Pancreatic ductal adenocarcinoma (PDAC) remains clinically managed largely through anatomical stage and performance status, despite major inter-patient heterogeneity and dynamic pathway adaptation during progression. In this review, we propose a hypothesis-generating, stage-aware framework in which clinical stage and established molecular subtypes are considered complementary rather than competing stratification axes. Stage-resolved transcriptomic modeling identified a directional separation across up-front resectable, borderline/locally advanced, primary metastatic and liver metastatic samples, with PC1 explaining 51.1% of the variance and separating early from metastatic states, whereas PC2 explained 30.2% and captured immune/stromal remodeling. We interpret these observations cautiously as pathway-level signals that require functional and clinical validation, not as an established biological paradigm. The model suggests a transition from MAPK-enriched, proliferative and partially immune-competent tumors toward metastatic ecosystems characterized by PI3K-AKT-mTOR engagement, MYC amplification, mitochondrial metabolism, proteostasis support and immune exclusion. We further distinguish approved standards, negative clinical experiences, early clinical signals and preclinical hypotheses. The central conclusion is that PDAC therapeutic stratification should integrate stage, molecular subtype, treatment line, tissue context and evidence level before pathway-directed interventions are clinically prioritized. Accordingly, this review should be read as a translational prioritization framework rather than as a treatment algorithm: it organizes where pathway-directed hypotheses are most biologically plausible, where they are clinically supported, and where they remain insufficiently validated for routine decision-making.

Pancreatic ductal adenocarcinoma with extensive peripancreatic vessel involvement is classified as locally advanced pancreatic cancer (LAPC). For this group of patients, the current standard of care does not include considering a potentially curative oncologic resection. However, recent advances in multiagent chemotherapy and surgical techniques are challenging this paradigm. The current determination of anatomic resectability is vague and unreliable. Here, we propose a definition of local resectability based on pre- and intraoperative assessment. This anatomic definition of resectability assumes careful patient selection based on tumor biology and patient condition. The preoperative evaluation of vascular anatomy and tumor involvement is conducted using 3-dimensional rendering of the pancreas protocol CT. Identifying a disease-free arterial or venous segment above and below the tumor ("suitable target") is the single critical factor determining anatomic resectability. Intraoperative isolation of these target vessels confirms the feasibility of vascular reconstruction before resection. This approach, which focuses on identifying target vessels rather than circumferential involvement, offers a more straightforward and clinically relevant method for assessing surgical eligibility in patients with LAPC at centers of excellence. In summary, reconstructability-based on surgical expertise and guided by tumor biology-now defines the modern paradigm of resectability in LAPC.

Background: Transcriptomic FOLFIRINOX-component sensitivity signatures have been clinically evaluated in resected and advanced PDAC, but their relevance and longitudinal stability in the neoadjuvant BR/LA setting are unknown. Patients and methods: We retrospectively studied 77 patients with borderline resectable or locally advanced PDAC treated with neoadjuvant FOLFIRINOX followed by resection. Pretreatment sensitivity to 5-fluorouracil, oxaliplatin and irinotecan was determined using previously developed locked transcriptomic classifiers and integrated into a regimen-level FOLFIRINOX classification. The primary molecular cohort comprised 53 patients whose pretreatment biopsies had ≥10% tumour cellularity. Cox models assessed associations with survival. Longitudinal changes were assessed in 35 paired tumours. Results: Thirty-one pretreatment tumours were classified as FOLFIRINOX-sensitive (FFX-Sens), and 22 were not classified as FOLFIRINOX-sensitive (FFX-Res). FFX-Sens status was associated with longer overall survival (OS; hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.25-0.93; p=0.029). In the complete-case model adjusted for baseline carbohydrate antigen 19-9 (CA19-9) and tumour size (n=50), the association with OS persisted (adjusted HR 0.47, 95% CI 0.23-0.96; p=0.037), whereas the adjusted association with disease-free survival was not statistically significant (adjusted HR 0.55, 95% CI 0.28-1.10; p=0.090). Among paired tumours, 15 changed from FFX-Sens to FFX-Res and four in the opposite direction (exact McNemar p=0.019). The OS association also persisted after adjustment for postoperative pathological factors (adjusted HR 0.40; p=0.015). Conclusions: Pretreatment FOLFIRINOX sensitivity was associated with OS under neoadjuvant FOLFIRINOX, while matched pretreatment and residual-tumour analyses revealed significant directional reclassification after treatment. These findings extend the clinical evaluation of validated drug-specific FOLFIRINOX sensitivity classifiers to the neoadjuvant setting and provide a longitudinal assessment of their stability during treatment. They support prospective evaluation of both pretreatment stratification and molecular reassessment of residual disease.

Pancreatic ductal adenocarcinoma shows early dissemination, stromal remodeling, and therapy resistance, but how tumor programs co-evolve with immune and stromal changes across stages remains unclear. We built a stage-resolved transcriptomic atlas using bulk RNA sequencing of FFPE samples from 443 untreated tumors spanning resectable, locally advanced, primary metastatic, and liver metastatic disease. Integrative modeling identified ten transcriptional programs with monotonic dynamics during progression. Early stages were enriched for epithelial differentiation and immune-stimulatory signals. Advanced stages showed increased cytoskeletal remodeling, vesicular trafficking, oxidative stress responses, and mitochondrial metabolism. Pathway analysis revealed enhanced PI3K-AKT-mTOR signaling and MYC target engagement in metastatic disease. Immune deconvolution showed loss of CD8+ T cells, dendritic cells, and M1 macrophages. Compact gene signatures stratified stage and survival and generalized to TCGA and ICGC cohorts. Functional assays confirmed greater invasiveness, altered redox balance, and mitochondrial dependence in advanced disease, suggesting stage-associated metabolic vulnerabilities.

Objective: To evaluate predictors of ideal postoperative trajectories after minimally invasive left pancreatectomy (MILP). Summary Background Data: Postoperative course after MILP can be assessed through the Ideal Outcome (IO), but no predictive tool is currently available. Methods: MILP performed between 2010–2022 across 55 French centers were included. 90-days IO required absence of mortality, severe complications, postoperative pancreatic fistula grade B/C (CR-POPF), reoperation, readmission, and length of stay (LOS)≤75 th percentile; Best Performer (BP) was IO with LOS≤25 th p. Predictors were evaluated using multivariable logistic regression and extreme gradient boosting (XGB). Model performance was assessed with nested cross-validation and 1,000-iteration bootstrap resampling. Results: Among 2,092 MILP, mortality was 1.3%, reoperation 5.6%, severe morbidity 17.9%, CR-POPF 18.8%, and readmission 15.3%; median LOS 9 days [IQR 7–13]. IO and BP occurred in 59.6% and 28.1%. Following a stepwise strategy, starting with a preoperative multivariable logistic regression model (AUC 0.57), then a preoperative-only XGBoost model (AUC 0.59), improved by inclusion of intraoperative variables (AUC 0.62); finally, after refining the endpoint to Best Performer (IO+LOS ≤25th percentile), the final XGBoost model achieved an AUC of 0.72 (95%CI 0.70–0.74). SHAP analysis identified center-volume and operative duration as the strongest contributors, followed by age, BMI, conversion, blood loss, and splenectomy. At the optimal threshold, sensitivity reached 0.78, specificity 0.57, PPV 0.41, and NPV 0.87. An online risk calculator is at disposal. Conclusions: Predicting ideal postoperative trajectory after MILP remains challenging; identifying determinants may help optimize postoperative pathways by integrating preoperative and intraoperative determinants of recovery.

BACKGROUND:Pancreatic resection (PR) may require portal/superior mesenteric vein resection (VR). Outcomes of minimally invasive PR (MIPR) with VR are poorly studied. METHODS:Multicentric retrospective cohort of MI pancreatoduodenectomy (MIPD) and left pancreatectomy (MILP) with or without VR between 2010 and 2021. Propensity score matching analysis stratified on age, sex, BMI, pancreas texture, tumor type, ASA score, conversion and surgical approach was performed. RESULTS:After matching, 234 MIPD were included, 78 (33.3%) with and 156 (66.7%) without VR. VR had greater blood loss (400 vs 300 mL; p = 0.033) and operative time (471 vs 430 min; p = 0.012). VR had 10.3% mortality compared to 4.5% (p = 0.097), similar severe morbidity (30.8% vs 37.8%: p = 0.313) and R0 resection rate (84.9% vs 90.8%: p = 0.252). After matching, 275 MILP, 25 (9%) with and 250 (91%) without VR were compared. VR had greater blood loss (350 vs 150mL; p = 0.019) and operative time (300 vs 240 min; p = 0.005). VR had 8% mortality versus 2% (p = 0.126), 19.2% severe morbidity versus 8% (p = 0.274) and lower R0 resection rate (58.3% vs 94.9%; p <0.001). CONCLUSION:MIPR with VR has non-significant increased postoperative mortality, lower R0 resection rate and therefore cannot be considered as a standard of care.

BACKGROUND:Postoperative pancreatic fistula (POPF) is the major driver of postoperative morbidity after pancreatoduodenectomy (PD) and a healthcare issue. In patients with pancreatic tumors the occurrence of POPF could lead to a complete failure of the oncologic strategy by delaying or annihilating the delivery of the indicated adjuvant chemotherapy. However, current preoperative prediction models lack precision. This study aimed to determine the ability of a high dimensional analysis of the patient's peripheral immune system before PD to predict POPF. METHODS:Twenty-two patients in the prospective IMMUNOPANC trial (NCT03978702) underwent PD. Blood samples collected preoperatively were analyzed by combining single-cell mass cytometry and a sparse machine-learning pipeline, Stabl, to identify the most relevant POPF-predictive features. The logistic regression model output was evaluated using a five-fold cross-validation procedure. RESULTS:Eight (36%) patients experience POPF (grade B, n = 7; grade C, n = 1). The multivariable predictive model includes 11 features-six natural killer, three CD8+ T, and two CD4+ T lymphocyte cell clusters-revealing a preoperative POPF lymphocyte signature (Pancreatic Fistula Lymphocyte Signature, PFLS). The Stabl algorithm identifies a predictive model classifying POPF patients with high performance (area under the receiver operating characteristic curve=0.81, P = 2.04e-02). CONCLUSIONS:In summary, preoperative circulating immune-cell composition can predict POPF in patients undergoing PD. The clinical application of the PFLS may enable the early identification of patients at high risk before pancreatic surgery, giving clinicians the opportunity to anticipate and mitigate POPF risk through tailored strategies in pre-, intra-, and post-operative settings.

OBJECTIVE:To evaluate predictors of ideal postoperative trajectories after minimally invasive left pancreatectomy (MILP). SUMMARY BACKGROUND DATA:Postoperative course after MILP can be assessed through the Ideal Outcome (IO), but no predictive tool is currently available. METHODS:MILP performed between 2010-2022 across 55 French centers were included. 90-days IO required absence of mortality, severe complications, postoperative pancreatic fistula grade B/C (CR-POPF), reoperation, readmission, and length of stay (LOS)≤75 th percentile; Best Performer (BP) was IO with LOS≤25 th p. Predictors were evaluated using multivariable logistic regression and extreme gradient boosting (XGB). Model performance was assessed with nested cross-validation and 1,000-iteration bootstrap resampling. RESULTS:Among 2,092 MILP, mortality was 1.3%, reoperation 5.6%, severe morbidity 17.9%, CR-POPF 18.8%, and readmission 15.3%; median LOS 9 days [IQR 7-13]. IO and BP occurred in 59.6% and 28.1%. Following a stepwise strategy, starting with a preoperative multivariable logistic regression model (AUC 0.57), then a preoperative-only XGBoost model (AUC 0.59), improved by inclusion of intraoperative variables (AUC 0.62); finally, after refining the endpoint to Best Performer (IO+LOS ≤25th percentile), the final XGBoost model achieved an AUC of 0.72 (95%CI 0.70-0.74). SHAP analysis identified center-volume and operative duration as the strongest contributors, followed by age, BMI, conversion, blood loss, and splenectomy. At the optimal threshold, sensitivity reached 0.78, specificity 0.57, PPV 0.41, and NPV 0.87. An online risk calculator is at disposal. CONCLUSIONS:Predicting ideal postoperative trajectory after MILP remains challenging; identifying determinants may help optimize postoperative pathways by integrating preoperative and intraoperative determinants of recovery.

BACKGROUND:Advances in pancreatic cancer surgery involve hepatotoxic chemotherapies and hepatic vasculature resections, increasing the risk of clinically relevant postpancreatectomy liver injury. The study aimed to analyze the incidence and impact of clinically relevant postpancreatectomy liver injury after pancreatectomy with hepatic vessel resection. METHODS:In this single-institutional study, patients undergoing pancreatectomy with resection of hepatic vessels (portal vein/superior mesenteric vein, celiac axis, and hepatic arteries) were analyzed. Arterial lactate, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, and Doppler ultrasound-derived resistive index were assessed postoperatively. Postoperative outcomes were assessed through 90 days. Clinically relevant postpancreatectomy liver injury was defined as American Association for the Study of Liver Diseases-defined liver failure and/or need for invasive treatment of liver complications. RESULTS:Among 116 patients (67% portal vein/superior mesenteric vein resection alone, 7% celiac axis/hepatic arteries alone, 26% portal vein/superior mesenteric vein + celiac axis/hepatic artery resection), 15 (13%) developed clinically relevant postpancreatectomy liver injury. Mortality was significantly higher in the clinically relevant postpancreatectomy liver injury group (47% vs 3%; P < .001). The proper hepatic artery resistive index was lower in the clinically relevant postpancreatectomy liver injury group (0.52 vs 0.65; P = .034), whereas the following 48-hour-peak blood tests were significantly higher in this group: Lac, bilirubin, aspartate aminotransferase, and alanine aminotransferase (all P < .01). Combined portal vein/superior mesenteric vein + celiac axis/hepatic arteries and elevated alanine aminotransferase 48-hour peak above 1680 U/L remained significantly associated with the occurrence of clinically relevant postpancreatectomy liver injury in multivariable analyses. Forty percent of clinically relevant postpancreatectomy liver injury occurred in the absence of vascular complications. CONCLUSION:Clinically relevant postpancreatectomy liver injury is associated with significant mortality. Low resistive index and markedly elevated biochemical markers within the first 48 hours correlate with clinically relevant postpancreatectomy liver injury and may be used to trigger earlier intervention. Given the associated morbidity and mortality, defining, preventing, and mitigating clinically significant postpancreatectomy liver injury is of the utmost importance.

Background and study aims: Biliary surgery is a common procedure, especially cholecystectomy (CCT). Its main adverse event (AE) is biliary duct injury (BDI). Management is poorly codified, particularly for complex BDIs not related to CCT (NONCCT-BDI). We decided to conduct a study in a tertiary center to evaluate clinical outcomes of BDI management. Patients and methods: A single-center retrospective study of patients diagnosed with a BDI between March 2002 and June 2022 was performed. The primary endpoint was the overall success rate for BDI management. Secondary endpoints were outcomes of BDI related to CCT (CCT-BDI) and non-CCT-BDI according to BDI location, need for a combination of procedures, and AEs. Results: Sixty-four patients were included. The overall success rate was 91.8%. Endoscopic retrograde cholangiopancreatography (ERCP) alone was efficient in 97.4% of patients. Endoscopy was key to successful treatment in 69% of patients. Forty-five percent of cases were non-CCT-BDI and the treatment success rate was 88.9%. The treatment success rate was significantly higher for Strasberg A BDIs (P = 0.0337). Conclusions: ERCP remains the best and least invasive treatment for hilar injuries, as evidenced by a high success rate. Management of NON-CCT-BDIs should be modeled after that of CCT-BDIs. Owing to the need for a combination of treatments, complex hilar injuries must be managed in expert centers.

Resection of the celiac artery (CA) during surgery for locally advanced pancreatic cancer (LAPC) carries a significant risk of hepatic and gastric ischemia.1,2 In addition, in the current context, where patients undergo intensive chemotherapy before surgery, a new complication has emerged: post-pancreatectomy liver injury (PPLI).3 A 59-year-old patient with biopsy-confirmed locally advanced pancreatic cancer arising from the pancreatic body (Video and Fig. 1) underwent extended neoadjuvant FOLFIRINOX (folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin). The patient was restaged using the A-B-C criteria,4 adding the target approach for anatomical feasibility,5 metabolic imaging, and survival prediction.6 The patient underwent extended pancreatosplenectomy, including resection of the left adrenal gland and the CA (Mayo Clinic class Ia), divestment of the superior mesenteric artery, and portal-superior mesenteric vein reconstruction using a left renal vein graft interposition. Arterial reconstruction was initially deemed unnecessary, as proper hepatic artery flow was maintained—albeit dampened—via the gastroduodenal artery, confirmed by visual inspection and Doppler ultrasound. Postoperatively, the course was notable for a rapid rise in alanine aminotransferase levels without overt clinical or radiological deterioration (Fig. 2). Emergency re-exploration was undertaken with the objective of hepatic arterial revascularization (Fig. 3). We hypothesized that, in the setting of underlying metabolic dysfunction–associated steatotic liver disease, arterial inflow was insufficient to meet the demands of an already vulnerable parenchyma, with increased intrahepatic resistance further compounding ischemic liver injury consistent with clinically relevant (CR)-PPLI. Liver biopsy confirmed acute steatohepatitis and extensive ischemic necrosis. Early postoperative recognition and grading of CR-PPLI is critical to prevent liver failure, as static imaging may fail to reflect dynamic hepatic perfusion. A disproportionate rise in alanine aminotransferase within 48 h is a key warning sign. Prospective multicenter studies are needed to better define the incidence, risk factors, and optimal management of CR-PPLI.

Research on the oncological outcomes of complementary pancreatoduodenectomy (PD) following incomplete (R1) endoscopic papillectomy (EP) for early-stage ampullary adenocarcinoma (AA) is limited, despite the increasing use of endoscopic approaches and the risks associated with PD. This study aimed to assess short- and long-term outcomes in patients undergoing complementary PD after EP R1 for AA. Between January 2010 and December 2022, four patient groups were compared: patients with complete endoscopic resection (EP R0), those with R1 margins after EP closely followed up without complementary surgery (EP R1), those who underwent complementary PD after R1 EP (EP + PD), and those who underwent upfront PD (uPD). The primary endpoint was the difference in survival rates (overall [OS] and disease-free [DFS]) between the EP R1 and EP + PD groups and morbidity and mortality rate comparison between the EP + PD and uPD groups. In the EP cohort (n = 56), the major complication was intraluminal hemorrhage (29

Objectives:Despite advancements in surgical techniques and perioperative care, pancreatic surgery remains a high-risk procedure with significant morbidity and mortality. Furthermore, understanding its impact on the immune system is essential for designing strategies that interact with it. The aim of this study was to elucidate the immunomodulation that occurs following pancreatectomy. Methods:Patients were recruited for the IMMUNOPANC trial (NCT03978702). We performed mass cytometry to analyse the circulating immune subpopulations and integrated the data using the hierarchical-stochastic neighbour embedding clustering analysis and Stabl algorithm. Results:Among the enrolled 39 patients, 33 (84.5%) had undergone pancreatectomy for neoplasia including 13 (39%) with pancreatic ductal adenocarcinoma. Twelve (32%) patients developed pancreatic fistula with a 90-day mortality rate of 2.5%. We phenotyped 156 samples and observed a significant increase in myeloid cells (26% vs. 34%, P = 0.018) after pancreatectomy. Natural killer cell proportions decreased on postoperative day one (POD1) compared with the preoperative levels (7% vs. 12%, P < 0.001). Similarly, both CD8+ and CD4+ T-cell proportions decreased significantly post-surgery (25% and 40%, respectively, P < 0.001). During a narrow window, we observed the alteration of NK cells, contraction of CD8+ T cells, and increase in the proportion of naive CD4+ T cells. These changes may be a result of the immune response to surgery but could also reflect lymphoid organ demargination. Conclusion:This study presents the first analysis of peripheral immune system trajectories following pancreatic surgery. Understanding these dynamics would facilitate the restoration of postoperative immunity, which is potentially crucial for recovery.

INTRODUCTION:En-bloc celiac axis resection (CAR) was first proposed by Lyon H. Appleby in 1952 for gastric cancer and later modified for pancreatic resections with gastric preservation by Nimura et al. in 1976. CAR remains uncommon, performed in fewer than 0.2 cases annually. Advancements in preoperative imaging and anatomy understanding, ischemic complication management, and centralization of care have improved outcomes. This report presents a robotic distal pancreatectomy (DP) with CAR and superior mesenteric artery (SMA) divestment. CASE REPORT:A 65-year-old woman presented with back pain. Imaging revealed biopsy-proven pancreatic adenocarcinoma in the pancreatic body, encasing the celiac, splenic, and common hepatic arteries with SMA abutment. Following four cycles of neoadjuvant FOLFIRINOX, follow-up imaging demonstrated stable disease without metastasis. The need for hepatic artery reconstruction was assessed intraoperatively, with alternative strategies detailed in the accompanying video. OPERATIVE TECHNIQUE:The patient underwent a distal pancreatectomy and splenectomy with class Ia CAR. Surgery was conducted in a caudal approach, lasted 420 minutes with minimal blood loss (100 ml). Laparoscopic ultrasound (lapUS) and indocyanine green (ICG) perfusion were used to assess resectability, vascular perfusion, and targeted blood vessels. The postoperative course was uneventful, except for a Grade B chyle leak managed conservatively. No liver or gastric ischemia occurred. Adjuvant chemotherapy was initiated two months postoperatively. CONCLUSION:Enhanced visualization, improved dexterity, and adjuncts including lapUS and ICG are potential benefits that are available to surgeons with the robotic platform when performing arterial divestment and CAR via a caudal approach.

Background: Splenectomy remains necessary in selected oncologic and hematologic indications but is associated with significant postoperative morbidity and mortality. The data on outcomes in this high-risk population remain limited, particularly in mixed cohorts. Methods: We conducted a retrospective cohort study including all patients undergoing splenectomy for oncologic or hematologic causes between 2009 and 2022 at a cancer referral center. The primary outcomes were the occurrence of major complications at day 90 and the 1-year all-cause mortality. Multivariate logistic regression was used to identify independent predictors. Results: Among the 8503 ICU admissions from surgical wards, 204 splenectomies were performed; 179 patients were analyzed. The median age was 64 years, and 100 patients (55.9%) were female. Splenectomy was performed for hematologic malignancies in 76 cases (42.5%) and for oncologic causes in 103 cases (57.5%). Laparotomy was used in 154 cases (86.0%), and metastasectomy was performed in 54 patients (30.2%). At day 90, 86 patients (48.0%) developed a major complication: 12 deaths (6.7%), 44 surgical complications (24.6%), and 71 episodes of sepsis (39.7%). In a multivariate analysis, weight loss (OR 3.39, 95% CI [1.32-8.70], p = 0.011), laparotomy (OR 4.38 [1.09-17.60], p = 0.038), and a higher SAPS II score (OR 1.08 per point [1.03-1.13], p = 0.003) were associated with complications, while metastasectomy was protective (OR 0.23 [0.08-0.67], p = 0.007). At one year, the mortality reached 22.4%. Independent predictors of death were sepsis at one year (OR 5.04, 95% CI [1.30-25.96], p = 0.029), the Charlson Comorbidity Index (OR 1.30 per point, 95% CI [1.04-1.68], p = 0.030), invasive mechanical ventilation (OR 14.94, 95% CI [2.83-118.93], p = 0.003), and a performance status >1 (OR 7.84, 95% CI [2.38-27.75], p < 0.001). Encapsulated bacteria were not isolated; sepsis was mainly due to Gram-negative and enterococcal organisms. Conclusions: Splenectomy in onco-hematologic patients is associated with high rates of sepsis and mortality. In addition to surgical factors, frailty, immune status, and infection independently contribute to the patients' outcomes. These results support risk-adapted perioperative strategies and long-term infectious surveillance in immunocompromised patients.