Faculty Bibliography

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.

BACKGROUND:Risk calculators (RCs) support clinicians estimating the likelihood that a pancreatic intraductal papillary mucinous neoplasm (IPMN) would progress so that surveillance might be discontinued for low-risk lesions. We tested the effect of an RC on clinicians' judgment and decision-making and identified their cancer risk threshold for changing their decision. PATIENTS AND METHODS/METHODS:We presented clinicians with three vignettes (V1, V2, and V3) of patients with low-risk IPMNs and asked them to assess the likelihood that the IPMN would progress to develop high-risk features and whether they would recommend continuing surveillance imaging. Clinicians were randomly assigned to the clinical vignettes alone (n = 35) or supplemented by data from the Dutch-American Risk Stratification Tool (DART-1 RC: n = 37). We compared clinicians' judgments and decisions between groups and assessed their cancer risk threshold (level of risk at which recommendation would change). RESULTS:Across all vignettes, the RC resulted in no change in clinicians' judged likelihood of IPMN progression (V1 8.49 vs. 8.41%, p = 0.09; V2 4.39 vs. 6.75%, p = 0.99; V3 13.61 vs. 13.29%, p = 0.27) or recommendation to continue surveillance (V1 57 vs. 41%, p = 0.78; V2 41 vs. 59%, p = 0.55; V3 66 vs. 34%, p = 0.31). Clinicians varied in their reported risk threshold (V1 9%, interquartile range [IQR] 2, 13%; V2 9% [IQR 1, 15%], V3 8% [IQR 3, 20%]). CONCLUSIONS:An RC did not significantly influence clinicians' risk perception or decision to continue surveillance, although the study was limited by low sample size. The cancer risk threshold at which clinicians would change their recommendation varies widely. Future work is needed to understand why RCs do not appear to alter decision-making.

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.

OBJECTIVE:To assess the prognostic impact of margin status in patients with resected intraductal papillary mucinous neoplasms (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and to inform future intraoperative decision-making on handling differing degrees of dysplasia on frozen section. SUMMARY BACKGROUND DATA/BACKGROUND:The ideal oncologic surgical outcome is a negative transection margin with normal pancreatic epithelium left behind. However, the prognostic significance of reresecting certain degrees of dysplasia or invasive cancer at the pancreatic neck margin during pancreatectomy for IPMN-derived PDAC is debatable. METHODS:Consecutive patients with resected and histologically confirmed IPMN-derived PDAC (2002-2022) from six international high-volume centers were included. The prognostic relevance of a positive resection margin (R1) and degrees of dysplasia at the pancreatic neck margin were assessed by log-rank test and multivariable Cox-regression for overall survival (OS) and recurrence-free survival (RFS). RESULTS:Overall, 832 patients with IPMN-derived PDAC were included with 322 patients (39%) having an R1-resection on final pathology. Median OS (mOS) was significantly longer in patients with an R0 status compared to those with an R1 status (65.8 vs. 26.3 mo P<0.001). Patients without dysplasia at the pancreatic neck margin had similar OS compared to those with low-grade dysplasia (mOS: 78.8 vs. 66.8 months, P=0.344). However, high-grade dysplasia (mOS: 26.1 mo, P=0.001) and invasive cancer (mOS: 25.0 mo, P<0.001) were associated with significantly worse OS compared to no or low-grade dysplasia. Patients who underwent conversion of high-risk margins (high-grade or invasive cancer) to a low-risk margin (low-grade or no dysplasia) after intraoperative frozen section had significantly superior OS compared to those with a high-risk neck margin on final pathology (mOS: 76.9 vs. 26.1 mo P<0.001). CONCLUSIONS:In IPMN-derived PDAC, normal epithelium or low-grade dysplasia at the neck have similar outcomes while pancreatic neck margins with high-grade dysplasia or invasive cancer are associated with poorer outcomes. Conversion of a high-risk to low-risk margin after intraoperative frozen section is associated with survival benefit and should be performed when feasible.

BACKGROUND:Little is known about the prognostic significance of pancreatic duct (PD) dilation following pancreatoduodenectomy for intraductal papillary mucinous neoplasms (IPMN). Although PD dilation is typically the hallmark radiographic feature of IPMN, other causes of PD dilation exist, including anastomotic stricture, pancreatitis, senescence, and postsurgical passive dilation. Therefore, PD dilation after pancreatoduodenectomy for IPMN represents a diagnostic and management dilemma. The purpose of this study was to evaluate the significance of PD dilation after pancreatoduodenectomy for noninvasive IPMN. METHODS:All patients who underwent pancreatoduodenectomy for noninvasive IPMN at nine pancreatic academic centers between 2013 and 2018 were included. Variables were entered prospectively into institutional databases and retrospectively reviewed for the purpose of this study. Dilation of the PD remnant was defined as a duct diameter of ≥5 mm, according to international guidelines. RESULTS:Four-hundred and eighty-one patients were included in this study. The mean age of the patients was 66 years (range 30-90). Patients were surveilled for a median of 4.5 (+/-2.3; max 10.6) years. During follow-up, 132 patients (27.4%) developed PD dilation in the remnant tissue after a median of 3.3 years. Multivariable analysis demonstrated that older age at the time of pancreatoduodenectomy (P=0.01) and longer surveillance duration (P=0.002) were predictors of PD dilation. Interestingly, neither the pathological IPMN subtype (branch-duct vs. main duct/mixed, P=0.96) nor the preoperative PD diameter (P=0.14) was associated with an increased risk of PD dilation in the remnant. During follow-up, IPMN recurrence was suspected in the remaining 72 patients (18.4%), solely because of ductal dilation on cross-sectional imaging in 97% (70/72). Completion pancreatectomy was performed in only 16 patients (3.3%), of whom only four (0.8%) had invasive carcinoma. Three of these four patients had high-grade dysplasia in the original pancreatoduodenectomy specimen, whereas only one had a low-grade dysplastic lesion initially. On multivariable analysis, no variable was predictive of IPMN recurrence in the remnant. CONCLUSIONS:New main duct dilation in the pancreatic remnant after pancreatoduodenectomy for IPMN is common, occurring in 27% of the patients. The duration of surveillance is the main factor associated with remnant PD dilation, suggesting that this is likely a physiologic phenomenon. Although recurrence of IPMN in the remnant is often suspected, only 0.8% of patients develop an invasive carcinoma in the pancreatic remnant requiring completion pancreatectomy.

OBJECTIVE:We aimed to better understand patients' treatment preferences and quantify the level of cancer risk at which treatment preferences change (risk threshold) to inform better counseling of patients with intraductal papillary mucinous neoplasms (IPMNs). SUMMARY BACKGROUND DATA/BACKGROUND:The complexity of IPMN management provides an opportunity to align treatment with individual preference. METHODS:We surveyed a sample of healthy volunteers simulating a common scenario: undergoing an imaging study that incidentally identifies an IPMN. In the scenario, the estimated risk of cancer in the IPMN was 5%. Patients were asked their treatment preference (surgery or surveillance), to quantify the level of cancer risk in the IPMN at which their treatment preference would change (i.e. risk threshold), and their level of cancer anxiety as measured on a 5-point Likert scale. We examined associations between participant characteristics, treatment preferences, and risk threshold using multivariable linear regression. RESULTS:The median risk threshold among the 520 participants was 25% (IQR 2.3-50%). The risk threshold had a bimodal distribution: 40% of participants had a risk threshold between 0-10% and 47% had a risk threshold above 30%. When informed that the risk of cancer was 5%, 62% of participants (n=323) preferred surveillance, and the remaining 38% (n=197) preferred surgery. After adjusting for potential confounders, participants who expressed "worry" or "extreme worry" about the malignancy risk of IPMN had significantly lower risk thresholds than participants who were "not at all worried" (Coefficient -12, 95%CI -21 to -2, P=0.015 and Coefficient -18, 95%CI -29 to -8, P<0.001, respectively). CONCLUSIONS:Participants varied in treatment preference and risk threshold of incidentally identified IPMNs. Given the uncertainty in estimating the true malignant potential of IPMNs, a better understanding of a patient's risk threshold, as influenced by patient concern about malignancy, will help inform the shared decision-making process.