Faculty Bibliography

Pancreatic ductal adenocarcinomas comprise a hierarchy of tumor cells that develop around a population of cancer stem cells. The cancer stem cells promote tumor growth and progression through a number of mechanisms, including differentiation into bulk tumor cells, metastasis, alteration of adjacent stromal cells, and evasion of conventional therapies. As with other cancer stem cells, pancreatic cancer stem cells (PCSCs) can be distinguished from bulk tumor cells based on their expression of unique surface markers, abilities to form spheres under nonadherent conditions and tumors in mice, and self-renewal and differentiation capacities. We review the markers used to identify PCSCs, the signaling pathways that regulate PCSC functions, the complex interactions between PCSCs and stromal cells, and approaches to therapeutically target PCSCs and improve treatment of patients with pancreatic cancer.

Protein kinases represent the most effective class of therapeutic targets in cancer; therefore, determination of kinase aberrations is a major focus of cancer genomic studies. Here, we analyzed transcriptome sequencing data from a compendium of 482 cancer and benign samples from 25 different tissue types, and defined distinct "outlier kinases" in individual breast and pancreatic cancer samples, based on highest levels of absolute and differential expression. Frequent outlier kinases in breast cancer included therapeutic targets like ERBB2 and FGFR4, distinct from MET, AKT2, and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specific dependencies in various cell lines, as tested by siRNA knockdown and/or pharmacologic inhibition. Outlier expression of polo-like kinases was observed in a subset of KRAS-dependent pancreatic cancer cell lines, and conferred increased sensitivity to the pan-PLK inhibitor BI-6727. Our results suggest that outlier kinases represent effective precision therapeutic targets that are readily identifiable through RNA sequencing of tumors.

BACKGROUND: The Society of University Surgeons (SUS) has an ongoing competitive funding program to support research training for residents. We sought to determine the career track of award recipients. METHODS: We included in the study SUS resident awardees who completed awards from 1989-2007. Characteristics of awardees and their academic productivity were extracted from curriculum vitae provided by awardees (n = 24), or from online sources (n = 7). RESULTS: Awardees spent an average of 2.7 y (range, 1-4 y) of dedicated research time during residency. Awardees averaged 9.8 publications (range, 1-32), with 5.4 as first author (range, 1-17), with their mentor within 3 y of award completion, with an average maximum impact factor of 5.7. A total of 25 residents (81%) pursued fellowships. At an average follow-up of 11.4 y (range, 4-22 y) from the end of the award and 7.2 y (range, 0-18 y) from end of clinical training, awardees had a Hirsch index of 14.5 (range, 2-48). At the time of the study, 26 awardees (84%) were in academic surgery. Of the 23 awardees who had completed surgical training >/= 3 y earlier, 11 (48%) received independent research funding, seven of whom (30%) received R01 or equivalent funding. CONCLUSIONS: The SUS resident research awardees had a productive research experience. Although our retrospective study cannot determine causation, the SUS award mechanism delivers on its promise of supporting junior surgeon-scientists who pursue academic careers and establish independent research programs. Further studies are needed to determine how rates of subsequent independent research funding can be improved.

BACKGROUND: The purpose of this study was to evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin, and radiation therapy (RT) in patients with localized pancreatic cancer. METHODS: Eligibility included confirmation of adenocarcinoma, resectable or borderline resectable disease, a performance status /=3 adverse events during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients underwent resection (63%), and complete (R0) resection was achieved in 36 of those 43 patients (84%). The median overall survival was 18.2 months (95% confidence interval, 13-26.9 months) for all patients, 27.1 months (95% confidence interval, 21.2-47.1 months) for those who underwent resection, and 10.9 months (95% confidence interval, 6.1-12.6 months) for those who did not undergo resection. A decrease in CA 19-9 level after neoadjuvant therapy was associated with R0 resection (P = .02), which resulted in a median survival of 34.6 months (95% confidence interval, 20.3-47.1 months). Fourteen patients (21%) are alive and disease free at a median follow-up of 31.4 months (range, 24-47.6 months). CONCLUSIONS: Preoperative therapy with full-dose gemcitabine, oxaliplatin, and RT was feasible and resulted in a high percentage of R0 resections. The current results are particularly encouraging, because the majority of patients had borderline resectable disease.

Wnt ligand expression and activation of the Wnt/beta-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here, we report the results of three different approaches to inhibit the Wnt/beta-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that beta-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant pancreatic intraepithelial neoplasia lesions. Second, we addressed the specific role of ligand-mediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Finally, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches showed that ligand-mediated activation of the Wnt/beta-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications.

OBJECTIVE: Endoscopic ultrasound-guided fine-needle aspiration and bile duct brushings are utilized in the cytologic evaluation of solid and cystic pancreaticobiliary tract lesions. We sought to determine the diagnostic accuracy of cytology. METHODS: Five hundred seventy-nine pancreatic resections with 727 corresponding cytology specimens were identified from 1997 to 2012. Histologic diagnoses included benign, carcinoma, pancreatic endocrine neoplasm (PEN), nonepithelial neoplasms, cystic neoplasms, and ampullary adenomas. Standard interpretative categories-nondiagnostic, negative, atypical, suspicious, and positive--were utilized for preoperative cytology specimens. RESULTS: For solid masses, the sensitivity and specificity of positive fine-needle aspiration (FNA) cytology for detecting carcinoma were 74 and 100 %, respectively. FNAs performed better than brushings (sensitivity, 40 %; specificity, 98 %) in detecting carcinomas. Similar findings were seen for PENs and nonepithelial neoplasms. For cystic lesions, the sensitivity of FNA for predicting malignancy was lower (24 %) with a specificity of 97 %. Sequentially combining suspicious and atypical categories with the positive category resulted in increases in sensitivity and decreases in specificity for all cases except for cystic lesions. CONCLUSIONS: Cytology adds to the assessment of solid masses, but its utility in cystic lesions is less clear. Consideration of a suspicious cytologic interpretation as a positive diagnosis for triaging patients to surgery is supported by our study.