Faculty Bibliography

BACKGROUND:Accurate preoperative malignancy risk assessment in intraductal papillary mucinous neoplasm (IPMN) is essential to balance timely intervention for high-grade dysplasia or invasive cancer (HGD/IC) against avoiding unnecessary or premature surgery in low-grade IPMN. This study aimed to externally validate the 2023 International Association of Pancreatology (IAP)/Kyoto guidelines and develop a combined prediction model incorporating routinely collected clinical data and laboratory parameters. METHODS:We conducted a retrospective cohort study of 194 patients who underwent resection for IPMN between 2012 and 2024. We evaluated the predictive performance of the current IAP/Kyoto criteria ("Kyoto model"), developed a clinical model using routinely available laboratory and clinical variables, and integrated both into a combined model. Model performance was assessed using discrimination and calibration metrics, with internal validation via bootstrapping and five-fold cross-validation. RESULTS:The Kyoto model demonstrated modest discrimination (AUC 0.62). The clinical model, incorporating neutrophil-to-lymphocyte ratio (NLR), smoking history, blood glucose, CA19-9, and alkaline phosphatase, achieved an optimism-corrected AUC of 0.76. Compared to the Kyoto model, the combined model (AUC 0.77) significantly improved discrimination and calibration (p < 0.001). At a predicted probability threshold of >0.75, the combined model achieved a 90% specificity and 91% positive predictive value for HGD/IC, identifying a high-risk subgroup suitable for surgical intervention. CONCLUSIONS:Integrating routinely collected clinical and laboratory parameters with guideline-based imaging features shows promise to enhance preoperative identification of high-risk IPMN in patients already being considered for surgical resection. The combined model offers a practical, high-specificity tool to support surgical decision-making in this selected population, though its performance metrics should not be extrapolated to unselected surveillance cohorts. External validation is required before broader clinical implementation.

Currently, no consensus exists regarding the definition of oligometastatic pancreatic ductal adenocarcinoma, its necessary diagnostic measures, and potential treatment approaches. To address these knowledge gaps, the OligoPanc project brought together an interdisciplinary group of experts to establish consensus using a modified Delphi process and clinical vignettes. Participants agreed that the number of metastatic lesions and the number of affected organs are key elements in defining oligometastatic pancreatic ductal adenocarcinoma. Specifically, up to three lesions in a single organ, either the liver or the lung, define oligometastatic pancreatic ductal adenocarcinoma and could be either synchronous or metachronous. Necessary diagnostics include a triple-phase contrast-enhanced CT scan of the chest and abdomen and MRI of the liver with a hepatocyte-specific contrast agent. In unclear cases, [¹⁸F]fluorodeoxyglucose-PET CT or MRI can be considered. A multidisciplinary tumour board is essential. Patient-intrinsic factors, including age, do not define oligometastatic disease but should be considered for any treatment decision. Systemic treatment before any local consolidative treatment, including surgery, stereotactic ablative radiotherapy, or other locally ablative techniques, is mandatory. The proposed definition should be incorporated into future trials to improve comparability and enable validation.

BACKGROUND:Pancreatic cancer with early onset is increasing but comparisons with average onset cases have yielded mixed results (EOPC versus AOPC; age <50 versus ≥50). We compared clinicopathologic features, prognosis, and molecular traits of resected EOPC versus AOPC. METHODS:We retrospectively included patients with PDAC resected between 2010 and 2017 from The National Cancer Database (NCDB). Clinicopathologic data were compared across EOPC versus AOPC. Kaplan-Meier curves and cox-regression were used to perform survival analysis. Molecular features were compared using data from the cBioPortal. RESULTS:24,078 patients with resected PDAC were included, of whom 1698 (7.1 %) had EOPC. Poor prognostic factors, including high grade, advanced T-stage, and lymphovascular invasion, were less prevalent in EOPC (All p < 0.05). Patients with EOPC more frequently received neoadjuvant (28 % vs. 22 %; p < 0.001) and adjuvant chemotherapy (68 % vs. 58 %; p < 0.001) and experienced improved OS (median OS 29.5 vs 25.9 months, p = 0.023; 5-year OS: 26.9 % vs 20.8 %). No differences in the presence of key driver mutations were observed between the two groups but some distinct oncogenic mutations were observed in EOPC. CONCLUSION/CONCLUSIONS:EOPC and AOPC are clinically similar but some cases of EOPC may harbor divergent molecular changes. These patients may have only marginally improved survival.

OBJECTIVE:The International Study Group of Pancreatic Surgery (ISGPS) aimed to uniform the definition and classification of mortality following pancreatic resections, to guide strategies for reducing preventable deaths and standardize reporting. BACKGROUND:Reported rates of mortality after pancreatic surgery vary widely depending on patient comorbidities, case mix, and institutional expertise and resources. Conventional reporting lacks granularity and fails to capture the mechanisms leading to death. A standardized classification rooted in causal analysis may provide a more meaningful framework to appraise outcomes and design targeted interventions. METHODS:A systematic review of the literature, focusing on mortality rates, causes of death, and existing classification systems after pancreatectomy was conducted. A consensus definition and tripartite classification were developed through iterative discussions, revisions, and final approval by the ISGPS board members. RESULTS:Postpancreatectomy mortality (PPM) was defined as death occurring within 90 days of any pancreatic resection, directly or indirectly attributable to a surgical complication and retrospectively linked to it through root-cause analysis. Three categories were established: PPM 1, vascular/technical complexity-related mortality (15-30%); PPM 2, pancreatectomy-specific complication-related deaths, mainly due to postoperative pancreatic fistula (POPF) and secondary systemic deterioration (45-65%); and PPM 3, cardiopulmonary and cerebrovascular deaths (10-25%). Each category reflects distinct mechanisms, timing of onset, intervention windows, and opportunities for rescue. DISCUSSION/CONCLUSIONS:The proposed ISGPS classification of mortality enables the development of targeted strategies to reduce potentially preventable deaths and provides a more robust framework for the appraisal and benchmarking of surgical outcomes. Prospective validation is warranted to standardize this newly defined quality metric, ensuring its consistent use in future reporting and ultimately enhancing surgical quality and patient safety on a global scale.

BACKGROUND:The 2024 Kyoto guidelines for the management of intraductal mucinous neoplasms (IPMNs) build on previous guidelines that consider worrisome features (WF) and high-risk stigmata (HRS) to recommend surveillance or resection. These new guidelines have not yet been validated. METHODS:Patients undergoing pancreatectomy for an IPMN at an academic medical center between 2012 and 2023 were included. IPMNs were categorized as low-grade dysplasia (LGD), high-grade dysplasia (HGD), or invasive carcinoma (IC). Preoperative imaging was used to determine HRS and WF in accordance with the 2024 Kyoto guidelines. We compared IPMNs with LGD to those with HGD or IC using univariate analyses and evaluated logistic regression models with c-statistics. RESULTS:Of 211 patients, 84 (40%) had LGD, 49 (23%) had HGD, and 78 (37%) had IC. Among HRS, obstructive jaundice (p = 0.004), pancreatic duct ≥ 10 mm (p < 0.001), and suspicious or positive cytology (p < 0.001) were significantly associated with HGD/IC. An increasing number of HRS were associated with higher rates of HGD/IC. Among WFs, an abrupt change in the caliber of pancreatic duct with distal pancreatic atrophy (p = 0.001) and cystic growth ≥ 2.5 mm/year (p = 0.033) were significantly associated with higher rates of HGD/IC. Increasing numbers of WFs were also associated with higher rates of HGD/IC. The 2024 Kyoto model showed improved discrimination (area under the curve [AUC] = 0.849) compared with the 2017 Fukuoka model (AUC=0.780, p = 0.06). CONCLUSION/CONCLUSIONS:The risk of HGD/IC in IPMNs increased in a stepwise fashion as the number of WFs increased. The 2024 guidelines represent an advancement over the 2017 guidelines, notably with the inclusion of suspicious cytology as an HRS.

Pancreatic ductal adenocarcinoma (PDAC) 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. Moreover, the current determination of anatomic resectability is vague and unreliable. Here we propose a definition of local resectability, based on pre- and intra-operative assessment. This anatomic definition of resectability assumes careful patient selection based on tumor biology and patient condition. The pre-operative evaluation of vascular anatomy and tumor involvement is conducted using 3D-rendering of pancreas-protocol computed tomography. Identifying a disease-free arterial or venous segment above and below the tumor involvement ("suitable target") is the single critical factor that determines 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 LAPC patients 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:Staging laparoscopy (SL) is performed to detect occult metastases in patients with localized pancreatic cancer. However, current guideline recommendations vary widely on routinely performing SL. This global survey investigated use and indications of SL. METHODS:An online survey was sent to members of nine international societies and working groups. Information was obtained about SL use, indications SL and adjunct diagnostic modalities across four clinical scenarios. RESULTS:Among 617 responding surgeons (76 countries, six continents), 82% used SL which varied between regions (Americas 90%, Asia 85%, Oceania 81%, Europe 76%, Africa 59%; P < 0.050). Most perform SL during the same session as the scheduled laparotomy (63-79%). A SL was mainly performed at the time of upfront surgery (71%), after (60%) or before (37%) neoadjuvant/induction therapy, and before radiotherapy (31%). SL was mainly performed in selected patients, either based on indeterminate/suspicious lesions on cross-sectional imaging (78-87%), resectability status (54-64%), and/or elevated CA19-9 level (60-69%). Most common used adjuncts were cytological lavage (37-55%) and intra-abdominal liver ultrasonography (36-50%). CONCLUSION/CONCLUSIONS:Despite considerable global variability, SL is widely used to detect occult metastases in pancreatic cancer, mainly in high-risk patients and often during the scheduled laparotomy. The observed variability highlights the need for more evidence leading to stronger guideline recommendations.

BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer with highly variable malignant potential. Current understanding of their biology remains incomplete, limiting accurate risk stratification and targeted interventions. OBJECTIVE:This study aimed to characterise the molecular and immune features of IPMN across different dysplasia grades and histological subtypes, with a focus on IPMN-associated invasive carcinoma (IPMN-IC). DESIGN/METHODS:Spatial whole-transcriptome profiling using Digital Spatial Profiling was conducted on 12 patients, capturing the full histological and dysplastic spectrum of IPMN and conventional pancreatic ductal adenocarcinoma. A total of 117 epithelial, immune and stromal areas of interest were analysed. An expanded cohort of 43 patients with IPMN was used to validate selected key markers. RESULTS:Transcriptomic analysis unveiled stage-specific molecular alterations and identified two distinct subsets of high-grade (HG) IPMN lesions: one resembling indolent lesions (HG) and the other IC (HG+). Key markers associated with divergent biological behaviours were identified, including MUC5AC and TFF1 in indolent lesions, and Claudin-1 in lesions with invasive potential. Immune profiling revealed a trajectory from activation to suppression during IPMN progression. Several characteristic immune checkpoint molecules, including CEACAM1 and CD44, were identified in IPMN-IC. CONCLUSION/CONCLUSIONS:This study provides a spatially resolved molecular map of IPMN progression, delineating key transcriptomic and immune signatures. These findings advance the understanding of IPMN biology and highlight potential biomarkers for risk stratification and therapeutic strategies.