Faculty Bibliography

The treatment of PDAC is transitioning from uniform cytotoxic chemotherapy toward precision strategies guided by molecular identity and disease stage. RAS and PARP inhibitors and personalized neoantigen vaccination have created new options across metastatic and resectable disease. Chemotherapy timing relative to surgery and post-resection surveillance represent other important axes of precision oncology. Seven trials addressing these dimensions may collectively redefine PDAC treatment.

OBJECTIVE:To identify modifiable hospital-level determinants of mortality after pancreas surgery and assess their cumulative protective effects through the development of a Hospital Resource Index (HRI) on a global scale. BACKGROUND:Ninety-day mortality rates after pancreas surgery vary globally (2%-10%); however, institutional factors affecting mortality remain poorly understood. Although caseload volume has driven centralization policies in many health care systems, it is not fully explanatory, and the impact of specific modifiable structural and process-related hospital factors remains unclear. METHODS:We linked patient outcome data from the 2021 PancreasGroup.org global prospective cohort to hospital infrastructure data from the PancreasGroup.org global survey. Binary availability of 20 hospital-level factors was assessed. Factors significantly associated with mortality on univariable multilevel regression were combined into an additive HRI. Multivariable logistic regression evaluated associations between HRI and 90-day mortality. RESULTS:Analyses included 2928 patients from 214 centers across 60 countries. Six hospital factors were significantly associated with lower mortality, including interventional radiology/endoscopy availability, structured nutrition support, evidence-based practice adoption, staff training, equipment maintenance, and favorable nurse-patient ratios. Each additional HRI point was associated with 12% lower mortality odds (OR: 0.88, 95% CI: 0.81-0.95, P=0.001), independent of caseload volume (OR: 0.73, P=0.014, optimal cutoff 55 cases per year), country's development index, and patient and procedural characteristics. Patients at hospitals with all 6 HRI resources had a 54% lower mortality rate compared with those at hospitals with none. CONCLUSIONS:The developed HRI showed cumulative protective effects on mortality after pancreas surgery, with volume remaining independently protective in the adjusted model, providing actionable targets for resource allocation to enhance pancreas surgery outcomes beyond centralization globally.

BACKGROUND:Although main duct (MD) and branch duct (BD) IPMNs differ in preoperative risk of malignant transformation, it remains unclear whether ductal subtype influences outcomes once invasive carcinoma develops and is resected. We compared recurrence and survival outcomes between these subtypes. METHODS:We identified patients with resected IPMN-derived pancreatic ductal adenocarcinoma (PDAC) from three institutions. Overall survival (OS) and recurrence-free survival (RFS) were estimated using Kaplan-Meier methods and compared with log-rank tests. Multivariable Cox regression models adjusted for age, T-stage, N-stage, histologic subtype, and adjuvant chemotherapy. RESULTS:Among 136 patients, 106 (78%) had MD-derived and 30 (22%) had BD-derived IPMN-associated PDAC. Median OS was 36.6 months and did not differ by subtype on log-rank (p = 0.472) or multivariable analysis (HR 0.45, 95% CI 0.15-1.31; p = 0.143). Median RFS was 41.8 months without significant difference by subtype on log-rank (p = 0.362) or adjusted analysis (HR 0.56, 95% CI 0.21-1.46; p = 0.234). CONCLUSIONS:In patients with resected IPMN-derived PDAC, ductal subtype was not significantly associated with OS. While clinically meaningful differences in RFS cannot be excluded, these findings suggest that once invasive cancer arises and is resected, ductal subtype alone may not provide additional prognostic information.

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 PATIENT AND METHODS: 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 Fig. 1 Preoperative planning and first operation: extended pancreatosplenectomy, including resection of the left adrenal gland and the celiac artery (CA) (Mayo Clinic class Ia), divestment of the superior mesenteric artery, and portal vein (PV)-superior mesenteric vein reconstruction using a left renal vein graft interposition (A and B). Abdominal phase computed tomography scan, axial view, showing the encasement of the CA but with a free proper hepatic artery (PHA) as a "suitable target" if needed. (C) Drawing of the tumoral involvement with CA encasement and left/anterior side of the superior mesenteric artery (SMA) abutment. PHA, gastroduodenal artery (GDA), and the biliary tract were free of tumor, allowing a Mayo Clinic class Ia CA resection. 15 mm was the distance measured from the tumor to the GDA, and 28 mm was the distance of SMA abutment on the left side. (D) Operative view highlighting the common hepatic artery (CHA) stump, the remnant head of the pancreas (HoP), the venous reconstruction with left renal vein interposition graft, SMA divestment, and the CA stump. IVC, inferior vena cava; LGA, left gastric artery; LGV, left gastric vein; LRV, left renal vein; SA, splenic artery; SMV, superior mesenteric vein PERIOPERATIVE MANAGEMENT: 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. Fig. 2 Postoperative liver enzyme kinetics during the first postoperative week. Alanine aminotransferase (ALT) levels demonstrated a sharp and rapid increase from the day of surgery to postoperative day (POD) 2, leading to re-operation for a supercharged hepatic artery (HA) revascularization. Following revascularization, ALT levels decreased promptly, with complete normalization of liver biochemical parameters by POD 7. AST, aspartate aminotransferase; CAR, celiac artery resection; INR, international normalized ratio POD, postoperative day Fig. 3 Second surgical procedure: final reconstruction and liver biopsy. (A) Drawing of the final reconstruction with a zoom (B) on the arterial bypass between the right renal artery and the common hepatic artery. (C) Liver biopsy showing acute steatohepatitis, with 75% macro- and micro-vesicular steatosis and extensive ischemic necrosis. (D) Zoom on the area of ischemic necrosis, showing infiltration of the liver by neutrophils, lymphocytes, and plasma cells. CA, celiac artery; CHA, common hepatic artery; GDA, gastroduodenal artery; GSV, great saphenous vein; HoP, head of pancreas; IVC, inferior vena cava; LGA, left gastric artery; LGV, left gastric vein; LRV, left renal vein; PHA, proper hepatic artery; PV, portal vein; RRA, right renal artery; RRV, right renal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein CONCLUSION: 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.

BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas present a broad spectrum of biological behavior, ranging from benign to malignant. Their management poses significant ethical dilemmas, particularly concerning diagnostic uncertainty, the risk of overdiagnosis and overtreatment, and resource allocation. METHODS:This qualitative study employed a constructivist approach to explore the ethical challenges faced by surgeons in managing IPMNs. Data were collected through focus group meetings (FGMs) with members of an expert working group at the Verona Evidence-Based Meeting on IPMNs (2020). Discussions were analyzed to identify key ethical concerns. RESULTS:The analysis highlighted several major ethical concerns: (1) decision-making under diagnostic uncertainty, (2) ethical challenges in patient communication, (3) overdiagnosis and over-surveillance due to defensive medicine and patient anxiety, (4) overtreatment through unnecessary surgery, and (5) issues of distributive justice in access to care and healthcare resource utilization. Participants emphasized the difficulty of balancing transparency with the need to minimize psychological distress in patients, as well as the challenge of applying international guidelines in diverse healthcare settings. CONCLUSIONS:Ethical decision-making in IPMN management requires balancing the risks of malignancy with the potential harms of overtreatment, while also considering patient autonomy and resource limitations. Enhancing decision-support tools, improving surgeon training in communication, and refining clinical guidelines to incorporate ethical considerations may help address these challenges. Further research is needed to develop strategies for more individualized and patient-centered care.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with increasing incidence and a dismal prognosis. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of PDAC progression with a previously unrecognized role in epigenomic regulation. We show that SPINK1 expression, which is highly dynamic across PDAC progression, is associated with key aggressive cancer phenotypic states and regulates cancer cell stemness and plasticity in both in vitro and patient samples. Mechanistically, our results suggest a new signaling axis where SPINK1 interacts with COL18A1 to promote its cleavage into endostatin, which then induces histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and highlight the SPINK1-COL18A1-endostatin signaling axis as a potential therapeutic target to combat PDAC aggressiveness.

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/CONCLUSIONS: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:Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. METHODS:Consecutive patients diagnosed with pancreatic adenocarcinoma and > 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). RESULTS:Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) -3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. -5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD -12%; 95% c.i. -35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD -12%; 95% c.i. -27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). CONCLUSIONS:Radiotherapy before resection of pancreatic cancer with > 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.