Casper H. J. van Eijck

Objective: To evaluate the use and impact of current surgical guidelines for chronic pancreatitis (CP) across Europe. Summary Background Data: Current guidelines recommend morphology-based surgery for CP, but international studies evaluating their use and impact are lacking. Methods: Post hoc analysis of the prospective multicenter ESCOPA study, including patients undergoing surgery for symptomatic CP at 22 centers in 13 countries (June 2021–November 2022), with 6-month follow-up. Patients were stratified by morphologic subtype: “isolated dilated main pancreatic duct (MPD),” “isolated enlarged pancreatic head (PH),” “combined dilated MPD and enlarged PH,” and “small duct disease.” Treatment was based on the European HaPanEU and International IAP-APA-JPS-EPC guidelines. Primary outcomes were 90-day major morbidity, mortality, and pain relief at 6 months. Practice variation was assessed, including a case-based survey. Results: Overall, 207 patients were included following surgery for CP, with 1.4% 90-day mortality and 72.6% pain relief. The surgical approach varied widely by morphologic subtype: duodenum-preserving pancreatic head resections (DPPHR) were most common for “combined dilated MPD and enlarged PH” (46.8%, P =0.016); whereas formal pancreatectomy predominated for “isolated dilated MPD” (63.3%, P =0.040) and “small duct disease” (66.0%, P =0.004). Guideline-concordant surgery (66%) was not associated with improved rates of major morbidity (12.9% vs. 18.8%, P =0.387), mortality (1.6% vs. 1.6%, P >0.999), or pain relief (75.3% vs. 66.7%, P =0.468). Outcomes were also comparable between drainage/parenchyma-preserving surgery and formal pancreatectomy. Survey findings confirmed practice variation, including the use of formal and V-shaped pancreatectomy for small duct disease. Conclusion: The substantial variation in surgical practice for CP across Europe highlights the need for unified guidelines with clear recommendations, particularly regarding formal and V-shaped pancreatectomy.

We present a remarkable case of long-term survival in a 43-year-old man with no significant medical history, diagnosed in 2018 with metastatic pancreatic ductal adenocarcinoma (PDAC). The patient initially experienced postprandial upper abdominal discomfort that progressed to obstructive jaundice, leading to the detection of a pancreatic head mass with metastatic lymphadenopathy. Despite the generally poor prognosis linked to metastatic PDAC, the patient achieved sustained disease control with FOLFIRINOX chemotherapy and later underwent surgical resection after complications related to vascular involvement. Next-generation sequencing (NGS) identified a rare KRAS-wildtype tumour with microsatellite instability (MSI) and a high tumour mutational burden (TMB). This case highlights the significance of comprehensive molecular profiling and personalised therapeutic strategies, which could improve outcomes for select patients with advanced PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and largely refractory to immune checkpoint inhibition because limited antigen-specific priming, myeloid suppression, dense desmoplasia, and abnormal vasculature enforce immune exclusion. CD40 links CD4+ T-cell help through CD40L/CD154 to antigen-presenting-cell (APC) licensing and CD8+ T-cell priming, making CD40 agonism a rational strategy to stimulate antitumor immunity in PDAC. CD40 is expressed on APCs and has also been reported on subsets of PDAC tumor cells, cancer-associated fibroblasts, and endothelial cells, indicating that CD40 agonists may affect immune activation, stromal/vascular remodeling, and context-dependent tumor-cell-intrinsic signaling. TRAF-dependent CD40 signaling activates canonical and non-canonical NF-kB, MAPK, and PI3K/AKT pathways, promoting APC maturation, IL-12-associated Th1 programming, macrophage repolarization, and matrix remodeling; tumor-intrinsic effects remain more variable, ranging from apoptotic to pro-survival programs. Clinically, CD40 agonists have shown pharmacodynamic immune engagement and manageable toxicity, mainly in combinations with chemotherapy, checkpoint inhibitors, and vaccine platforms, but efficacy remains inconsistent, and randomized validation is incomplete. Baseline CD40 expression has not reliably predicted benefit. Future development should prioritize spatially resolved tumor-immune profiling, longitudinal pharmacodynamic biomarkers, optimized sequencing, and agent-specific dosing strategies. This review integrates CD40 expression, signaling, and clinical evidence in PDAC to support more rational, biomarker-guided development of CD40-directed immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and is largely refractory to immune checkpoint inhibition, reflecting limited antigen-specific priming, dominant myeloid suppression, dense desmoplasia, and abnormal vasculature that together enforce immune exclusion. CD40 is a central costimulatory receptor that links CD4⁺ T cell help (via CD40L/CD154) to antigen-presenting cell (APC) licensing and effective CD8⁺ T cell priming, positioning CD40 agonism as a rational strategy to enhance antitumor immunity in PDAC. In addition to robust expression on APC populations (DCs, macrophages, and B cells), CD40 has been reported on subsets of PDAC tumor cells and stromal compartments (including fibroblasts and endothelial cells), implying that CD40-directed therapies may engage multiple cellular nodes and influence both immune activation and microenvironmental remodeling. Mechanistically, CD40 signaling integrates TRAF-dependent pathways (canonical/non-canonical NF-κB, MAPK, and PI3K/AKT) that can promote APC maturation, IL-12-associated Th1 programming, macrophage repolarization, and matrix remodeling that may reduce physical barriers to immune infiltration; however, tumor-intrinsic CD40 signaling can be context-dependent and has been linked to divergent survival or apoptotic outcomes in different settings. Clinically, multiple CD40 agonists are in development, predominantly in combination regimens with chemotherapy, checkpoint blockade, and/or vaccine platforms, with evidence of pharmacodynamic immune engagement but variable efficacy and incomplete randomized validation. Baseline CD40 expression has not consistently predicted benefit, underscoring the need for spatially resolved profiling and on-treatment pharmacodynamic biomarkers to guide patient selection, sequencing, and regimen optimization. Ongoing studies and next-generation, tumor-localized agonist formats will define whether CD40 agonism can deliver consistent, durable clinical benefit in PDAC.

IntroductionSocial deprivation, which is exaggerated by lower household income, shortens life expectancy and worsens cancer survival. In pancreatic adenocarcinoma, novel treatment strategies aim to extend survival and centralization of care has increased distance to hospital. The effect of distance to hospital and different treatment regimens on survival stratified by household income remains unexplored.MethodsA nationwide retrospective study using Netherlands Cancer Registry data (2017–2022) included patients with localized pancreatic adenocarcinoma. Patients were categorized into three groups based on household income (lowest, intermediate and highest income) and two distance groups based on median distance to hospital. Multivariable logistic and Cox regression analyses assessed the effect of lower household income and distance on treatment and survival. Kaplan-Meier curves were used for univariable survival analysis.ResultsAmong 5,926 patients, individuals from lower household income received less anti-cancer treatment (44% lowest vs. 63% highest, P<0.001). Living within 14km increased the likelihood of resection (Odds ratio (OR) 1.44, 95%CI 1.28-1.63, P<0.001) and adjuvant chemotherapy (OR 1.29, 95%CI 1.18–1.71, P<0.001). Median survival was 7 months (lowest income), 9 months (intermediate), and 11 months (highest income) (P<0.001). In the multivariable analysis, worse survival in the lowest income group persisted after case-mix adjustment (HR (highest vs lowest): 0.92, 95% CI 0.86-0.98, P<0.001). However, after additional adjustment for treatment differences, survival differences between income groups disappeared (P=0.180).ConclusionLower household income negatively impacts the likelihood of receiving treatment for patients with pancreatic adenocarcinoma. Additionally, distance to hospital is negatively associated with the probability of receiving resection and subsequent treatment.

Purpose: Balancing therapeutic benefit and treatment burden remains a major challenge in administering FOLFIRINOX for advanced pancreatic ductal adenocarcinoma (PDAC). More than 60% of patients experience grade ≥ 3 adverse events (AEs), and only about 30% achieve a tumour response. This study examines the value of FOLFIRINOX chemotherapy by contextualising treatment efficacy, toxicity, and durability of response within ethical, financial, and person-centred frameworks. The aim is to support shared decision-making and optimise clinical outcomes and quality of life. Methods: Patients with advanced PDAC receiving palliative FOLFIRINOX were included. Radiologic response was assessed using RECIST 1.1 at sequential time points during and after therapy. Patients were classified as having either progressive disease or disease control, the latter encompassing complete response, partial response, and stable disease. Results: Amongst 84 advanced PDAC patients, 14 (17%) discontinued FOLFIRINOX before completing four cycles due to grade ≥ 3 AEs. Another four patients (5%) terminated FOLFIRINOX treatment after four cycles despite exhibiting disease control. Overall, 36 (43%) patients had at least one FOLFIRINOX-related grade ≥ 3 AE. Amongst the 66 patients who completed ≥ 4 cycles, 52 (79%) achieved disease control at FOLFIRINOX completion. However, disease control declined rapidly after therapy, falling to 41% at 6 months, 21% at 1 year, and 11% at 2 years. LAPC patients achieved disease control more frequently than patients with metastatic disease. Nevertheless, both groups experienced steep declines in disease control over time, from 85% and 69% at treatment completion to 32% and 4% at 1 year in LAPC and metastatic PDAC, respectively. Overall, 36 patients (55%) received subsequent systemic or locoregional therapies, most commonly gemcitabine/nab-paclitaxel (6%), SBRT (17%), or immunotherapy combined with SBRT (11%). Conclusion: Whilst FOLFIRINOX achieves high initial disease control in advanced PDAC, its benefit is limited by substantial toxicity and poor durability. Only a minority of patients maintain disease control beyond 6 months, which is strongly associated with improved survival. These findings suggest a need to redefine ‘valuable FOLFIRINOX chemotherapy’ to encompass not only initial response but also sustained disease control, toxicity management, and shared decision-making to optimise the benefit of FOLFIRINOX for patients.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a high risk of venous thromboembolism (VTE), which is burdensome and associated with decreased survival. Although neoadjuvant treatment is increasingly used in patients with PDAC, data on VTE in this setting remain scarce. This study evaluated VTE incidence during (neo)adjuvant therapy for resectable and borderline resectable PDAC and its relation to survival. METHODS: This study included patients from the investigator-initiated, multicenter, randomized controlled phase III PREOPANC-2 trial. Patients were randomly assigned to neoadjuvant 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin followed by surgery (FFX arm) or neoadjuvant gemcitabine-based chemoradiotherapy (CRT), followed by surgery and adjuvant gemcitabine (CRT arm). VTE was defined as both incidental and symptomatic lower- or upper-extremity deep vein thrombosis, pulmonary embolism (PE), splanchnic vein thrombosis, and catheter-related thrombosis. VTE occurrence was retrospectively evaluated from random assignment to 12 months after random assignment. The association with overall survival (OS) was analyzed using Cox regression analysis. RESULTS: VTE was diagnosed in 28 of 325 patients (9%): nine (3%) preoperatively and 19 (8%) postoperatively. Most VTEs were symptomatic (54%). Although a higher proportion of patients developed postoperative VTE in the CRT arm (FFX 3% v CRT 12%, P = .02), the 12-month cumulative incidence did not differ between arms (6% v 11%, P = .06). Two patients died from PE-related causes in the CRT arm. VTE was independently associated with reduced OS (adjusted time-varying hazard ratio, 2.13, P = .002). CONCLUSION: VTE occurred in 9% of patients with (borderline) resectable PDAC undergoing (neo)adjuvant treatment in the year after random assignment and was associated with decreased OS. These results underscore the need for standardized reporting of thromboembolic events in clinical trials and future studies assessing the potential benefits of thromboprophylaxis during neoadjuvant therapy.

Background/Objectives: Stereotactic body radiotherapy (SBRT) aims to prolong overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC) with vascular contact without progression of disease after (m)FOLFIRINOX. The primary objective of this study was to determine the potential value of SBRT. Methods: This nationwide, retrospective cohort study included patients with PDAC without progression of disease after at least four cycles of (m)FOLFIRINOX. The study comprised two cohorts, the SBRT and the No SBRT group. A landmark analysis excluded patients with a follow-up or OS time less than 12 months to minimize immortal time bias in the SBRT group. The primary outcome was OS from diagnosis. Secondary outcomes were the histopathological characteristics after resection. Results: Overall, 331 patients were included, of whom 231 were in the landmark analysis. In the overall cohort, the median OS was 20.7 months in the SBRT group versus 15.7 months in the No SBRT group (p = 0.004). In the landmark analysis, the median OS was 23.2 months in the SBRT group compared to 22.3 months in the No SBRT group (p = 0.554). These results indicate the presence of immortal time bias in the overall cohort in favor of the SBRT group. In the subgroup after resection, ypT0-2 (95% versus 76.5% [p = 0.026]), ypN0 (75% versus 37.3% [p < 0.004]), and absence of perineural invasion (50% versus 68.6% [p = 0.015]) were more prevalent in the SBRT group. Conclusions: In a landmark analysis, including only patients who survived at least 12 months after diagnosis, we found no difference in median OS between (m)FOLFIRINOX-only and (m)FOLFIRINOX with consecutive SBRT.