable to > 1 mm upfront patients (31.6 months)—and significantly better than ≤ 1 mm upfront patients (19.6 months, p = 0.045). The model predicted ≤ 1 mm margins with AUCs of 0.772 (95% CI: 0.705–0.838) and 0.723 (95% CI: 0.657–0.789) in internal and external validation. Conclusion NACT—not ACT—selectively rescues high‐risk patients destined for ≤ 1 mm margins. Our radiomics model enables preoperative identification, supporting personalized neoadjuvant therapy.
ABSTRACT Background Count‐based nodal staging classifies periampullary and pancreatic head carcinoma by the number of involved nodes. Because extranodal extension (ENE) occurs only in node‐positive disease, its prognostic value must be judged against node‐positive patients without ENE. We examined whether ENE adds prognostic information beyond nodal count among node‐positive patients after pancreatoduodenectomy. Methods We analysed 304 consecutive pancreatoduodenectomies (October 2019–May 2025; median lymph node yield 24). The primary analysis was restricted to node‐positive patients ( n = 125), with node‐positive ENE‐negative patients as reference, using Cox regression adjusted for N2 versus N1, perineural invasion, age and pancreatic head primary. Sensitivity analyses added pathological covariates and adjuvant therapy, applied a 90‐day landmark, and excluded non‐adenocarcinoma histology. Results ENE was identified in 26 patients (8.6%), constituting 20.8% of node‐positive cases. Among node‐positive patients, 2‐year overall survival was 55.2% with ENE versus 80.1% without (log‐rank p < 0.001). ENE was independently associated with mortality (HR 3.23, 95% CI 1.56–6.67; p = 0.002), whereas N2 versus N1 (HR 1.15; p = 0.69) and perineural invasion (HR 1.00; p = 0.99) were not. The association persisted in all sensitivity analyses (HR range 2.49–3.14), including the 90‐day landmark (HR 2.97) and adenocarcinoma‐only (HR 2.49) cohorts. Conclusions Among node‐positive patients, ENE was associated with survival beyond nodal count. These findings are hypothesis‐generating; they support routine synoptic reporting of ENE and warrant multi‐centre validation before any staging implication is considered.
ABSTRACT Background Postoperative pancreatic fistula (POPF) remains a significant source of morbidity following pancreaticoduodenectomy (PD), and whether internal or external stenting better mitigates POPF after robotic PD (RPD) remains unclear. Methods A retrospective review was conducted of patients who underwent RPD with internalized or externalized pancreatic duct stents at a single academic institution (2020–2026). POPF was graded by ISGPS criteria, with risk stratified by Fistula Risk Score (FRS) and Alternative FRS (A‐FRS). Ninety‐day outcomes were recorded. Results Of 182 patients, 83 (45.6%) received an externalized stent. Age, sex, BMI, and PDAC proportion were similar between internal and external stent groups, as was fistula risk (74.7% vs. 71.1% intermediate/high risk) (all p > 0.05). Overall POPF rate was nearly identical (18.2% vs. 18.1%; p = 0.985), with most fistulas (73.5%) being biochemical leaks and no Grade C fistulas. Among low/intermediate A‐FRS patients, clinically‐relevant POPF rates were comparable (2.6% vs. 2.9%; p = 0.994). In high A‐FRS patients, external stenting was associated with significantly fewer clinically‐relevant POPFs (0.0% vs. 21.7%) and more biochemical leaks (35.7% vs. 8.7%, p = 0.04). External stenting did not increase length of stay or readmission. Conclusions In high fistula‐risk RPD patients, external stenting was associated with fewer clinically‐relevant POPFs, suggesting externalization may prevent progression to clinically‐relevant POPF.
ABSTRACT Background and Objectives Many patients undergoing neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC) experience treatment intolerance or disease progression during initial therapy. Although chemotherapy switch is increasingly utilized, response rates and oncologic outcomes remain poorly defined. Methods Patients were identified from a prospectively maintained database of individuals undergoing neoadjuvant therapy for localized PDAC from 2012 to 2023. Eligible patients underwent chemotherapy switch between 5‐fluorouracil and gemcitabine regimens with curative intent. Favorable response was defined as complete or partial radiographic response by RECIST, or stable disease with a ≥ 50% decline in CA 19‐9 relative to levels before switch. Outcomes were measured from the date of chemotherapy switch. Results Out of 161 patients, 41% achieved favorable response. Body/tail, borderline resectable, and locally advanced disease were independently associated with nonfavorable response. Among favorable responders, 49% underwent resection versus 11% of nonresponders. Favorable response was independently associated with improved progression‐free and overall survival, including among unresected patients. Overall, 47% derived meaningful oncologic benefit through favorable response, resection, or both. Conclusions Chemotherapy switch offers a reasonable strategy in select patients with localized PDAC experiencing inadequate response or intolerance of initial therapy. This composite response framework identifies chemosensitive tumor biology, informs surgical decision‐making, and stratifies prognosis.
