Patient-derived xenograft models for pancreatic adenocarcinoma demonstrate retention of tumor morphology through incorporation of murine stromal elements.

Direct implantation of viable surgical specimens provides a representative preclinical platform in pancreatic adenocarcinoma. Patient-derived xenografts consistently demonstrate retained tumor morphology and genetic stability. However, the evolution of the tumor microenvironment over time remains poorly characterized in these models. This work specifically addresses the recruitment and incorporation of murine stromal elements into expanding patient-derived pancreatic adenocarcinoma xenografts, establishing the integration of murine cells into networks of invading cancer cells. In addition, we provide methods and observations in the establishment and maintenance of a patient-derived pancreatic adenocarcinoma xenograft model. A total of 25 histologically confirmed pancreatic adenocarcinoma specimens were implanted subcutaneously into nonobese diabetic severe combined immunodeficiency mice. Patient demographics, staging, pathological analysis, and outcomes were analyzed. After successful engraftment of tumors, histological and immunofluorescence analyses were performed on explanted tumors. Pancreatic adenocarcinoma specimens were successfully engrafted in 15 (60%) of 25 attempts. Successful engraftment does not appear to correlate with clinicopathologic factors or patient survival. Tumor morphology is conserved through multiple passages, and tumors retain metastatic potential. Interestingly, despite morphological similarity between passages, human stromal elements do not appear to expand with invading cancer cells. Rather, desmoplastic murine stroma dominates the xenograft microenvironment after the initial implantation. Recruitment of stromal elements in this manner to support and maintain tumor growth represents a novel avenue for investigation into tumor-stromal interactions.

Failure to follow evidence-based best practice guidelines in the treatment of severe acute pancreatitis.

OBJECTIVES: Evidence-based guidelines for the treatment of severe acute pancreatitis have been established. This study was conducted to investigate the hypothesis that deviation from guidelines occurs frequently. METHODS: With institutional review board approval, the outside medical records of patients with severe pancreatitis who were transferred to the study institution during the period from July 2005 to May 2012 were reviewed. Severe pancreatitis was defined using the Atlanta Classification criteria. Records were reviewed with respect to published guidelines defining the appropriate use of imaging, antibiotics and nutritional support. RESULTS: A total of 538 patients with acute pancreatitis were identified. Of 67 patients with severe acute pancreatitis, 44 (66%) were male. The mean age of the patients was 55 years. Forty-five of 61 (74%) patients for whom relevant data were available were imaged upon admission, but only 15 (31%) patients were imaged appropriately by computerized tomography with i.v. contrast to assess the presence of necrosis or other complications. In patients for whom relevant data were available, prophylactic antibiotics were initiated in the absence of culture data or a specific infectious target in 26 (53%) patients. Total parenteral nutrition (TPN) was administered to 38 (60%) of 63 patients for whom relevant data were available; only 10 (17%) patients received enteric feeding. No nutritional support was provided to 15 (23%) patients. CONCLUSIONS: Adherence to best practice guidelines in the treatment of severe pancreatitis is poor. The consistent application of current knowledge might improve outcomes in these patients.

Nicotine Reduces Survival via Augmentation of Paracrine HGF-MET Signaling in the Pancreatic Cancer Microenvironment.

PURPOSE: The relationship between smoking and pancreatic cancer biology, particularly in the context of the heterogeneous microenvironment, remains incompletely defined. We hypothesized that nicotine exposure would lead to the augmentation of paracrine growth factor signaling between tumor-associated stroma (TAS) and pancreatic cancer cells, ultimately resulting in accelerated tumor growth and metastasis. EXPERIMENTAL DESIGN: The effect of tobacco use on overall survival was analyzed using a prospectively maintained database of surgically resected patients with pancreatic cancer. Nicotine exposure was evaluated in vitro using primary patient-derived TAS and pancreatic cancer cells independently and in coculture. Nicotine administration was then assessed in vivo using a patient-derived pancreatic cancer xenograft model. RESULTS: Continued smoking was associated with reduced overall survival after surgical resection. In culture, nicotine-stimulated hepatocyte growth factor (HGF) secretion in primary patient-derived TAS and nicotine stimulation was required for persistent pancreatic cancer cell c-Met activation in a coculture model. c-Met activation in this manner led to the induction of inhibitor of differentiation-1 (Id1) in pancreatic cancer cells, previously established as a mediator of growth, invasion and chemoresistance. HGF-induced Id1 expression was abrogated by both epigenetic and pharmacologic c-Met inhibition. In patient-derived pancreatic cancer xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression by qRT-PCR and phospho-Met levels by ELISA. Similarly, elevated levels of phospho-Met in surgically resected pancreatic cancer specimens correlated with reduced overall survival. CONCLUSIONS: Taken together, these data demonstrate a novel, microenvironment-dependent paracrine signaling mechanism by which nicotine exposure promotes the growth and metastasis of pancreatic cancer.