Gemcitabine-induced epithelial-mesenchymal transition-like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal-like phenotype.

Growing body of evidence suggests that epithelial-mesenchymal transition (EMT) is a critical process in tumor progression and chemoresistance in pancreatic cancer (PC). The aim of this study was to analyze the role of EMT-like changes in acquisition of resistance to gemcitabine in pancreatic cells of the mesenchymal or epithelial phenotype. Therefore, chemoresistant BxPC-3, Capan-2, Panc-1, and MiaPaca-2 cells were selected by chronic exposure to increasing concentrations of gemcitabine. We show that gemcitabine-resistant Panc-1 and MiaPaca-2 cells of mesenchymal-like phenotype undergo further EMT-like molecular changes mediated by ERK-ZEB-1 pathway, and that inhibition of ERK1/2 phosphorylation or ZEB-1 expression resulted in a decrease in chemoresistance. Conversely, gemcitabine-resistant BxPC-3 and Capan-2 cells of epithelial-like phenotype did not show such typical EMT-like molecular changes although the expression of the tight junction marker occludin could be found decreased. In pancreatic cancer patients, high ZEB-1 expression was associated with tumor invasion and tumor budding. In addition, tumor budding was essentially observed in patients treated with neoadjuvant chemotherapy. These findings support the notion that gemcitabine treatment induces EMT-like changes that sustain invasion and chemoresistance in PC cells.

Factors associated with fatal liver failure after extended hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) is the leading cause of posthepatectomy mortality. This study aimed to revisit the etiology and pattern of PHLF and its role in posthepatectomy morbidity and mortality. METHODS: The pattern and etiology of PHLF and subsequent morbidity and mortality were analysed in the subgroup of patients without cirrhosis undergoing an extended hepatectomy (≥4 segments) over a 5 year period. PHLF was defined using ISGLS criteria and/or 50-50 and/or peak serum bilirubin >7 mg/dl. RESULTS: Among 285 included patients (median age 62 [20-89]), 81 (28%) developed PHLF with higher rates of major complications (38%) and mortality (27%) than patients without PHLF (13% and 2%, respectively; p < 0.001). Twenty-six patients (9%) died, 22 of whom had PHLF. Of these 22 patients, only 4 patients died from complications purely-attributed to PHLF. All the remaining 18 patients had additional peri-operative factors that contributed to the mortality of which severe vascular events were the most common. CONCLUSION: PHLF is associated with higher rates of morbidity and mortality following extended resection. The etiology of PHLF is multifactorial with vascular events being common precipitant. The multifactorial origin of PHLF may explain the low predictive value of current clinical risk scores.

Relevance of the ISGLS definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies.

OBJECTIVE: To assess the relevance of the International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure compared with 2 well-established criteria, 50-50 and PeakBili>7, as early predictors of posthepatectomy outcome. BACKGROUND: There is limited data on the postoperative use of ISGLS definition of posthepatectomy liver failure as early predictor of outcome. METHODS: Between 2007 and 2012, a total of 680 hepatectomies were analyzed from a prospective database. The value of each definition for prediction of 3-month major complications (Clavien III-V) and mortality was assessed either within 10 days of surgery or on postoperative day 5. RESULTS: Three-month major morbidity and mortality rates were 16.5% and 4.4%, respectively. Within 10 days, 79 patients fulfilled ISGLS definition compared with 24 for 50-50 and 44 for PeakBili>7 criteria. Sensitivities of ISGLS definition and 50-50 and PeakBili>7 criteria for prediction of major morbidity and mortality were 35.8, 17.4, 24.8% and 56.7, 36.7, 56.7%, respectively. Patients with no positive score had a risk of death or major complication below 5% and 15%, respectively. In patients with a positive score, the ISGLS definition was the least relevant to predict major complications and mortality (positive predictive values of 49.4% and 21.8% vs 79.2% and 47.8% for 50-50 and 61.4% and 40.5% for PeakBili>7 criteria). The relative risk of death was 6.9 (95% confidence interval, 3.1-15.4) if the ISGLS definition was evaluated on postoperative day 5 versus 21.1 (95% confidence interval, 7.7-57.7) for 50-50 and 21.7 (95% confidence interval, 7.4-63.3) for PeakBili>7 criteria. CONCLUSIONS: ISGLS definition was less discriminatory than 50-50 and PeakBili>7 criteria in identifying patients at risk of posthepatectomy major complications or death.