Faculty Bibliography

BACKGROUND:The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. METHODS:Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. RESULTS:We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). CONCLUSION/CONCLUSIONS:CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.

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 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.

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.

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: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.

BACKGROUND:Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms. METHODS:We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients. RESULTS:Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255). CONCLUSIONS:A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

OBJECTIVE:To develop a predictive model of oncologic outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) undergoing resection after neoadjuvant or induction chemotherapy use. BACKGROUND:Early recurrence following surgical resection for PDAC is common. The use of neoadjuvant chemotherapy prior to resection may increase the likelihood of long-term systemic disease control. Accurately characterizing an individual's likely oncologic outcome in the perioperative setting remains challenging. METHODS:Data from patients with PDAC who received chemotherapy prior to pancreatectomy at a single high-volume institution between 2007-2018 were captured in a prospectively collected database. Core clinicopathologic data were reviewed for accuracy and survival data were abstracted from the electronic medical record and national databases. Cox-proportional regressions were used to model outcomes and develop an interactive prognostic tool for clinical decision-making. RESULTS:A total of 581 patients were included with a median OS and RFS of 29.5 (26.5-32.5) and 16.6 (15.8-17.5) months, respectively. Multivariable analysis demonstrates OS and RFS were associated with type of chemotherapeutic used and the number of chemotherapy cycles received preoperatively. Additional factors contributing to survival models included: tumor grade, histopathologic response to therapy, nodal status, and administration of adjuvant chemotherapy. The models were validated using an iterative bootstrap method and with randomized cohort splitting. The models were well calibrated with concordance indices of 0.68 and 0.65 for the final OS and RFS models, respectively. CONCLUSION/CONCLUSIONS:We developed an intuitive and dynamic decision-making tool that can be useful in estimating OS, RFS and location-specific disease recurrence rates. This prognostic tool may add value to patient care in discussing the benefits associated with surgical resection for PDAC.