Jan Sven David Mieog

Background: Complete surgical resection is the cornerstone of curative treatment for pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (eCCA). Distinguishing tumor margins intraoperatively from fibrosis or inflammation remains challenging, contributing to incomplete resections and poorer outcomes. Near-infrared (NIR) fluorescence imaging enables real-time tumor identification and margin assessment. Antibody-based NIR fluorescent probes show favorable tumor-to-background ratios (TBRs) but are limited by prolonged circulation and hepatic clearance, which increases background signal. Peptide-based probes, such as cRGD-ZW800-1 (cyclic pentapeptide (cRGD) conjugated to an 800 nm fluorophore ZW800-1), which target integrins upregulated in these cancers, have shorter half-lives, enabling administration closer to surgery than with antibody-based probes while achieving high tumor contrast. This study evaluates the safety and feasibility of cRGD-ZW800-1 for fluorescence-guided surgery in PDAC and eCCA. Methods: In this open-label phase II trial, 21 patients undergoing pancreatectomy received cRGD-ZW800-1 (0.025 or 0.05 mg/kg) 2–4 or 18–24 hours preoperatively in four cohorts. Feasibility was predefined as ex vivo visualization with a TBR ≥ 1.5. Intraoperative imaging assessed tumor delineation, margins, vascular involvement, and suspected metastases. Findings were correlated with histopathology and integrin expression. Results: No probe-related adverse events occurred. All evaluable tumors met the feasibility criteria, with a median TBR of 3.0. A trend toward higher contrast was observed with the 0.025 mg/kg dose administered 18–24 hours before surgery. Fluorescence remained detectable after neoadjuvant therapy. Intraoperative imaging confirmed all irradicable vascular margins and provided surgically relevant information in over half of the patients, including confirmation of metastatic disease. Fluorescence imaging contributed to an intraoperative change in surgical management in two patients. Pathological analyses showed co-localization of fluorescence with integrin expression. Conclusions: cRGD-ZW800-1 was safe and reliably enabled visualization of PDAC and eCCA. The results demonstrate feasibility and suggest potential clinical utility in supporting surgical assessment, warranting further investigation in prospective, multicentre trials of intraoperative margin assessment, surgical radicality, and oncological outcomes.

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.

Background: Although robot-assisted pancreatoduodenectomy (RPD) enhances patient recovery, it could be associated with higher costs than open pancreatoduodenectomy (OPD), potentially limiting its widespread adoption. High-level evidence comparing costs of RPD and OPD is lacking. This analysis in a randomized trial compared costs and cost-effectiveness between RPD and OPD. Methods: Predefined cost-effectiveness analysis in the international randomized DIPLOMA-2 trial (ISRCTN27483786) comparing RPD and OPD in patients with primary resectable neoplasm in 14 centers in 6 European countries (2022–2023). Primary outcomes were mean total hospital costs (euro) at 6 months postoperatively and cost-effectiveness based on costs per quality-adjusted life year (QALY; incremental cost-utility ratio). Three analyses were performed: (1) costs, (2) QALYs including Health-Related Quality of Life (HR-QoL), and (3) cost-effectiveness with probabilities at various willingness-to-pay (WTP) thresholds. Results: Overall, 268 patients were included (170 RPD, 98 OPD). No significant difference in total hospital costs was found between RPD and OPD (€30,956 vs. €28,271, P =0.538). The intraoperative costs were €5,491 higher with RPD (€11,906 vs. €6,451, P P =0.518). The HR-QoL index scores were comparable at 1 and 3 months, but worse at 6 months with RPD (Δ−0.08 [−0.15 to −0.001]). Consequently, over 6 months a QALY loss was observed with RPD (Δ−0.02 [−0.07 to 0.01]) with a <30% probability of RPD being cost-effective across various WTP thresholds. Conclusion: This analysis in a randomized trial found no significant differences in costs between RPD and OPD up to 6 months. Nonsignificantly lower QALYs at 6 months with RPD resulted in a <30% probability that RPD is cost-effective compared with OPD within 6 months after surgery in selected patients in high-volume centers.

Aims/hypothesis: In individuals undergoing total pancreatectomy, an additional islet autotransplantation (total pancreatectomy with islet autotransplantation [TPIAT]) can be performed. We investigated the degree to which islet secretory function is preserved after TPIAT and assessed the relation to glycaemic control using continuous glucose monitoring. Methods: Eligibility for TPIAT was assessed by a multidisciplinary team. The cohort consisted of all individuals undergoing TPIAT from 2014 to 2024. To assess islet secretory function, participants were subjected to a 2 h liquid meal stimulation test prior to TPIAT, at 3 months and annually post TPIAT. Glycaemic control was assessed using continuous glucose monitoring and HbA _1c . Results: Twenty-six individuals were included, of whom 88.5% had chronic pancreatitis. At baseline, 57.7% had prediabetes (HbA _1c 39–47 mmol/mol [5.7–6.4%] or a fasting glucose 5.6–6.9 mmol/l) or diabetes, and 46.2% had undergone previous pancreatic surgery. Islet secretory function determined by C-peptide area under the curve (AUC _C-peptide ) was 45% of baseline at 3 months post TPIAT. Preservation of islet secretory function was independent of preoperative glycaemic status and previous surgery. At 3 months, time in range was 75.2 ± 26.1%, and time in range was positively correlated with AUC _C-peptide ( p <0.0001). After 3 months islet function did not significantly change, which was reflected in a stable BETA-2 score. Conclusions/interpretation: Nearly half of islet secretory function is retained after TPIAT. These results can facilitate shared decisions on the potential benefits of islet autotransplantation after total pancreatectomy, even in individuals with (pre)diabetes and previous pancreatic surgery.

Background: In expert centers, surgical resection rates of locally advanced pancreatic cancer (LAPC) following induction chemotherapy have increased beyond 20% with subsequent 25% five-year overall survival (OS). In the Netherlands, however, the historical low 8% LAPC resection rate compared with 23% in international expert centers reflects relative reluctance. Thereby, opportunities to achieve long-term survival in appropriately selected patients may be missed. This study evaluated whether nationwide implementation of international multidisciplinary best-practice for LAPC management is feasible while maintaining surgical safety benchmarks (in-hospital/30-day major morbidity <50% and mortality ≤5%). Methods: A multidisciplinary protocol was designed in collaboration with four international experts and prospectively implemented nationwide within the Dutch Pancreatic Cancer Group (DPCG) (2022-2024). This observational cohort included consecutive patients diagnosed with LAPC, defined by DPCG criteria. Eligible patients had radiologically non-progressive disease after at least four months of multi-agent chemotherapy. All patients who underwent resection were included in this safety analysis. A predefined sub-group analysis included patients with National Comprehensive Cancer Network (NCCN) LAPC. Primary outcomes included in-hospital/30-day major morbidity (i.e., Clavien-Dindo grade ≥IIIa) and mortality. The expected number of resections was 53. Results: Overall, 180 patients with LAPC underwent surgical exploration, of whom 155 (86%) underwent resection in 11 centers. Most (74%) resections were performed in the three LAPC surgical centers. Extended resections were performed in 77% of patients, including portomesenteric venous (60%), multivisceral (23%), and arterial (21%) resections. In-hospital/30-day major morbidity rate was 44% and mortality rate was 0.6%, both within pre-established safety benchmarks. Benchmarks were also reached for patients with NCCN LAPC (49% major morbidity, 2% mortality). Conclusion: Nationwide implementation of the international best-practice for LAPC was feasible with nearly three times more resections performed than expected, while morbidity and mortality remained well within predefined safety benchmarks.

Background: There is a paucity of data on the cost‐utility of endoscopic ultrasonography‐guided gastroenterostomy (EUS‐GE) compared with surgical gastrojejunostomy (SGJ) as palliative treatment of malignant gastric outlet obstruction. Methods: In the ENDURO trial, 98 patients with malignant gastric outlet obstruction from 12 Dutch hospitals were randomized between EUS‐GE ( N = 48) and SGJ ( N = 50). Cost utility was evaluated from a healthcare perspective with a time horizon of 1 month. A bottom‐up approach was used to calculate the costs of each intervention, including the per‐minute price of the endoscopy and operating room (OR), considering personnel, construction, inventory and overhead costs. Other in‐hospital costs were calculated using insurance claim data. Effectiveness was displayed as quality‐adjusted life years (QALY). Bootstrapping was performed to estimate uncertainty. Results: The calculated per‐minute price for the endoscopy room was €8.64 (US $9.34). The per‐minute price for an OR was €11.78 (US $12.74). The mean intervention costs were estimated at €4405.40 (US $4762.68) for EUS‐GE and €3393.71 (US $3668.93) for SGJ. Mean total in‐hospital costs were lower following EUS‐GE (€5172 [US $5591]) than after SGJ (€10,458 [US $11,306]), mainly due to a shorter length of hospital stay following EUS‐GE. Bootstrapping showed that 99.9% of iterations resulted in lower costs for EUS‐GE. Mean difference in 1‐month QALY contribution was 0.004 in favor of EUS‐GE. Most iterations fall within the bottom right quadrant (95.6%) of the cost‐effectiveness plane, indicating lower costs and improved QALY contribution for EUS‐GE. Discussion: In this study, EUS‐GE was more cost effective than SGJ. The additional intervention costs were clearly outweighed by a decrease in in‐hospital costs after the procedure.

INTRODUCTION: A deeper understanding of the factors influencing survival in patients with pancreatic ductal adenocarcinoma (PDAC) is essential for optimizing treatment strategies. This study investigates the independent association of body composition parameters with overall survival in patients with PDAC. METHODS: This retrospective multisite cohort study included patients diagnosed with PDAC. Diagnostic computed tomography scans were retrieved, and body composition was evaluated using a validated deep learning-based segmentation algorithm that measured tissue volume and density in a 20 cm vertical abdominal section. RESULTS: A total of 1,666 patients with PDAC were included, 938 male (56.3%) and median age 69 years (interquartile range 61–76). In the subgroup of patients who underwent surgical resection (n = 509), myosteatosis (intramuscular infiltration of adipose tissue; hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.16–2.11, P = 0.004), sarcopenic obesity (HR 1.75, 95% CI 1.06–2.91, P = 0.03), and less subcutaneous adipose tissue (HR 1.09, 95% CI 1.03–1.16, P = 0.002) were associated with higher mortality. In patients receiving palliative systemic therapy (n = 439), lower skeletal muscle density (HR 1.43, 95% CI 1.03–1.99, P = 0.03) was associated with higher mortality. In patients who did not undergo tumor-targeted treatment (n = 718), less visceral adipose tissue (HR 1.04, 95% CI 1.01–1.08, P = 0.02) was associated with higher mortality. DISCUSSION: Body composition parameters, derived from computed tomography scans at the time of PDAC diagnosis, particularly low skeletal muscle density, sarcopenic obesity, and low adipose tissue, are independently associated with overall survival in patients with PDAC. Evaluating body composition at diagnosis could enhance clinical decision-making and enable more personalized treatment strategies.