Faculty Bibliography

BACKGROUND:The National Comprehensive Cancer Network guidelines consider pancreatic cancer with celiac axis (CA), proper hepatic artery (PHA), and superior mesenteric artery (SMA) involvement unresectable. Thus, technical reports and video illustrations of these operations are rare. We report the stepwise management of multivascular reconstruction for Mayo Clinic class IIIb CA resections at New York University Langone Health, a dedicated center of excellence in pancreatic surgery. METHODS:We illustrated the management of a 56-year-old patient with biopsy-confirmed pancreatic ductal adenocarcinoma arising from the pancreatic body and involving the CA, PHA, SMA, and mesentericoportal venous axis. PERIOPERATIVE MANAGEMENT/UNASSIGNED:The preoperative stepwise considerations include: 1) mandatory patient selection; 2) planning vascular reconstructability; 3) tailoring risk assessment while carefully considering the need for total pancreatectomy, total gastrectomy, and mesenteric/hepatic revascularization; and 4) 3D-reconstruction for arterial evaluation. The key intraoperative considerations include: 1) selective and sequential clamping for vascular reconstruction in a "domino" fashion, to minimize warm ischemic time 2) a combined multi-surgeon approach to comprehensively tackle vascular reconstructions; 3) a low threshold for total pancreatectomy to avoid pancreatic leak; and 4) two-stage surgery to reassess the blood supply to the liver and stomach for on-demand gastric preservation instead of a theoretically advised total gastrectomy. CONCLUSION/CONCLUSIONS:Liver, stomach, and bowel vascularization present life-threatening risks that require an extensive preoperative evaluation and a multidisciplinary approach. Our stepwise management for these extensive operations includes total pancreatectomy, "domino" vascular reconstruction, and two-stage surgery.

BACKGROUND:Early recurrence in intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) is poorly defined. Predictors are lacking and needed for patient counseling, risk stratification, and postoperative management. This study aimed to define and predict early recurrence for patients in resected IPMN-derived PDAC and guide management. METHODS:A lowest p value for survival after recurrence (SAR) was used to define early recurrence in resected IPMN-derived PDAC from five international centers. Overall survival (OS) and SAR were compared using log-rank tests. A multivariable logistic regression identified odds ratios (ORs) with 95 % confidence intervals (CIs) for early recurrence. Rounded ORs were used to stratify patients into low-, intermediate-, and high-risk groups using upper and lower quartile score distributions. Adjuvant chemotherapy was assessed by Cox regression and log-rank tests for OS in risk groups. RESULTS:Recurrence developed in 160 (42 %) of 381 patients. Early recurrence was defined at 10.5 months and observed in 61 patients (38 % of recurrences). The median SAR for the patients with early recurrence was 8.3 months (95 % CI, 3.1-16.1 months) compared with 12.9 months (95 % CI, 5.2-27.5 months) for the patients with late recurrence. The independent predictors of early recurrence were CA19-9 (OR, 3.80; 95 % CI, 1.54-9.41) and N2 disease (OR, 7.29; 95 % CI, 3.22-16.49). The early recurrence rates in the low-, intermediate-, and high-risk groups were respectively 1 %, 14 %, and 32 %. Adjuvant chemotherapy was associated with improved OS only for the high-risk patients (hazard ratio, 0.50; 95 % CI, 0.32-0.79). CONCLUSION/CONCLUSIONS:In IPMN-derived PDAC, the optimal cutoff for early recurrence is 10.5 months. Both CA19-9 and N stage predict early recurrence. Adjuvant chemotherapy is associated with survival benefit only for high-risk patients.

BACKGROUND:The existence of sociodemographic disparities in pancreatic cancer has been well-studied but how these disparities have changed over time is unclear. The purpose of this study was to longitudinally assess patient management in the context of sociodemographic factors to identify persisting disparities in pancreatic cancer care. METHODS:Using the National Cancer Database, patients diagnosed with pancreatic ductal adenocarcinoma from 2010 to 2017 were identified. The primary outcomes were surgical resection and/or receipt of chemotherapy. Outcome measures included changes in associations between sociodemographic factors (i.e., sex, age, race, comorbidity index, SES, and insurance type) and treatment-related factors (i.e., clinical stage at diagnosis, surgical resection, and receipt of chemotherapy). For each year, associations were assessed via univariate and multivariate analyses. RESULTS:Of 75,801 studied patients, the majority were female (51%), White (83%), and had government insurance (65%). Older age (range of OR 2010-2017 [range-OR]:0.19-0.29), Black race (range-OR: 0.61-0.78), lower SES (range-OR: 0.52-0.94), and uninsured status (range-OR: 0.46-0.71) were associated with lower odds of surgical resection (all p < 0.005), with minimal fluctuations over the study period. Older age (range-OR: 0.11-0.84), lower SES (range-OR: 0.41-0.63), and uninsured status (range-OR: 0.38-0.61) were associated with largely stable lower odds of receiving chemotherapy (all p < 0.005). CONCLUSIONS:Throughout the study period, age, SES, and insurance type were associated with stable lower odds for both surgery and chemotherapy. Black patients exhibited stable lower odds of resection underscoring the continued importance of mitigating racial disparities in surgery. Investigation of mechanisms driving sociodemographic disparities are needed to promote equitable care.

BACKGROUND:The American Joint Committee on Cancer (AJCC) eighth edition is based on pancreatic intraepithelial neoplasia-derived pancreatic ductal adenocarcinoma (PDAC), a biologically distinct entity from intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer. The role of nodal disease and the AJCC's prognostic utility for IPMN-derived pancreatic cancer are unclear. This study aimed to evaluate the prognostic role of nodal disease and the AJCC eighth-edition N-staging for IPMN-derived pancreatic cancer. METHODS:Upfront-surgery patients with IPMN-derived PDAC from four centers were stratified according to the AJCC eighth-edition N stage. Disease characteristics were compared using descriptive statistics, and both overall survival (OS) and recurrence-free survival (RFS) were evaluated using log-rank tests. Multivariable Cox regression was performed to determine the prognostic value of N stage for OS, presented as hazard ratios with 95 % confidence intervals (95 % CIs). A lowest p value log-rank statistic was used to derive the optimal cutoff for node-positive disease. RESULTS:For 360 patients, advanced N stage was associated with worse T stage, grade, tubular histology, and perineural and lymphovascular invasion (all p < 0.05). The median OS was 98.3 months (95 % CI 82.8-122.0 months) for N0 disease, 27.8 months (95 % CI 24.4-41.7 months) for N1 disease, and 18.1 months (95 % CI 16.2-25.9 months) for N2 disease (p < 0.001). The AJCC N stage was validated and associated with worse OS (N1 [HR 1.64; range, 1.05-2.57], N2 [HR2.42; range, 1.48-3.96]) and RFS (N1 [HR 1.81; range, 1.23-2.68], N2 [HR 3.72; range, 2.40-5.77]). The optimal cutoff for positive nodes was five nodes. CONCLUSION/CONCLUSIONS:The AJCC eighth-edition N-staging is valid and prognostic for both OS and RFS in IPMN-derived PDAC.

BACKGROUND:The American Joint Committee on Cancer (AJCC) eighth edition is based on pancreatic intraepithelial neoplasia-derived pancreatic ductal adenocarcinoma (PDAC), a biologically distinct entity from intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer. The role of nodal disease and the AJCC's prognostic utility for IPMN-derived pancreatic cancer are unclear. This study aimed to evaluate the prognostic role of nodal disease and the AJCC eighth-edition N-staging for IPMN-derived pancreatic cancer. METHODS:Upfront-surgery patients with IPMN-derived PDAC from four centers were stratified according to the AJCC eighth-edition N stage. Disease characteristics were compared using descriptive statistics, and both overall survival (OS) and recurrence-free survival (RFS) were evaluated using log-rank tests. Multivariable Cox regression was performed to determine the prognostic value of N stage for OS, presented as hazard ratios with 95 % confidence intervals (95 % CIs). A lowest p value log-rank statistic was used to derive the optimal cutoff for node-positive disease. RESULTS:For 360 patients, advanced N stage was associated with worse T stage, grade, tubular histology, and perineural and lymphovascular invasion (all p < 0.05). The median OS was 98.3 months (95 % CI 82.8-122.0 months) for N0 disease, 27.8 months (95 % CI 24.4-41.7 months) for N1 disease, and 18.1 months (95 % CI 16.2-25.9 months) for N2 disease (p < 0.001). The AJCC N stage was validated and associated with worse OS (N1 [HR 1.64; range, 1.05-2.57], N2 [HR2.42; range, 1.48-3.96]) and RFS (N1 [HR 1.81; range, 1.23-2.68], N2 [HR 3.72; range, 2.40-5.77]). The optimal cutoff for positive nodes was five nodes. CONCLUSION/CONCLUSIONS:The AJCC eighth-edition N-staging is valid and prognostic for both OS and RFS in IPMN-derived PDAC.

INTRODUCTION/BACKGROUND:Prognostic markers for overall survival (OS) in resected pancreatic ductal adenocarcinoma (PDAC) are well-established but remain unclear following neoadjuvant therapy (NAT). This systematic review and meta-analysis aimed to determine factors associated with OS following NAT in resected PDAC. METHODS:The PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL databases were systematically searched from inception till May 2024. Studies that reported univariable and multivariable hazard ratios (HRs) were included if patients underwent NAT and resection for localized PDAC. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using generic inverse-variance random-effects models. RESULTS:Among 2,208 unique articles identified by the search, 92 were included in the meta-analysis. Eighty-five of these were of 'good' and 7 of 'poor' quality. The NAT regimen was described in 84 studies, of which 62 included patients treated with FOLFIRINOX (FFX). Margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT were prognostic for OS, while age, sex, perineural invasion, baseline tumor size, and baseline CA19-9 were not. The test for subgroup differences between ypN-substages was not significant in the multivariable model. Neoadjuvant FFX was associated with better survival than other regimens. CONCLUSIONS:This meta-analysis identified margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT as prognostic factors for OS in patients with resected localized PDAC following NAT.

PURPOSE/OBJECTIVE:Local and distant progression remain common following resection of resectable pancreatic ductal adenocarcinoma (PDAC) despite adjuvant multiagent chemotherapy. We report a prospective institutional phase I trial incorporating adjuvant GVAX vaccine, low-dose cyclophosphamide (Cy) and SBRT followed by FOLFIRINOX (FFX) among patients who underwent resection of high-risk PDAC. PATIENTS AND METHODS/METHODS:The study design was a modified 3+3. Cohort 1 received 5-fraction SBRT to 33 Gy to the tumor bed and 25 Gy to elective nodes followed by 6 cycles of full dose FFX. After toxicity review, cohort 2 had SBRT and were switched to modified FFX (mFFX). Cohort 3 had 1 cycle of Cy/GVAX followed by SBRT, mFFX, and 4 cycles of maintenance Cy/GVAX with 6-month Cy/GVAX boosts until progression. RESULTS:19 patients were enrolled with a median follow-up of 36.2 months. To be eligible, patients were required to have close/positive margins (within ≤1 mm) (71%) and/or lymph node metastasis (79%). Overall, 63% of patients had both. In cohort 1, 67% of patients received 6 cycles of FFX; in cohort 2, 75% received 6 cycles of modified FFX. In cohort 3, 12 patients received the first dose of Cy/GVAX and SBRT with 10 individuals (83%) receiving 6 cycles of mFFX. Cohort 3 had acceptable levels of grade ≥3 thrombocytopenia, neutropenia, and diarrhea after two cycles of mFFX. Median OS/DFS for the overall cohort and cohort 3 was 36.2/18.2 months and 61.3/24.1 months, respectively. 1-year and 2-year OS for cohort 3 was 83%/75%, respectively. At last follow-up (median= x), 5 patients were alive (42%) in cohort 3. CONCLUSION/CONCLUSIONS:This is the first prospective trial to evaluate adjuvant GVAX, Cy, SBRT, and mFFX in resected PDAC patients with high-risk features. This combination regimen was well tolerated with limited toxicity and promising survival outcomes, warranting future studies to validate this regimen in the adjuvant setting.

BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) is resected at smaller sizes compared to its biologically distinct counterpart, pancreatic intraepithelial neoplasia (PanIN)-derived PDAC. Thus, experts proposed T1 sub-staging for IPMN-derived PDAC. However, this has never been validated. METHODS:Consecutive upfront surgery patients with IPMN-derived PDAC from five international high-volume centers were classified by the proposed T1 sub-staging classification (T1a ≤ 0.5, T1b > 0.5 and ≤1.0, and T1c >1.0 and ≤2.0 cm) using the invasive component size. Kaplan-Meier and log-rank tests were utilized to compare overall survival (OS). A multivariable Cox-regression was used to determine hazard ratios (HR) with confidence intervals (95%CI). RESULTS:Among 747 patients, 69 (9.2%), 50 (6.7%), 99 (13.0%), and 531 patients (71.1%), comprised the T1a, T1b, T1c, and T2-4 subgroups, respectively. Increasing T-stage was associated with elevated CA19-9, poorer grade, nodal positivity, R1-margin, and tubular subtype. Median OS for T1a, T1b, T1c, and T2-4 were 159.0 (95%CI:126.0-NR), 128.8 (98.3-NR), 77.6 (48.3-108.2), and 31.4 (27.5-37.7) months, respectively (p < .001). OS decreased with increasing T-stage for all pairwise comparisons (all p < .05). After risk-adjustment, age > 65, elevated CA19-9, T1b [HR : 2.55 (1.22-5.32)], T1c [HR : 3.04 (1.60-5.76)], and T2-4 [HR : 3.41 (1.89-6.17)] compared to T1a, nodal positivity, R1-margin, and no adjuvant chemotherapy were associated with worse OS. Disease recurrence was more common in T2-4 tumors (56.4%) compared to T1a (18.2%), T1b (23.9%), and T1c (36.1%, p < .001). CONCLUSION/CONCLUSIONS:T1 sub-staging of IPMN-derived PDAC is valid and has significant prognostic value. Advancing T1 sub-stage is associated with worse histopathology, survival, and recurrence. T1 sub-staging is recommended for future guidelines.