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Background: Even after surgical resection, most patients with localized pancreatic ductal adenocarcinoma (PDAC) succumb to disease recurrence. Current animal models do not recapitulate this pattern of disease recurrence. Our goal was to develop a clinically relevant, immunocompetent model of PDAC resection to study recurrence and evaluate therapy. Methods: Pancreatic cancer cells derived from tumors arising in KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice were co-injected with stromal cells (pancreatic stellate cells) into the pancreas of immunocompetent mice to simulate the stroma-rich tumors seen in human PDAC. After allowing tumors to form, we resected these localized tumors and followed the mice for tumor recurrence. Circulating tumor cells (CTCs) were isolated, and systemic chemotherapy or immunotherapy was administered following tumor resection. Results: Tumors formed by co-injection of KPC cells and stromal cells demonstrated a dense desmoplastic reaction similar to that seen in human disease. Resection at days 15 and 21 after implantation revealed uniform tumor volumes of 92 ± 19 mm3 on day 15 and 444 ± 54 mm3 on day 21. Histology of resected tumors showed negative margins. Resembling human PDAC, mice that underwent resection showed improved median survival (58 vs 47 days) but most animals developed intra-abdominal recurrence on follow-up. Adjuvant chemotherapy (median survival 69 vs 58 days), but not immunotherapy (median survival 69 vs 65 days) tended towards improved survival as seen in human disease. Circulating tumor cells were reliably identified from mice with and without resection, suggesting utility of this model in studying tumor metastases and recurrence. Conclusion: We describe an immunocompetent animal model that recapitulates human disease in morphology and recurrence patterns. We show that it can be used to evaluate therapy in clinical scenarios associated with surgical resection and may help characterize factors responsible for disease recurrence. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle (L0). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L0, however dasatinib was reduced to 50 mg (L−1) given side effects observed in the first two patients. At L−1, a DLT occurred in 1/6 patients and dose was re-escalated to L0, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L1) where 1/6 patients experienced a DLT. Although L1 was tolerable, dose escalation was stopped as investigators felt L1 was within the optimal therapeutic window. Most frequent toxicities were anemia (89%), elevated aspartate aminotransferase (79%), fatigue (79%), nausea (79%), elevated alanine aminotransferase (74%), lymphopenia (74%), leukopenia (74%), neutropenia (63%), and thrombocytopenia (63%), most Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objectives: Currently, no reasonable staging system exists for pancreatic neuroendocrine tumors (PNET) to guide treating physicians. The aim of this study was to devise a staging system of relevant prognostic factors to better predict overall survival in PNET.Methods: A prospective 300 patient cohort and a review of the Surveillance Epidemiology and End Results database identified 6,447 patients with PNET from 1973 to 2008. Significant prognostic factors were created for an initial. Tumor: T (T1: ≤3 cm and localized to pancreas, T2: >3 cm and localized to the pancreas; T3: extension to adjacent organs and vessels), grade: G (G1: well/moderate and G2: poor/undifferentiated), and metastasis: M (M0: no distant mets, M1: distant mets) staging system.Results: Significant predictors of survival on multivariate analysis included age, size, grade, and metastasis. Based on the TGM staging system: stage 1 (T1-2, G1, M0), stage 2 (T1-2, G2, M0), stage 3 (T3G2M0, Tany, G1, M1), stage 4: (Tany, G2, M1) was created with survival being statistically different between stages (p < 0.0001). Median survival rates were stage 1, 55 months; stage 2, 50 months; stage 3, 46 months; and stage 4, 25 months.Conclusions: Incorporation of this newly developed staging system into clinical practice will improve the ability to predict prognosis and aid in stratification of patients for clinical trials. [ABSTRACT FROM AUTHOR]

The Papanicolaou Society of Cytopathology (PSC) has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature for pancreatobiliary cytology, ancillary testing and post-procedure management. All documents are based on the expertise of the authors, a review of the literature and discussions of the draft document at several national and international meetings over an 18 month period and synthesis of online comments of the draft document on the PSC web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on the follow-up and treatment options for patients after procedures performed for obtaining cytology samples for the evaluation of biliary strictures and solid and cystic masses in the pancreas. These recommendations follow the six-tiered terminology and nomenclature scheme proposed by committee III. [ABSTRACT FROM AUTHOR]

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing and postbiopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed. [ABSTRACT FROM AUTHOR]

Context.--PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4- based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC. Objective.--To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas. Design.-Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N=19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9. Results.--PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue. Conclusions.--PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC. [ABSTRACT FROM AUTHOR]

Introduction: This study investigates the ability of endoscopic ultrasound (EUS) and computed tomography (CT) to predict a margin negative (R0) resection and the need for venous resection in patients undergoing pancreaticoduodenectomy (PD).Methods: Patients with pancreatic head adenocarcinoma undergoing surgery with intent to resect during the last 5 years were identified. EUS and CT data on vascular involvement were collected. Preoperative imaging was compared to intraoperative findings and final pathology. Contingency table analysis using Fisher's exact test identified imaging features of EUS and CT associated with unresectability and positive margins.Results: Seventy-six patients met study criteria. Forty-seven (62%) underwent potentially curative PD. The R0 resection rate was 70%. There were 16 unresectable patients because of locally advanced disease. Venous involvement>180 degrees and arterial involvement>90 degrees by CT had 100% positive predictive value for failure to achieve R0 resection (p<.01). If patients with prestudy biliary stents were excluded, EUS venous abutment or invasion also predicted R0 failure (p=.02). Combined but not individual EUS and CT findings were predictive of need for vein resection.Conclusions: Pancreas protocol CT imaging appears to be a better predictor of resectability compared to EUS. EUS accuracy is affected by the presence of biliary stents. [ABSTRACT FROM AUTHOR]

Exocrine pancreatic insufficiency (EPI) is frequently seen in patients with pancreatic cancer (PDAC) and is thought to contribute to nutritional complications. While EPI can be pharmacologically temporized with pancreatic enzyme replacement therapy (PERT), there is lack of clear evidence informing its use in PDAC. Here we aim to survey pancreatic surgeons regarding their utilization of PERT in the management of EPI for PDAC. An online survey was distributed to the members of The Americas Hepato-Pancreato-Biliary Association (AHPBA) and The Pancreas Club. 86.5% (180/208) of surgeons prescribe PERT for at least some resectable/borderline resectable PDAC cases. Only a minority of surgeons order investigations to confirm EPI before starting PERT (28.1%) or test for adequacy of therapy (28.3%). Few surgeons believe that PERT has an effect on overall survival (19.7%) or disease-free survival (6.25%) in PDAC. PERT is widely prescribed in patients with resectable/borderline resectable PDAC, but investigations establishing EPI and assessing PERT adequacy are underutilized. A substantial proportion of surgeons are unclear as to the effect of PERT on survival outcomes in PDAC. These data call for prospective studies to establish guidelines for optimal use of PERT and its effects on survival outcomes in PDAC. [ABSTRACT FROM AUTHOR]

Background: Controversy persists regarding the management of patients with intraductal papillary mucinous neoplasms (IPMN). International consensus guidelines stratify patients into high-risk, worrisome, and low risk categories.Study Design: The medical records of 7 institutions were reviewed for patients who underwent surgical management of IPMN between 2000 and 2015.Results: There were 324 patients included in the analysis; 60.4% of patients had main-duct/mixed type, and 39.7% had branch-duct IPMN. The median cyst size was 2.65 cm, invasive cancer (IC) or high-grade dysplasia (HGD) was present in 42% (n = 136); 68.9% of patients with high-risk, 40.0% of patients with worrisome, and 24.6% of patients with low risk features exhibited HGD/IC. Multivariate analysis demonstrated that only 1 of 3 high-risk features and 2 of 7 worrisome features predicted the presence of HGD/IC. Positive predictive values for HGD/ IC in patients with obstructive jaundice and lymphadenopathy were 0.83 (95% CI 0.65 to 0.94) and 0.69 (95% CI 0.39 to 0.91), respectively. In the absence of high-risk features, HGD/IC was still present in 57.4% of patients with 2 or more worrisome features. Regression analysis demonstrated that each additional worrisome factor present was additive in predicting HGD/IC in a linear fashion (odds ratio 1.39; 95% CI 1.08 to 1.80; p < 0.01).Conclusions: These data demonstrate that the current consensus guidelines for surgical resection of IPMN may not adequately stratify and identify patients at risk for having HGD or invasive cancer. Patients with multiple worrisome features, in the absence of high-risk factors, should be considered for resection. [ABSTRACT FROM AUTHOR]

Background: Level 1 data demonstrate that adjuvant chemotherapy (ACT) improves survival after surgical resection of pancreatic ductal adenocarcinoma (PDAC), (adjuvant gemcitabine, CONKO-001 study; adjuvant 5-FU, ESPAC3 study). The role of adjuvant chemoradiation therapy (ACRT) remains controversial. What is less clear is whether adjuvant therapy influences patterns of recurrence. The purpose of this study was to perform the first multicenter study analyzing patterns of recurrence after adjuvant therapy for PDAC.Study Design: Patients undergoing resection for PDAC from 8 medical centers over a 10-year period were analyzed. Demographics, tumor characteristics, operative treatment, type of adjuvant therapy, recurrence pattern, and survival were reviewed. Using Cox-proportional hazards multivariate (MV) regression, the impact of ACT and ACRT on overall survival (OS), local recurrence (LR), and distant recurrence (DR) was investigated.Results: There were 1,130 patients who were divided into those having surgery alone (n = 392), ACT (n = 291), or ACRT (n = 447). Median follow-up was 18 months. Compared with patients undergoing surgery alone, ACT, but not ACRT, demonstrated a significant OS advantage on MV analysis. Patients receiving ACT had significantly fewer recurrences (LR and DR); those receiving ACRT had significantly less LR but not DR. On subset MV analysis, ACT and ACRT resulted in less LR in patients with lymph node (LN) positive and margin negative disease. No improvements in LR, DR, or OS were seen in margin positive patients with either ACT or ACRT.Conclusions: This is the first analysis demonstrating differences in recurrence patterns in PDAC patients based on type of adjuvant therapy. Adjuvant chemotherapy provided an OS advantage likely related to its effect on reducing both LR and DR. Adjuvant chemoradiation therapy appears to decrease LR, but not DR, and therefore has less impact on OS. Future investigations and treatment protocols should consider additional ACT rather than ACRT in the treatment of PDAC. [ABSTRACT FROM AUTHOR]