Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method.

This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Background: Pancreatitis is a known risk factor for pancreatic cancer; however, an unknown fraction of the disease is thought to be a consequence of tumor-related duct obstruction. Patients and methods:A pooled analysis of a history of pancreatitis and risk of pancreatic cancer was carried out considering the time interval between diagnoses and potential modification by covariates. Adjusted pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from 10 case-control studies (5048 cases of ductal pancreatic adenocarcinoma and 10 947 controls) taking part in the International Pancreatic Cancer Case-Control Consortium (PanC4). Results:The association between pancreatitis and pancreatic cancer was nearly three-fold at intervals of >2 years between diagnoses (OR: 2.71, 95% CI: 1.96-3.74) and much stronger at intervals of ≤2 years (OR: 13.56, 95% CI: 8.72-21.90) probably reflecting a combination of reverse causation and antecedent misdiagnosis of pancreas cancer as pancreatitis. The younger (<65 years) pancreatic cancer cases showed stronger associations with previous (>2 years) pancreatitis (OR: 3.91, 95% CI: 2.53-6.04) than the older (≥65 years) cases (OR: 1.68, 95% CI: 1.02-2.76; P value for interaction: 0.006).Conclusions: Despite a moderately strong association between pancreatitis (diagnosed before >2 years) and pancreatic cancer, the population attributable fraction was estimated at 1.34% (95% CI: 0.612-2.07%), suggesting that a relatively small proportion of pancreatic cancer might be avoided if pancreatitis could be prevented.

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This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.

Background:Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs).Methods:Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs.Results:Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment.Conclusions:Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.

Background. Occupational exposure to acrylamide was associated with excess mortality from pancreatic cancer, though in the absence of dose-risk relationship. Few epidemiological studies have examined the association between acrylamide from diet and pancreatic cancer risk.Patients and methods. We considered this issue in a combined set of 1975 cases of pancreatic cancer and 4239 controls enrolled in six studies of the Pancreatic Cancer Case-Control Consortium (PanC4). We calculated pooled odds ratios (ORs) and their 95% confidence intervals (CI) by estimating study-specific ORs through multivariate unconditional logistic regression models and pooling the obtained estimates using random-effects models.Results. Compared with the lowest level of estimated dietary acrylamide intake, the pooled ORs were 0.97 (95% CI, 0.79-1.19) for the second, 0.91 (95% CI, 0.71-1.16) for the third, and 0.92 (95% CI, 0.66-1.28) for the fourth (highest) quartile of intake. For an increase of 10 µg/day of acrylamide intake, the pooled OR was 0.96 (95% CI, 0.87-1.06), with heterogeneity between estimates (I 2 = 67%). Results were similar across various subgroups, and were confirmed when using a one-stage modelling approach.Conclusions. This PanC4 pooled-analysis found no association between dietary acrylamide and pancreatic cancer.

4098 Background: Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Determining modifiable prognostic factors may be a key step in improving outcomes of these patients with overall poor survival. Pancreatic adenocarcinoma is often associated with diabetes. Our aim is to determine whether diabetes worsens disease specific mortality in resectable pancreatic cancer patients. Methods: In this study, we reviewed 298 patients with resected pancreatic adenocarcinoma in our surgical database at MD Anderson Cancer Center between August 1992 and July 2003. Patients were classified into diabetics (N = 87) (defined as those carrying the diagnosis of diabetes (DM) at time of presentation or on long term therapy for DM) and nondiabetics (N = 211). Univariate (log-rank) and Multivariate (Cox Regression) analyses were performed. Results: Compared to nondiabetics, patients with DM had a poorer overall survival with a median survival of 19.8 vs 29.2 months (p = 0.01). On multivariate analysis, correcting for known poor prognosticators in resectable patients: staging, histologic tumor differentiation and retroperitoneal margin status, diabetes was a significant independent risk factor for increased overall mortality (OR 1.55, 95% CI 1.15–2.07, p = 0.004). Disease-specific mortality was also higher in diabetics vs. non-diabetics with a median survival of 29.87 vs. 21.47 months (OR 1.37 95% CI 1.00–1.89 p = 0.048). Stage specific mortality was also higher among diabetics. Potential etiologies will be discussed. Conclusions: Diabetes worsens disease specific and overall mortality in patients with pancreatic cancer. Diabetes may be a modifiable risk factor and should be considered while prognosticating patients with resectable pancreatic cancer. Further studies are needed to determine whether treatment of diabetes improves outcomes. No significant financial relationships to disclose.