The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival.

BACKGROUND: The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival. METHODS: Pancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon resection. Homogenates were subjected to multiplex analysis of 41 inflammatory mediators. RESULTS: Twenty-three mediators were significantly elevated in adenocarcinoma specimens compared to nonmalignant controls. Increased intratumoral IL-8 concentrations associated with larger tumors (P = .045) and poor differentiation (P = .038); the administration of neoadjuvant chemotherapy associated with reduced IL-8 concentrations (P = .003). Neoadjuvant therapy was also associated with elevated concentrations of Flt-3 L (P = .005). Elevated levels of pro-inflammatory cytokines IL-1ß (P = .017) and TNFα (P = .033) were associated with a poor histopathologic response to neoadjuvant therapy. Elevated concentrations of G-CSF (P = .016) and PDGF-AA (P = .012) correlated with reduced overall survival. Conversely, elevated concentrations of FGF-2 (P = .038), TNFα (P = .031) and MIP-1α (P = .036) were associated with prolonged survival. CONCLUSION: The pancreatic cancer microenvironment harbors a unique inflammatory milieu with potential diagnostic and prognostic value.

Standardization of surgical care in a high-volume center improves survival in resected pancreatic head cancer.

BACKGROUND: Durable clinical gains in surgical care are frequently reliant on well-developed standardization of practices. We hypothesized that the standardization of surgical management would result in improved long-term survival in pancreatic cancer. METHODS: Seventy-seven consecutive, eligible patients representing all patients who underwent pancreaticoduodenectomy and received comprehensive, long-term postoperative care at the University of Florida were analyzed. Patients were divided into prestandardization and poststandardization groups based on the implementation of a pancreatic surgery partnership, or standardization program. RESULTS: Standardization resulted in a reduction in median length of stay (10 vs 12 days; P = .032), as well as significant gains in disease-free survival (17 vs 11 months; P = .017) and overall survival (OS; 26 vs 16 months; P = .004). The improvement in overall survival remained significant on multivariate analysis (hazard ratio = .46, P = .005). CONCLUSIONS: Standardization of surgical management of pancreatic cancer was associated with significant gains in long-term survival. These results suggest strongly that management of pancreatic head adenocarcinoma be standardized likely by regionalization of care at high performing oncologic surgery programs.

Oncologic and Perioperative Outcomes Following Selective Application of Laparoscopic Pancreaticoduodenectomy for Periampullary Malignancies.

BACKGROUND: Data are sparse regarding patient selection criteria or evaluating oncologic outcomes following laparoscopic pancreaticoduodenectomy (LPD). Having prospectively limited LPD to patients with resectable disease defined by National Comprehensive Cancer Network (NCCN) criteria, we evaluated perioperative and long-term oncologic outcomes of LPD compared to a similar cohort of open pancreaticoduodenectomy (OPD). METHODS: Consecutive patients (November 2010-February 2014) undergoing pancreaticoduodenectomy (PD) for periampullary adenocarcinoma were reviewed. Patients were excluded from further analysis for benign pathology, conversion to OPD for portal vein resection, and contraindications for LPD not related to their malignancy. Outcomes of patients undergoing LPD were analyzed in an intention-to-treat manner against a cohort of patients undergoing OPD. RESULTS: These selection criteria resulted in offering LPD to 77 % of all cancer patients. Compared to the OPD cohort, LPD was associated with significant reductions in wound infections (16 vs. 34 %; P = 0.038), pancreatic fistula (17 vs. 36 %; P = 0.032), and median hospital stay (9 vs. 12 days; P = 0.025). Overall survival (OS) was not statistically different between patients undergoing LPD vs. OPD for periampullary adenocarcinoma (median OS 27.9 vs. 23.5 months; P = 0.955) or pancreatic adenocarcinoma (N = 28 vs. 22 patients; median OS 20.7 vs. 21.1 months; P = 0.703). CONCLUSIONS: The selective application of LPD for periampullary malignancies results in a high degree of eligibility as well as significant reductions in length of stay, wound infections, and pancreatic fistula. Overall survival after LPD is similar to OPD.

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.