Prognostic Relevance of Stage Migration in Patients with Hepatocellular Carcinoma: A Multicenter Cohort Study

POSTER PRESENTATIONS Conclusions: Data confirmed that HFD induced in mice biochemical and histological alterations in liver typical of human NAFLD and demonstrated that coffee supplementation can reverse that status by reducing ALT, macrovesicular steatosis and ballooning degeneration. Interestingly, coffee consumption reduced body weight gain in mice fed HFD and determined changes in the expression of intestinal epithelium ZO-1 and claudin. All in all the data suggested that the protective effect of coffee on NAFLD may be mediated by an amelioration of gut permeability. SAT-343 HEPATOCELLULAR AUTOPHAGY DEFICIENCY IN MICE MODULATES THE UNFOLDED PROTEIN RESPONSE IN A PATHWAY SELECTIVE MANNER W.J. Kwanten1, Y.-P. Vandewynckel2, W. Martinet3, B.Y. De Winter1, P.P. Michielsen1,4, V. Van Hoof5, A. Driessen6, J.-P. Timmermans7, P. Bedossa8, H. Van Vlierberghe2, S.M. Francque1,4. 1Laboratorium of Experimental Medicine and Pediatrics - Gastroenterology & Hepatology, University of Antwerp, Wilrijk (Antwerp); 2Department of Hepatology and Gastroenterology, Ghent University, Ghent; 3Laboratory of Physiopharmacology, University of Antwerp, Wilrijk (Antwerp); 4 Department of Gastroenterology and Hepatology; 5Department of Clinical Chemistry; 6Department of Pathology, Antwerp University Hospital, Edegem (Antwerp); 7Laboratory of Cell Biology and Histology, University of Antwerp, Wilrijk (Antwerp), Belgium; 8Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France E-mail: [email protected] Background and Aims: Autophagy is an important cellular process involved in the breakdown of cytoplasmic content via a lysosomal pathway in order to maintain cellular homeostasis. Autophagy is constitutionally active, but can be upregulated in case of cellular stress. The unfolded protein response (UPR) is another key homeostatic mechanism activated upon accumulated misfolded proteins in the endoplasmic reticulum. Both autophagy and the UPR are implicated in the pathophysiology of NAFLD. Although the UPR is known to promote autophagic flux, the reciprocal effects are less well known. Therefore we studied the effects of hepatocellular autophagy-deficiency on the three different UPRpathways. Methods: The essential autophagy gene Atg7 was cell-specifically deleted via the Cre-LoxP technology and use of an albumin-promoter to create hepatocyte-specific autophagy-deficient mice. These mice were compared to their wild type littermates at an age of 9–10 weeks. Key mediators and chaperones of the distinct UPR pathways (i.e. IRE1, ATF6, PERK) were studied with rt-PCR and western blotting, as well as the executioner caspase-3/7 activity. Results: Hepatocellular autophagy-deficient mice did not develop fasting-induced steatosis and exhibit severe parenchymal injury, as previously described. The hepatic expression of IRE1a, its endoribonuclease activity and its downstream effectors were not significantly altered. Although the expression of ATF6 itself was unchanged ( p = 0.22), its active cleaved fragment was robustly decreased in autophagy-deficient mice. The transcription and protein levels of ATF6-regulated chaperones were concordantly reduced ( p < 0.05). In contrast, the PERK pathway was significantly activated in the autophagy-deficient mice ( p < 0.05). CHOP, a central effector of UPR-mediated apoptosis downstream of PERK, was increased in these mice ( p < 0.001) as was confirmed by the increased executioner caspase-3/7 activity (p < 0.01). Conclusions: These results demonstrate that autophagy has a reciprocal and pathway-selective effect on UPR, with a diminished cytoprotective ATF6 pathway and an enhanced pro-apoptotic PERK pathway upon autophagy-deficiency. These effects might partially explain the absence of fasting-induced steatosis and the observed significant hepatic lesions.

Liver tumours: Management SAT-055 PROGNOSTIC RELEVANCE OF STAGE MIGRATION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA: A MULTICENTER COHORT STUDY A. Vitale1, F. Farinati1, M. Polacco1, P. Burra1, F. Trevisani2, U. Cillo1, ITA. LI.CA. 1Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua; Azienda Università Di Padova, Padova; 2 Department of Medical and Surgical Sciences, Division of Semeiotics, Alma Mater Studiorum – University of Bologna, Bologna, Italy E-mail: [email protected] Background and Aims: Patients with hepatocellular carcinoma (HCC) are usually staged at first tumor presentation using Barcelona Clinic Liver Cancer (BCLC) classification. The aim of this study is to evaluate the prognostic impact of staging and treatment reassessment after first line therapies in a large cohort of HCC patients from the ITA.LI.CA database. Methods: Among patients of the ITA.LI.CA database (n = 6,579), we selected 1,196 patients enrolled between January 2000 and March 2015, who had a complete staging re-assessment of recurrent/ persistent tumor after a first line non-transplant therapy. Based on restaging and response to first line therapy, enrolled patients were stratified in two subgroups according to stage migration: a) Stable/ progression group: patients with stable/progressive disease or stage progression after 1 line therapy; b) Downstaging group: patients with partial/complete response and stable/improved stage after 1 line therapy. Patient, liver function, and tumor characteristics both at first presentation and at re-staging were included in a Cox survival model. Results: At first presentation 96 patients were stage 0 (8%), 620 stage A (52%), 222 (19%) stage B, and 258 stage C (21%); 619 patients underwent curative therapies (resection or ablation, 52%), 495 transarterial therapies (41%), 51 Sorafenib (4%), and 31 other systemic therapies (3%). After a median follow-up period of 10 months (IQR 5– 20 months), 77 patients were stage 0 (7%), 559 stage A (47%), 231 (19%) stage B, 289 stage C (24%), and 40 stage D (3%); 242 patients underwent curative therapies (transplantation, resection or ablation, 20%), 446 trans-arterial therapies (37%), 253 Sorafenib (21%), 79 other systemic therapies (7%), and 176 best supportive care (15%). At re-staging, 726 patients (61%) were classified in the downstaging group (median survival, 56 months), and 470 (39%) in the stable/ progression group (median survival, 23 months, p < 0.001). Multivariate Cox analysis showed that only variables at re-staging were independent survival predictors: BCLC re-staging ( p < 0.001), MELD score ( p < 0.001), therapy after re-staging ( p < 0.001), downstaging group ( p = 0.0060), AFP ( p = 0.034). Subgroup analysis showed that discrimination ability of BCLC re-staging was maintained only in the downstaging group. Conclusions: HCC patients may change their tumor stage after firstline therapy. Stage migration has a strong prognostic impact on HCC patient survival and management strategy. SAT-058 HIGH-POWERED MICROWAVES ABLATION OF INTERMEDIATE HEPATOCELLULAR CARCINOMA IN CIRRHOSIS: A MULTICENTER, PROSPECTIVE STUDY A. Giorgio1, P. Gatti2, C. Coppola3, G. Iaquinto4, B. Santoro5, F. Amendola6, V. Giorgio7. 1Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno; 2Internal Medicine Unit, Fasano Hospital, Brindisi; 3Interventional US Unit, Department of Internal Medicine, Gragnano Hospital, Napoli; 4Interventional US Unit, Department of Gastroenterology, S.Rita Clinical Institute, Avellino; 5Interventional Ultrasound Unit, Istituto Clinico Athena, Caserta; 6Internal Medicine Unit, Tortorella Clinical Institute, Salerno; 7Pediatrics, Fondazione Policlinico Gemelli, Rome, Italy E-mail: [email protected]

Journal of Hepatology 2016 vol. 64 | S631–S832

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