Faculty Bibliography

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

BACKGROUND:Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery. METHODS:Using an institutional database, PDAC patients undergoing liver resection for isolated metastasis were identified. Their overall survival (OS), treatment factors, and clinicopathological variables associated with survival were also evaluated. RESULTS:Forty-seven patients underwent curative-intent surgery for metastatic PDAC to the liver between 2000 and 2019. Median OS was 21.9 months from diagnosis. Fourteen patients underwent unplanned resection of radiographically occult liver metastasis during pancreatectomy with median OS of 8.7 months. On the other hand, 29 patients received systemic chemotherapy followed by planned resection; this cohort had the most favorable prognosis following aggressive surgery with median OS being 38.1 months from diagnosis and 24.1 months from surgery. Preoperative chemotherapy (HR = 7.1; p = .002) and moderate to well differentiation of the primary tumor (HR = 3.7; p = .003) were associated with prolonged survival in multivariate analysis, whereas lymph node metastases, response to preoperative therapy, number of liver metastasis, and extent of liver surgery were not. CONCLUSIONS:In select patients with PDAC and isolated liver metastasis, curative-intent surgery can result in meaningful survival. This aggressive approach seems most beneficial in patients following induction chemotherapy.

OBJECTIVES/OBJECTIVE:We analyze successes and failures of pushing the boundary in vascular pancreatic surgery to establish safety of conduit reconstructions. SUMMARY BACKGROUND DATA/BACKGROUND:Improved systemic control from chemotherapy in pancreatic cancer is increasing the demand for surgical solutions of extensive local vessel involvement, but conduit-specific data are scarce. METHODS:We identified 63 implanted conduits (41% autologous vessels, 37% allografts, 18% PTFE) in 56 pancreatic resections of highly selected cancer patients between October 2013 and July 2020 from our prospectively maintained database. Assessed parameters were survival, perioperative complications, operative techniques (anatomic and extra-anatomic routes) and conduit patency. RESULTS:For vascular reconstruction, 25 arterial and 38 venous conduits were utilized during 39 pancreatoduodenectomies, 14 distal pancreatectomies and 3 total pancreatectomies. The median postoperative survival was 2 years. A Clavien-Dindo grade ≥IIIa complication was apparent in 50% of the patients with a median Comprehensive Complication Index of 29.6. The 90-day mortality in this highly selected cohort was 9%. Causes of mortality were conduit-related in 3 patients, late postpancreatectomy hemorrhage in 1 patient and early liver metastasis in 1 patient. Image-based patency rates of conduits were 66% and 45% at postoperative days 30 and 90, respectively. CONCLUSIONS:Our perioperative mortality of vascular pancreatic surgery with conduits in the arterial or venous system is 9%. Reconstructions are technically feasible with different anatomic and extra-anatomic strategies, while identifying predictors of early conduit occlusion remains challenging. Optimizing reconstructed arterial and venous hemodynamics in the context of pancreatic malignancy will enable long-term survival in more patients responsive to chemotherapies.

OBJECTIVE:To establish an evidence-based cut-off and predictors for early recurrence in patients with resected locally advanced pancreatic cancer (LAPC). SUMMARY BACKGROUND DATA/BACKGROUND:It is unclear how many and which patients develop early recurrence after LAPC resection. Surgery in these patients is probably of little benefit. METHODS:We analyzed all consecutive patients undergoing resection of LAPC after induction chemotherapy who were included in prospective databases in the Netherlands (2015-2019) and the Johns Hopkins Hospital (2016-2018). The optimal definition for "early recurrence" was determined by the post-recurrence survival (PRS). Patients were compared for overall survival (OS). Predictors for early recurrence were evaluated using logistic regression analysis. RESULTS:Overall, 168 patients were included. After a median follow-up of 28 months, recurrence was observed in 118 patients (70.2%). The optimal cut-off for RFS to differentiate between early (n=52) and late recurrence (n=66) was 6 months (P<0.001). OS was 8.4 months (95%CI 7.3-9.6) in the early recurrence group (n=52) versus 31.1 months (95%CI 25.7-36.4) in the late/no recurrence group (n=116) (P<0.001). A preoperative predictor for early recurrence was post-induction therapy CA19-9≥100 U/mL (OR4.15, 95%CI 1.75-9.84, P=0.001). Postoperative predictors were poor tumor differentiation (OR4.67, 95%CI 1.83-11.90, P=0.001) and no adjuvant chemotherapy (OR6.04, 95%CI 2.43-16.55, P<0.001). CONCLUSION/CONCLUSIONS:Early recurrence was observed in one third of patients after LAPC resection and was associated with poor survival. Patients with post-induction therapy CA19-9 ≥100 U/mL, poor tumor differentiation and no adjuvant therapy were especially at risk. This information is valuable for patient counseling before and after resection of LAPC.

A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

OBJECTIVES/OBJECTIVE:To identify factors associated with concordance between World Health Organization (WHO) grade on cytological analysis (c-grade) and histopathological analysis (h-grade) of surgical specimen in patients with PanNETs and examine trends in utilization and accuracy of EUS-FNA in preoperatively predicting grade. BACKGROUND:WHO grading system is prognostic in pancreatic neuroendocrine tumors (PanNETs). The concordance between c-grade and h-grade is reported to be between 60% and 80%. METHODS:A multicenter retrospective study was performed on patients undergoing resection for PanNETs at four high-volume centers. Patients with functional or syndrome-associated tumors, and those receiving neoadjuvant therapy were excluded. Factors associated with concordance between c-grade and h-grade and trends of utilization of EUS-FNA were assessed. RESULTS:Of 1,336 patients included, 682 (51.1%) underwent EUS-FNA; 567 (83.1%) were diagnostic of PanNETs and WHO-grade was reported for 293 (51.7%) patients. The concordance between c-grade and h-grade was 78.2% with moderate inter-rater agreement (Kc=0.48,p<0.001). Significantly higher rates of concordance were observed in patients with smaller tumors (<2 vs. ≥2 cm, 88.9% vs. 72.7%,p=0.001). Highest concordance (97.9%) was observed in patients with small tumors undergoing assessment between 2015-2019 with near-perfect inter-rater agreement (Kc=0.88,p<0.001)An increase in the utilization of EUS-FNA (46.7% to 62.1%) was observed over the last 2 decades (p<0.001). EUS-FNA was more frequently diagnostic of PanNETs (p<0.001), and WHO-grade was more frequently reported (<0.001). However, concordance between c-grade and h-grade did not change significantly (p=0.056). CONCLUSION/CONCLUSIONS:Recently, a trend towards increasing utilization and improved diagnostic accuracy of EUS-FNA has been observed in PanNETs. Concordance between c-grade and h-grade is associated with tumor size with near-perfect agreement when assessing PanNETs >2 cm in size.

OBJECTIVE:The aim of the study was to assess the association between persistent CTCs and subsequent recurrence in patients who were clinically recurrence free approximately 12 months postoperatively. BACKGROUND:Circulating tumor cells have been proposed as biomarkers to predict survival in pancreatic cancer. Some patients demonstrate persistent CTCs postoperatively which could represent minimal residual disease. METHODS:Patients from previously published prospective CLUSTER trial without clinical evidence of recurrence 12 months postoperatively and CTC testing performed 9-15 months postoperatively were included. Presence of epithelial (eCTCs) and transitional CTCs (trCTCs) was evaluated as predictor of recurrence. Kaplan-Meier curve, log-rank test, and Cox model were used for survival analysis. RESULTS:Thirty-three of 129 eligible patients (CLUSTER trial) were included. The trCTC positive and negative patients were well-balanced in clinicopathological features. Patients with trCTCs had a recurrence rate per-person-month of 10.3% compared to 3.1% in trCTCs negative patients with a median time to recurrence of 3.9 versus 27.1 months, respectively. On multivariable analysis trCTCs positivity was associated with higher risk of late recurrence (HR:4.7,95%CI:1.2-18.3, P=0.024). Fourteen (42.4%) patients recurred during the second postoperative year. 1-year postoperative trCTCs positivity was associated with a higher rate of recurrence during the second year (OR:13.1,95%CI:1.6-1953.4,P=0.028, AUC=0.72). Integrating clinicopathological features with trCTCs increased the AUC to 0.80. A majority of trCTCs positive patients (N=5, 62.5%) had multi-site recurrence, followed by local-only (N=2, 25.0%) and liver-only (N=1, 12.5%) recurrence. This was in striking contrast to trCTCs negative patients, where a majority (N=6, 66.7%) had a local-only recurrence, followed by liver-only (N=2, 22.2%) and multi-site (N=1, 11.1%) recurrence. CONCLUSION/CONCLUSIONS:In patients deemed to be clinically disease free 12 months postoperatively, trCTCs positivity is associated with higher rates of subsequent recurrence with distinct patterns of recurrence. CTCs could be used a putative biomarker to guide patient prognostication and management in pancreatic cancer.

OBJECTIVES/OBJECTIVE:The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in initiation of adjuvant therapy. BACKGROUND:Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. While systemic therapies improve survival in resected patients, factors such as a delay in initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS:A retrospective study was performed on PDAC patients enrolled in the prospective CLUSTER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (ISET; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify two CTC types: epithelial CTCs (eCTCs), expressing pan-cytokeratin, and transitional CTCs (trCTCs), expressing both pan-cytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in receipt of adjuvant therapy was defined as initiation of therapy ≥8 weeks after surgical resection. Clinicopathological features, CTCs characteristics, and outcomes were analyzed. RESULTS:Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, presence of transitional CTCs (trCTCs, P=0.002) and absence of adjuvant therapy (P=0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs. 17.9 mo, P=0.004) or no administration of adjuvant chemotherapy (3.4 vs. NR, P=0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy (P=0.293). CONCLUSION/CONCLUSIONS:Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.

OBJECTIVE:To validate the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system for patients with invasive carcinomas arising in association with IPMN (IPMN-associated PDAC). BACKGROUND DATA/BACKGROUND:Although several studies have validated AJCC systems in patients with conventional PDAC, their applicability to IPMN-associated PDAC has not been assessed. METHODS:275 patients who underwent resection for IPMN-associated PDAC between 1996 and 2015 at three tertiary centers and had data on the size of the invasive component and lymph node status were identified. Concordance probability estimates (CPE) were calculated and recursive partitioning analysis was employed to identify optimal prognostic cutoffs for T and N. RESULTS:The CPE for both the 7th and 8th editions of the AJCC schema was relatively good (0.64 in both) and similar for colloid and tubular subtypes (0.64 in both). The 8th edition introduced T1a sub-staging and a new distinction between N1 and N2. The utility of the former was confirmed, although the latter did not improve prognostic discrimination. The successful validation of the 8th edition of the AJCC criteria in patients with tubular and colloid subtypes allowed us to compare these patients in early vs late T and N stages which showed that when there is advanced disease, the prognostic superiority of colloid tumors over their tubular counterparts diminishes. CONCLUSIONS:Our findings support the use of the AJCC 8th edition in the IPMN-associated PDAC population, but suggest that certain cutoffs may need to be revisited. In advanced AJCC stages, patients with colloid vs tubular subtype have comparable prognosis.