Cascinu, S.

CHESSA, LUCHINO

Corbelli, J.

Daniele, B.

Faloppi, L.

Foschi, G. F.

Gardini, 5.6. A. C.

Marisi, G.

Masi, G.

Negri, F.

Santini, D.

Scarpi, E.

SCARTOZZI, MARIO

Silvestris, N.

Tamburini, E.

Zagone, V.

English

Archivio istituzionale della ricerca - Università di Cagliari

Background and Aims: Plasma levels of Von Willebrand factor(VWF) are increased in cirrhotics with endotoxemia, severe portalhypertension, liver dysfunction, and independently predict clinicaloutcome. Acute bacterial infections, a life threatening complicationof cirrhosis, further contributes to increase VWF, whose impact onthe hemostatic balance has never been addressed by ad hoc clinicalstudies. We wondered whether acute bacterial infections may leadto a pro-hemostatic imbalance in cirrhosis that worsens prognosis.Methods: We prospectively collected clinical and laboratory data of83 patients hospitalized for decompensated cirrhosis and screenedfor acute bacterial infection. Baseline examinations included themain pro-(FVIII) and anti-coagulants (antithrombin, AT, protein C,PC), VWF, d-dimer, and Factor II (FII). Endogenous Thrombin Potential(ETP) allowed testing for the in vitro thrombin generation in platelet-poor plasma and thromboelastography to assess for whole bloodhypercoagulability. Intra-hospital mortality and complications suchas organ dysfunction were collected.Results: There were 54 infected and 29 infection-free patients, themeanMELD scorewas 18.6 ± 6.8 vs 15.0 ± 5.9 (p = 0.018), and the VWF627 ± 329 vs 436 ± 152 (p = 0.003), respectively. Infection wasassociated with high levels of FVIII, d-dimer and low levels of AT,PC, FII. Bymultivariable analysis FVIII (p = 0.031) and VWF (p = 0.023)were associated with infection, independently of MELD. In infectedpatients VWF levels correlated with FVIII (R = 0.658, p < 0.001),significantly influencing in vitro hypercoagulability when measuredby thromboelastography (high maximum clot firmness, MCF, lowclotting formation time, CFT, p < 0.05), not by ETP. These resultssuggest a pro-hemostatic imbalance involving pro- and anti-coagulant factors and platelets. During hospitalization, 24 patientsexperienced a complication, 10 of them died, MELD score being astrong predictor of outcome. Interestingly, high levels of FVIIIsignificantly increased the risk of severe outcome as predicted byMELD (p = 0.005) in association with a pro-hemostatic imbalancemeasured by thromboelastography.Conclusions: Acute bacterial infections lead to increased plasmalevels of VWF and FVIII that drive a pro-hemosttaic imbalanceresulting in worsened prognosis in cirrhotic patients.THU-400CRITICAL ROLEOFHEPATOCYTEDEATH IN THEPATHOPHYSIOLOGYOF ACUTE ON CHRONIC LIVER FAILURE: ASSOCIATION BETWEENTHE EXTENT OF HEPATOCYTE DEATH AND TYPES OFPRECIPITATING EVENTZ. Cao1, Y. Wang1, L. Chen1, X. Xiang1, Y. Liu1, J. Lu1, L. Lin1, Q. Xie1,H. Wang1. 1Department of infectious diseases, Rui-Jin hospital affiliatedto Shanghai Jiao-Tong University School of medicine, Shanghai, ChinaE-mail: estherlucifer@163.comBackground and Aims: Acute on chronic liver failure (ACLF) usuallydevelops from a precipitating event on the basis of establishedcirrhosis. Current pathophysiological hypothesis for ACLF is thatprecipitating events may primarily cause acute liver injury,subsequently trigger inflammation response and eventually lead tomultiple organ failures. The aim of the study was to investigate therole of hepatocytes death in such process.Methods: 66 ACLF patients were identified from a prospective cohortof 117 patients with acute decompensated cirrhosis (ADC) admittedto Rui-Jin hospital from February 2013 to August 2014. 50 healthyvolunteers (HC) and 50 patients with compensated cirrhosis (CC)were enrolled as controls. Precipitating events were categorized intohepatic alone, extra-hepatic alone and mixed events (hepatic andextra-hepatic). Hepatocyte death was assessed by the serologicalmeasurements of cell death biomarkers, M30-antigen (hepatocytesapoptosis) and M65-antigen (hepatocytes total death).Results: Among those with ACLF, 18 were precipitated by hepaticevent alone (Hepatic-ACLF), 19 by extra-hepatic event alone(Extrahepatic-ACLF) and 23 by both hepatic and extra-hepaticevents (Mixed-ACLF). Another 6 had no obvious precipitating event.Median serum M30-antigen in ACLF was 10.5-fold (p < 0.001), 2.6-fold (p < 0.001), and 1.7-fold (p < 0.001) higher than in HC, CC andADC. SerumM65-antigen in HBV-ACLF was 31.5-fold (p < 0.001), 3.3-fold (p < 0.001), and 3.2-fold (p < 0.001) higher than in HC, CC andADC. Both M30- and M65-antigen significantly correlated with theseverity scores of cirrhosis, CTP (both p < 0.001) and MELD (both p <0.001). ROC analysis revealed that both serum M30-antigen (AUC0.71, p < 0.001) and M65-antigen (AUC 0.78, p < 0.001) could welldiscriminate ACLF from ADC. Mixed-ACLF demonstrates the highestlevel of serum hepatocytes death (M30: 19.6-fold of HC, M65:85.9-fold of HC) followed by that fromHepatic-ACLF (M30: 9.8-fold ofHC, M65: 32.2-fold of HC) and Extrahepatic-ACLF (M30: 5.6-fold ofHC, M65: 16.8-fold of HC). Serum M30- and M65-antigen fromExtrahepatic-ACLFwas relatively lowand even close to that from ADC(M30: 6.2-fold of HC, M65: 9.9-fold of HC).Conclusions: Markedly elevated hepatocyte death is crucial for thedevelopment of ACLF. Hepatic rather than extra-hepatic precipitatingevent is the primary reason for massive hepatocyte death. However,extra-hepatic injury may help exaggerating the extent of hepatocytedeath in ACLF.Clinical trials in progressTHU-480MULTICENTRIC PROSPECTIVE STUDY OF VALIDATION OFANGIOGENESIS POLYMORPHISMS IN HCC PATIENTS TREATEDWITH SORAFENIB. INNOVATE STUDYA.C. Gardini1, L. Faloppi2, B. Daniele3, G.F. Foschi4, S. Cascinu5,G. Marisi1, G. Masi6, L. Chessa7, F. Negri8, E. Scarpi1, D. Santini9,J. Corbelli10, N. Silvestris11, E. Tamburini12, V. Zagonel13, M. Scartozzi2.1IRST-IRCCS, Forli; 2University of Cagliari, Cagliari; 3Ospedale Rummo,Benevento; 4Interne Medicine, Faenza; 5University of Modena, Modena;6University of Pisa, Pisa; 7Dipartimento Scienze Mediche “Mario Aresu”,Cagliari; 8University of Parma, Parma; 9Policlinico Universitario CampusBio-Medico, Roma; 10Oncology Unit, Faenza; 11Oncologico Bari, Bari;12Oncologia Rimini, Rimini; 13IOV Veneto, Padova, ItalyE-mail: andrea.casadei@irst.emr.itBackground and Aims: Preclinical data suggested that significantHCC growth is dependent on angiogenesis, and an increase intumour dimension may induce vascular endothelial cellproliferation.SNPs in VEGF,VEGFR,HIF1α, angiopoietin2 and eNOS genes have alsobeen correlated to tumour neoangiogenesis through differentbiological mechanisms.In the ALICE-2 study patients (PT) receiving sorafenib were tested forHIF-1α,VEGF-A and VEGF-C SNPs.At multivariate analysis rs12434438 of HIF-1α,rs2010963 of VEGF-Aand rs4604006 of VEGF-C have been confirmed as independentfactors for PFS and OS. At the combined analysis of significant SNPsthe presence of 2 favourable alleles of VEGF compared to only 1 or tonone favourable alleles, identifies three populations with differentPFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p < 0.0001) and OS(respectively: 19.0 vs 13.5 vs 7.5 months; p < 0.0001). Furthermorethe presence of GG genotype of rs12434438 (HIF-1α)select apopulation with a particularly poor outcome independently fromthe clinical effect of the two VEGF SNPs(PFS: 2.6 months,p < 0.0001;OS:6.6 months,p < 0.0001).In ePHAS study PT homozygous for a specific haplotype (Ht1:T-4b ateNOS-786/eNOS VNTR) showed a lower median PFS(2.1vs6.2months, p < 0.0001)and OS(5.0vs14.9 months, p < 0.0001)comparedto other genotypes. The multivariate analysis confirmed specifichaplotype as the only independent prognostic factor.POSTER PRESENTATIONSS291Journal of Hepatology 2016 vol. 64 | S213–S424On the basis of these premises we want to validate in a prospectivestudy the potential role of VEGF,VEGFR,HIF-1, Ang2 and eNOS SNPs inPT with HCC treated with sorafenib.Methods: This is a prospective non pharmacological study. The studypopulation consisted of PT with advanced-stage HCC and PT noteligible for locoregional treatments or liver transplantation. Theprimary aim of the study is to validated the prognostic or predictiverole of eNOS,Ang2,HIF-1, VEGF and VEGFR SNPs in relation to clinicaloutcome of PT treated with sorafenib.THU-481PROGNOSIS OF ACUTE LIVER FAILURE PATIENTS DUE TODIFFERENT ETIOLOGY TREATED WITH ARTIFICIAL LIVERD. Andayani1, L. Li1. 1Zhejiang University, Hangzhou, ChinaE-mail: andayani.dewi@ymail.comBackground and Aims: Acute liver failure (ALF) is one conditionthat is characterized with encephalopathy and coagulopathy whichcan lead to multiorgan system failure. ALF has high mortality rateand requires immediate efficient and effective treatment. Nowadays,liver transplant has become the most effective treatment so far. Dueto the limited availability and donor resources, many researcheshave been studied to develop a new technique of treatment.Artificial liver has many functions, such as for detoxification,correction of coagulopathy, suppression of inflammation, andpromotion of liver cell regeneration. This could be an alternativeprocedure to prolong the survival time of ALF patients. The aim ofthis study is to determine the survival time of ALF patients treatedwith artificial liver.Methods: The datawill be collected from ALF patients with differentetiology in our hospital from 1st January 2006–31st December 2015for survival rate analysis. Patients with ALF who received artificialliver treatment will become the experimental group. ALF patientswhich do not receive artificial liver treatmentwill become the controlgroup. The survival rate from both the groups within twenty eightdays will be compared. Parameters of the laboratory results include:INR, ammonia, hepatic enzymes, serum bilirubin, serum creatinineare monitored in this study. This study uses Li’s artificial liver system(Li-ALS) which pair low-volume plasma exchange (low-volume PE)with plasma filtration adsorption (PFA).Conclusions: This study is expected to determine the effectiveness ofartificial liver in prolonging survival time and in decreasing themortality rate from ALF.THU-482ENDURANCE-3: A PHASE 3, RANDOMIZED, OPEN-LABEL,ACTIVE-CONTROLLED STUDY TO COMPARE EFFICACY AND SAFETYOF ABT-493/ABT-530 TO SOFOSBUVIR CO-ADMINISTERED WITHDACLATASVIR IN ADULTS WITH HCV GENOTYPE 3 INFECTIONG. Foster1, E. Gane2, A. Asatryan3, S. POL4, F. Poordad5, J. Vierling6,J. Kort3, C.-W. Lin3, S.S. Lovell3, T.I. Ng3, F. Mensa3. 1Queen MaryUniversity of London, Barts Health, London, United Kingdom; 2AucklandCity Hospital, Auckland, New Zealand; 3AbbVie Inc., North Chicago, IL,United States; 4Groupe Hospitalier Cochin-Saint Vincent De Paul, Paris,France; 5The Texas Liver Institute/University of Texas Health ScienceCenter, San Antonio, TX; 6Baylor College of Medicine; Baylor – St. Luke’sAdvanced Liver Therapies, Houston, TX, United StatesE-mail: evan.graf@abbvie.comBackground and Aims: Hepatitis C viral (HCV) infection is a globalhealth problem affecting over 170 million people worldwide. HCVgenotype 3 (GT3) infection is commonly found in Latin America (5% >30%), Europe (20% > 40%) and Asia (30% > 45%), and affects 12% of HCVpatients in the United States. Studies have shown that thecombination of sofosbuvir (SOF) and daclatasvir (DCV) achieved12-week sustained virologic response (SVR12) in 96% of HCV GT3-infected, treatment-naive patients without cirrhosis following a12-week treatment regimen. Currently, 2 next-generation direct-acting antiviral agents (DAA), ABT-493 (identified by AbbVie andEnanta), an HCV NS 3/4A protease inhibitor and ABT-530, an NS5Ainhibitor, are being developed for the treatment of all 6 major HCVgenotypes. In a phase 2b study (M14-868 Part 1), promising efficacyand safety results were obtained in GT3-infected patients receivingABT-493 and ABT-530 for 12weeks. In this phase 3 study, the efficacyand safety of ABT-493 and ABT-530 combinationwill be confirmed intreatment-naive non-cirrhotic HCV GT3-infected patients anddirectly compared to the standard-of-care SOF + DCV regimen.Results: This is a Phase 3, randomized, open-label, active-controlled,multicenter study. Patients will be randomized approximately 2:1across 2 arms. Arm A will enroll approximately 230 HCV GT3-infected, treatment-naïve patients without cirrhosis whowill receiveABT-493/ABT-530 300mg/120mgQD for 12weeks. Arm Bwill enrollapproximately 115 HCV GT3-infected, treatment-naïve patientswithout cirrhosis who will receive SOF 400 mg + DCV 60 mg QD for12 weeks. Patients who complete or prematurely discontinue thetreatment will be followed for 24 weeks after their last dose of studydrugs to evaluate efficacy and the emergence and persistence of viralvariants. The first primary objective of this study is to demonstratenon-inferiority of the ABT-493/ABT-530 regimen compared to SOF +DCV by analyzing the percentage of patients achieving SVR12following 12 weeks of treatment with ABT-493/ABT-530.Additionally, pharmacokinetics of the study drugs will be analyzedin the study.THU-483PHARMACOKINETICS OF THE ANTIFIBROTIC DRUG PIRFENIDONEIN CHILD PUGH A AND B CIRRHOTIC PATIENTS COMPARED TOHEALTHY AGE-MATCHED CONTROLSJ.L. Poo1, R. Bernal1, J.R. Aguilar1, R. Alonso1, R. Balderas1, E. Piñeyro2,M. Gómez2, J. Escobar3, C.Mora4, N. Hernandez5, R.Magaña3, P. Peña6.1Pharma Research Unit, AMIC, Pachuca; 2Pharma Research Unit,IPHARMA, Monterrey; 3Clinical Research Unit; 4Clinica Research Unit;5Drug Development Unit, Cellpharma; 6Clinical Research Unit,Cellpharma, Mexico City, MexicoE-mail: consultorio.jpoo@gmail.comBackground and Aims: Pirfenidone (PF) has demonstrated anti-inflammatory and anti-fibrogenic effects in experimental models ofcirrhosis and also in open trials with humans affected with hepaticfibrosis caused by different etiologies. Since the EMA and FDAauthorization for PF usage in the treatment of patients withIdiopathic Pulmonary Fibrosis, this novel antifibrotic agent iscurrently in phase II and III clinical development for the treatmentof other fibrotic diseases including liver, skin, renal, cardiac andmultiple sclerosis. Considering the wide variation in liver function inpatients with cirrhosis we aimed to evaluate PF pharmacokinetics.Methods:A total of 24 subjects (9men and 15 nonpregnantwomen),aged 58 ± 12 entered the trial; 8 subjects had cirrhosis Child Pugh A,and 8 Child Pugh B and 8 were age-matched healthy volunteers, withno fibrosis result (F0) by using a non invasive validated serologic test(Fibrotest™, Bio Predictive). All volunteers received orally two600 mg tablets of a slow release formulation of PF, in the morningand in fasted state. Subjects remained in a phase I clinical study unitthroughout treatment and for 36 hours after PF administration. Serialblood samples were collected prior to dosing (0 hour) and at 1, 2, 2.5,3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 30 and 36 hours after dosing. Analysis wasdone with mass spectrometry.Results:Cirrhosiswas alcohol related in 6, HCV in 6, Autoimmune in 2and NASH related in 2 patients. Main pharmacokinetic parametersper group revealed the following results:PKparametersNon Cirrotics(Healthy-F0)N = 8Child Pugh ACirrhotics(N = 8)Child Pugh BCirrhotics(N = 8)AUC 0-t (μg/mL*h) 57.8 ± 24.0 210.6 ± 43.2 205.4 ± 60.0AUC 0-α (μg/mL*h) 62.1 ± 23.3 231.6 ± 59.3 287.2 ± 165.5C max (μg/mL) 6.6 ± 2.6 12.4 ± 0.9 11.7 ± 3.3T max (h) 4.1 ± 0.8 5.0 ± 0.7 4.4 ± 0.3T ½ (h) 4.8 ± 0.7 8.6 ± 2.1 7.4 ± 3.6POSTER PRESENTATIONSS292 Journal of Hepatology 2016 vol. 64 | S213–S424

STUDY OF VALIDATION OF ANGIOGENESIS POLYMORPHISMS IN HCC PATIENTS TREATEDWITH SORAFENIB. INNOVATE STUDY

https://iris.unica.it/bitstream/11584/185180/1/J%20Hepatology%202016%2c%20Multicentric%20Prospective%20Study.pdf

STUDY OF VALIDATION OF ANGIOGENESIS POLYMORPHISMS IN HCC PATIENTS TREATEDWITH SORAFENIB. INNOVATE STUDY

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