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Digestive and Liver D

isease

49 S1

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Vol . 49 / S

1 ( 2017 ) e1 – e71

VOLUME 49 SUPPLEMENT 1 16 FEBRUARY 2017 ISSN 1590-8658

Abstracts of the 50th A.I.S.F. –Italian Association for the Study of the Liver –

Annual Meeting 2017Rome, 23–24 February 2017

An International Journal of Gastroenterology and Hepatology

Digestiveand Liver Disease

Italian Association for the Study of the Liver (AISF)Italian Association for the Study of the Pancreas (AISP) Italian Association for Digestive Endoscopy (SIED)Italian Society of Gastroenterology (SIGE)

Italian Society of Pediatric Gastroenterology and Hepatology (SIGENP)Italian Group for the Study of Infl ammatory Bowel Disease (IG-IBD)Fédération Francophone de Cancérologie Digestive (FFCD)

SECTION EDITORS

Basic ScienceGianfranco Alpini, Temple, USA

Romina Mancinelli, Rome, Italy

Theresa T. Pizarro, Cleveland, USA

Digestive EndoscopyAndres Cardenas, Barcelona, Spain

Arnulf Ferlitsch, Vienna, Austria

Cesare Hassan, Rome, Italy

Helmut Neumann, Mainz, Germany

Emanuele Rondonotti, Como, Italy

Digestive OncologyThomas Aparicio, Paris, France

Côme Lepage, Dijon, France

General GastroenterologyMaura Corsetti, Leuven, Belgium

Nicola de Bortoli, Pisa, Italy

Edoardo Savarino, Padua, Italy

Radu Tutuian, Bern, Switzerland

Umberto Volta, Bologna, Italy

ImagingAnnalisa Berzigotti, Bern, Switzerland

Cristina Bezzio, Garbagnate Milanese, Italy

Federica Furfaro, Rozzano, Italy

Giovanni Maconi, Milan, Italy

Infectious DiseaseAntonella D’Arminio Monforte, Milan, Italy

Infl ammatory Bowel DiseaseAlessandro Armuzzi, Rome, Italy

Emma Calabrese, Rome, Italy

Stephen Collins, Hamilton, Canada

Laurent Peyrin-Biroulet, Vandoeuvre, France

Liver DiseaseTarik Asselah, Clichy, France

Jaime Bosch, Barcelona, Spain

Maurizia Brunetto, Pisa, Italy

Patrizia Burra, Padua, Italy

Alessia Ciancio, Turin, Italy

Alessandra Dell’Era, Milan, Italy

Rafael Esteban Mur, Barcelona, Spain

Silvia Fargion, Milan, Italy

Vincenzo La Mura, San Donato Milanese, Italy

Ana Lleo, Milan, Italy

Salvatore Petta, Palermo, Italy

Fabio Piscaglia, Bologna, Italy

Pancreatic DiseaseGabriele Capurso, Rome, Italy

Alberto Malesci, Milan, Italy

Pediatric GastroenterologySalvatore Cucchiara, Rome, Italy

SurgeryMassimo Falconi, Milan, Italy

Roberto Santambrogio, Milan, Italy

Statistical ConsultantFederico Ambrogi, Milan, Italy

Editors EmeritiGabriele Bianchi-Porro, Milan, Italy

Mario Angelico, Rome, Italy

Editor in ChiefRoberto de Franchis, Milan, Italy

Co-EditorsSavino Bruno, Milan, Italy

Maurizio Vecchi, San Donato Milanese, Italy

Managing EditorSilvia Malosio, Milan, Italy

Editorial AssistantBrenda Dionisi, Milan, Italy

EDITORIAL BOARD

Domenico Alvaro, Rome, Italy

Angelo Andriulli, Foggia, Italy

Paolo Angeli, Padua, Italy

Adolfo Francesco Attili, Rome, Italy

Gabrio Bassotti, Perugia, Italy

Laurent Beaugerie, Paris, France

Robert Benamouzig, Bobigny, France

Antonio Benedetti, Ancona, Italy

Marc Benninga, Amsterdam, Netherlands

Marina Berenguer, Valencia, Spain

Roman Bogorad, Cambridge, USA

Jean-Pierre Bronowicki, Vandoeuvre-Lès-Nancy, France

William R. Brugge, Boston, USA

Elisabetta Buscarini, Crema, Italy

Nicola Caporaso, Naples, Italy

Carlo Catassi, Ancona, Italy

Umberto Cillo, Padua, Italy

Agostino Colli, Lecco, Italy

Dario Conte, Milan, Italy

Gino Roberto Corazza, Pavia, Italy

Enrico Corazziari, Rome, Italy

Antonio Craxì, Palermo, Italy

Gianfranco Delle Fave, Rome, Italy

A. Jack Demetris, Pittsburgh, USA

Sharon DeMorrow, Temple, USA

Philippe Ducrotte, Rouen, France

Amal Dutta, Dallas, USA

Stefano Fagiuoli, Bergamo, Italy

Massimo Fantini, Messina, Italy

P. Marco Fisichella, Boston, USA

Heather Francis, Temple, USA

Mirella Fraquelli, Milan, Italy

Dennis Freshwater, Birmingham, UK

Giovanni Battista Gaeta, Naples, Italy

Antonio Gasbarrini, Rome, Italy

Eugenio Gaudio, Rome, Italy

Stefano Ginanni Corradini, Rome, Italy

Shannon Glaser, Temple, USA

Pietro Invernizzi, Milan, Italy

Robert Jensen, Baltimore, USA

Michel Kahaleh, New York, USA

David Laharie, Pessac, France

René Laugier, Marseille, France

Astrid Liévre, Saint-Cloud, France

Patrick Maisonneuve, Milan, Italy

Riccardo Marmo, Salerno, Italy

Marco Marzioni, Ancona, Italy

Carlo Merkel, Padua, Italy

David Mutimer, Birmingham, UK

Mattijs Numans, Leiden, Netherlands

Jean Marc Phelip, Saint Etienne, France

Paola Piccolo, Rome, Italy

Antonio Pinna, Bologna, Italy

Massimo Puoti, Milan, Italy

Franco Radaelli, Como, Italy

Alessandro Repici, Milan, Italy

Oliviero Riggio, Rome, Italy

Mario Rizzetto, Turin, Italy

Renato Romagnoli, Turin, Italy

Massimo Rugge, Padua, Italy

Tilman Sauerbruch, Bonn, Germany

Jean-Cristophe Saurin, Pierre-Benite, France

Vincenzo Savarino, Genoa, Italy

Laurent Siproudhis, Rennes, France

Etienne Sokal, Brussels, Belgium

Mario Strazzabosco, New Haven, USA

Giacomo Carlo Sturniolo, Padua, Italy

Pier Alberto Testoni, Milan, Italy

Guiseppe Tisone, Rome, Italy

Michael Trauner, Vienna, Austria

Vincenzo Villanacci, Brescia, Italy

Alrefai Waddah, Chicago, USA

Frank Zerbib, Bordeaux, France

Huiping Zhou, Richmond, USA

Official Journal of:

Vol. 49 Supplement 1 (2017)

Contents Vol . 49 Supplement 1 ( 16 February 2017 )

Index Medicus (MEDLINE), Current Contents/Clinical Practice,Science Citation Index and EMBASE/Excerpta Medica

Sociedad Iberoamericana de Información Cient ıfi ca (SIIC)

Associato alla Unione Stampa Periodica Italiana

Abstracts of the 50th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2017 Rome, February 23rd-24th, 2017: Selected oral communications e1

Abstracts of the 50th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2017 Rome, February 23rd-24th, 2017: Selected Posters Thursday e19

Abstracts of the 50th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2017 Rome, February 23rd-24th, 2017: Selected Posters Friday e43

A.I.S.F. 2017: Abstracts Evaluation Procedure e71

Abstracts of the 50th A.I.S.F. – Italian Association for the Study of the Liver – Annual Meeting 2017

Rome, 23-24 February 2017

Digestive and Liver Disease 49S (2017) e1–e18

Contents lists available at ScienceDirect

Digestive and Liver Disease

journa l homepage: www.e lsev ier .com/ locate /d ld

Abstracts of the 50th A.I.S.F. – Italian Association for the Study of the

Liver – Annual Meeting 2017 Rome, February 23rd–24th, 2017:

Selected oral communications

OC-01

Increased hepatic glucose production andinsulin resistance are associated to increasedplasma concentrations of glucogenic aminoacids in subjects with NAFLD

M. Gaggini 1, C. Rosso 2, F. Carli 1, V. Della Latta 1,

D. Ciociaro 1, M. Marietti 2, E. Buzzigoli 1,

M.L. Abate 2, R. Gambino 2, M. Cassader 2,

A. Smedile 2, E. Bugianesi 2, A. Gastaldelli 1

1 Cardio-Metabolic Risk Laboratory, Institute of

Clinical Physiology, CNR, Pisa, Italy2 Division of Gastroenterology and Hepatology and

Lab. of Diabetology, Department of Medical Sciences,

University of Torino, Torino, Italy

Introduction: The liver plays a central role in the regulation

of glucose metabolism, being the major site of endogenous glu-

cose production (EGP) during fasting and of glucose storage (as

glycogen) during postprandial state. NAFLD subjects have increased

insulin resistance (mainly hepatic, Hep-IR) and are at higher risk of

hyperglycemia and type-2 diabetes (T2DM). However, the patho-

physiological mechanisms for increased EGP and Hep-IR are still

not known.

Aim: Since both amino-acids (AA) and lipids contributes

through gluconeogenesis to EGP, the goal was to evaluate if

concentrations of glucogenic AA (glutamate, alanine, branched

chain amino acids (BCAA), and aromatic amino acids (AAA)) were

increased and associated with EGP and Hep-IR in lean non-diabetic

NAFLD.

Materials and methods: We studied 44 non-diabetic subjects

with biopsy proven NAFLD (29 non-obese and 15 obese) and 20

non-obese controls (CT). We measured fasting EGP (by tracer infu-

sions), plasma AA and free fatty acid (FFA) concentrations by GCMS

and calculated Hep-IR (EGPxInsulin), HOMA and Adipo-IR (FFAxIn-

sulin).

Results: From CT to NAFLD non-obese to NAFLD obese

we observed the increase in EGP (584 ± 44 to 710 ± 23 to

839 ± 40 �mol/min, p < 0.0002) and Hep-IR (52 ± 6 to 96 ± 6

to 166 ± 23 �mol/kg/min × mU/l, p < 0.001). Both EGP and ln(Hep-

IR) increased proportionally to ln(ALT) (R = 0.47 and R = 0.55,

p < 0.0005), ln(AST) (R = 0.39 and R = 0.48, p < 0.003), and fibrosis

(R = 0.55 and R = 0.44, p < 0.001). EGP correlated positively with

ln(BCAA) (R = 0.35, p < 0.009), ln (AAA) (R = 0.48, p < 0.0002),

and ln(glutamate) (R = 0.29, p < 0.03); ln(Hep-IR) with ln (AAA)

(R = 0.33, p < 0.01), and ln(alanine) (R = 0.29, p < 0.03). Fibrosis

score was positively correlated to ln(AAA) (R = 0.34, p < 0.005),

ln(glutamate) (R = 0.38, p < 0.001), ln(BCAA) (R = 0.30, p < 0.01),

ln(alanine) (R = 0.29, p < 0.02).

Conclusions: In NAFLD, higher glucogenic AA concentrations

are positively associated to increased EGP, Hep-IR and fibrosis and

might explain, at least in part, the increased risk of hyperglycemia

and T2DM observed in NAFLD.

Funded by: FP7/2007-2013under grant agreement no. HEALTH-

F2-2009-241762, FLIP; PRIN2009ARYX4T; Horizon2020 under

grant agreement no. 634413, EPoS.

http://dx.doi.org/10.1016/j.dld.2017.01.005

OC-02

The hepatic expression of lysosomal acid lipase(LAL) is reduced in NAFLD patients, andassociated with features of geneticallydetermined LAL deficiency and NAFLD activityscore

U. Vespasiani-Gentilucci 1, F. Valentini 1,

S. Carotti 2, F. Vorini 1, M. Zingariello 2,

M. Francesconi 2, G. Galati 1, P. Gallo 1,

A. De Vincentis 1, C. Dell’Unto 1, S. Morini 2,

A. Picardi 1

1 Internal Medicine and Hepatology Unit, University

Campus Bio-Medico, Rome, Italy2 Laboratory of Microscopic and Ultrastructural

Anatomy, CIR, University Campus Bio-Medico, Rome,

Italy

Background: Lysosomal acid lipase (LAL) is responsible for

breakdown of neutral lipids in hepatocytes. Genetically deter-

mined LAL deficiency (Cholesteryl Ester Storage Disease – CESD-

and Wolman disease – WD) is characterized by lysosomal impair-

ment and consequent microvescicular steatosis. Recently, acquired

reductions of peripheral LAL activity were described in NAFLD

patients.

1590-8658/

e2 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18

Aims: To determine hepatic LAL expression in a population of

NAFLD patients, and to verify its association with blood LAL activity

and hepatic phenotype.

Material and methods: Liver biopsy samples from 105 sub-

jects, 82 NAFLD patients and 23 controls (peritumoral healthy

liver), were studied. In a subgroup of 44 patients, blood LAL activ-

ity was determined also in dried-blood-spot (DBS). NAFLD grading

and staging were assessed according NAFLD activity score (NAS)

and Brunt’s criteria, respectively. Expression of LAL and LAMP1

(lysosomal marker) were analyzed by immunohistochemistry. LAL

expression was classified according to a specific score (LALs), while

LAMP1 positivity was used to recognize and count lipolysosomes

and lipid-loaded Kupffer cells (KCs).

Results: Hepatic LAL expression was reduced in NAFLD patients

with respect to controls [LALs 3 (1.8–3.1) Vs 3 (3.0–3.0), p < 0.001).

In the NAFLD group, hepatic LAL expression: – was reduced in

patients with blood LAL activity <0.8 nmol/spot/h compared to

those with activity ≥0.8 nmol/spot/h [2.4 (2.2–2.6) Vs 2.7 (2.5–2.8),

p = 0.03]; – was reduced in patients with ≥25% with respect to

those with <25% of microvescicular steatosis [2.4 (2.3–2.5) Vs 2.7

(2.6–2.8), p < 0.01];); – was inversely correlated with lipolyso-

somes and lipid-loaded KCs (r = −0.35; p = 0.01; r = −0.41; p < 0.01,

respectively); – was inversely correlated with NAS (r = −0.52;

p < 0.001 – was not significantly associated with fibrosis (r = −0.15,

p = 0.2).

Conclusion: The present results are the first to suggest that

hepatic LAL expression reduced in NAFLD patients and associ-

ated with blood LAL activity, some features of CESD and WD

(microvescicular steatosis, lipolysosomes, lipid-loaded KCs), and

NAFLD activity (NAS).


OC-03

Serial combination of noninvasive toolsimproves the diagnostic accuracy of severe liverfibrosis in patients with nonalcoholic fatty liverdisease

S. Petta 1, V.W.-S. Wong 2,3, C. Cammà 1,

J.-B. Hiriart 4, G.L.-H. Wong 2,3, J. Vergniol 4,

A.W.-H. Chan 5, V. Di Marco 1, W. Merrouche 4,

H.L.-Y. Chan 2,3, F. Marra 6, B. Le-Bail 7,8,

U. Arena 6, A. Craxì 1, V. de Ledinghen 4,7

1 Sezione di Gastroenterologia, Di.Bi.M.I.S.,

University of Palermo, Italy2 Department of Medicine and Therapeutics, The

Chinese University of Hong Kong, Hong Kong3 State Key Laboratory of Digestive Disease, The

Chinese University of Hong Kong, Hong Kong4 Centre d’Investigation de la Fibrose hépatique,

Hôpital Haut-Lévêque, Bordeaux University Hospital,

Pessac, France5 Department of Anatomical and Cellular Pathology,

The Chinese University of Hong Kong, Hong Kong6 Dipartimento di Medicina Sperimentale e Clinica,

Università degli Studi di Firenze, Italy7 INSERM U1053, Bordeaux University, Bordeaux,

France8 Service de Pathologie, Hôpital Pellegrin, Bordeaux

University Hospital, Bordeaux, France

Background/aims: The accuracy of available noninvasive tools

for staging severe fibrosis in patients with nonalcoholic fatty

liver disease(NAFLD) is still limited. We assessed the diagnostic

performance of paired or serial combination of noninvasive tools

in NAFLD patients.

Methods: We analyzed data from 741 patients (287 training

cohort, and 474 validation cohort) with a histological diagnosis

of NAFLD. Severe fibrosis was defined as fibrosis ≥F3 according to

Kleiner classification. The GGT/PLT, APRI, AST/ALT, BARD, FIB-4, and

NFS scores were calculated according to published algorithms. Liver

stiffness measurement (LSM) was performed by FibroScan.

Results: In the entire cohort LSM, NFS and FIB-4 were the best

noninvasive tools for staging F3–F4 fibrosis (AUC 0.863, 0.774, and

0.792, respectively), with LSM having the highest sensitivity (90%),

and the highest NPV (94%), and NFS and FIB-4 the highest speci-

ficity (97% and 93%, respectively), and the highest PPV (73% and 79%,

respectively). The paired combination of LSM with FIB-4 strongly

reduced the likelihood of wrongly classified patients (2.7%), at the

price of a high uncertainty area (54.1%), and of a low overall accu-

racy (43%). Otherwise, the serial combination with the second test

used in patients in the grey area of the first test and in those with

high LSM values (>9.6 KPa) or low NFS or FIB-4 values (<−1.455 and

<1.30, respectively) overall increased the diagnostic performance

generating an accuracy ranging from 69.8% to 70.1%, an uncertainty

area ranging from 18.9% to 20.4% and a rate of wrong classification

ranging from 9.2% to 11.3%.

Conclusions: The serial combination of LSM with FIB-4 has a

good diagnostic accuracy for the noninvasive diagnosis of severe

fibrosis in NAFLD.


OC-04

The combination of mucus-degradinggram-negative bacteria and reducedantimicrobial peptides drives adipose tissueinflammation and NAFLD progression in micelacking NLRP3-inflammasome

I. Pierantonelli 1, C. Rychlicki 1, D. Giordano 1,

A. Giordano 2, S. Uzzau 3,4, A. Gastaldelli 5,

L. Sartini 2, L. Trozzi 1, A. Benedetti 1,

M. Marzioni 1, S. Cinti 2,6, G. Svegliati-Baroni 1,6

1 Department of Gastroenterology, Università

Politecnica delle Marche, Ancona, Italy2 Department of Experimental and Clinical Medicine,

Università Politecnica delle Marche, Ancona, Italy3 Porto Conte Ricerche, Parco Scientifico e

Tecnologico della Sardegna, Alghero, Italy4 Department of Biomedical Sciences, Università di

Sassari, Sassari, Italy5 Cardiometabolic Risk Lab, Institute of Clinical

Physiology, National Council of Research (CNR), Pisa,

Italy6 Obesity Center, Università Politecnica delle Marche,

Ancona, Italy

Introduction and aims: Lack of NLRP3-inflammasome, a sen-

sor of altered homeostasis, is associated with Non-Alcoholic Fatty

Liver Disease (NAFLD) progression. Aim of the present study was

to evaluate the mechanisms of this effect that are still unknown.

Methods: Nlrp3−/− and wild-type (WT) mice were fed a high-fat

diet with fructose in drinking water (HFHC) or a chow diet, for 12

weeks.

Results: Nlrp3−/−-HFHC showed higher body weight, fat mass,

hepatic PPAR�2 expression (that regulates lipid uptake and stor-

age) and triglyceride content in the liver compared to WT-HFHC,

associated with increased hepatic oxidative stress, TNFa and MCP1

Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e3

expression and NAS score. Nlrp3−/−-HFHC showed greater adi-

pose tissue inflammation evaluated by immunohistochemistry

for MAC-2 positive crown-like-structures and TNFa and MCP1

expression. Steatosis was unrelated to different intestinal lipid

absorption, since HFHC diet reduced fecal triglyceride content

independently from the genotype. A pathogenetic microbiota was

observed in Nlrp3−/−-HFHC characterized by increased levels of

mucus-degrading bacteria Akkermansia and LPS-producing Pro-

teobacteria, such as Desulfovibrio. Bacterial translocation was

higher in Nlrp3−/−-HFHC but occurred without significant dif-

ferences in Zonulin-1 and E-cadherin protein expression. The

evaluation of immune response against intestinal microorganisms

(anti-microbial pathway, AMPs) showed a genotype-independent

reduction of RELM�, which regulates mucus synthesis, whereas

the expression of the antibacterial peptide Ang-4 was signifi-

cantly lower in Nlrp3−/−-HFHC, thus favoring bacterial penetration

susceptibility. Bacterial translocation induced higher hepatic

expression of TLR4 (as LPS receptor) and TLR9 (as receptor for

double-strand bacterial DNA). Most of the effects observed in

Nlrp3−/−-HFHC were restored by antibiotic treatment that reduced

gut bacterial load and gram-negative species.

Conclusions: The combination of mucus-degrading gram-

negative bacteria and impaired AMPs efficiency drives adipose

tissue inflammation and NAFLD progression mediated by increased

bacterial translocation. This study identifies in the AMPs-

microbiota cross-talk a specific target for NAFLD therapy.


OC-05

Steatohepatitis and type 2 diabetes mellitus areinfluenced by genetic susceptibility to increasedintestinal permeability in patients withnon-alcoholic fatty liver disease

V. Giorgio 1, L. Miele 1, S. Petta 2, A. Liguori 1,

R. Pastorino 3, G. Marrone 1, M. Biolato 1,

C. Araneo 1, F.G. Vaccaro 1, C. Cefalo 1, D. Arzani 3,

G.L. Rapaccini 1, A. Gasbarrini 1, S. Boccia 3,

A. Craxì 2, A. Grieco 1

1 Internal Medicine and Gastroenterology Area,

Fondazione Policlinico Universitario A. Gemelli,

Catholic University of Rome, Rome, Italy2 Sezione di Gastroenterologia, Dipartimento

Biomedico di Medicina Interna e Specialistica,

University of Palermo, Palermo, Italy3 Institute of Public Health Section of Hygiene,

Catholic University of Rome, Rome, Italy

Introduction and aim: Individual susceptibility to increased

intestinal permeability (IP) has now been considered as a key fac-

tor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD)

and type 2 diabetes mellitus (T2DM).

The aim of our study was to assess whether a single nucleotide

polymorphisms (SNP) (rs2542151 G→T) of Protein Tyrosine Phos-

phatase Non-Receptor Type 2 (PTPN2), known to be involved in

regulation of IP, is associated with type 2 diabetes mellitus and

non-alcoholic steatohepatitis (NASH).

Material and methods: We recruited a prospective consecu-

tive cohort of NAFLD cases and healthy controls among Caucasian

patients from two Italian tertiary care centers. Zonulin serum lev-

els were used to assess IP in the study population. Unconditional

multiple logistic regression models were used to investigate the

association between selected SNP (PTPN2 rs2542151 G→T), comor-

bidities and histological severity of liver disease.

Results: We enrolled 416 cases (males 69.2%, mean age

45.1 ± 13.8 ys) and 377 controls (males 67.1%, mean age

41.3 ± 3.1 ys). Serum zonulin levels were significantly higher in

NAFLD subjects (7.0 ± 3.5 vs 0.9 ± 0.6 pg/ml, p < 0.05). Liver biopsy

was available for 307 patients (65.8%); 151/307 (49.2%) had NASH.

In patients’ population the analysis showed that PTPN2 rs2542151

G→T is associated with the presence of T2DM (OR 1.63 95% CI

1.03–2.59 p < 0.05). At a subgroup analysis of patients who under-

went liver biopsy, rs2542151 G→T of PTPN2 was associated with

the presence of NASH (OR 2.85 95% CI 1.15–7.07 p < 0.05).

Conclusions: Our study shows that rs2542151 G→Tof PTPN2

is associated with the presence of NASH and higher prevalence of

T2DM in patients affected by NAFLD. These results further suggest

that individual genetic susceptibility to an impaired IP is linked

to a higher severity of fatty liver disease and the presence of type

2-diabetes mellitus in NAFLD patients.


OC-06

Down-regulation of hepatic MBOAT7 byhyperinsulinemia favors steatosis development

M. Meroni 1, P. Dongiovanni 2, R. Rametta 2,

G.A. Bassani 3, S. Badiali 4, S. Romeo 5, S. Gatti 3,

L. Valenti 1,2

1 Department of Pathophysiology and

Transplantation, Università degli Studi di Milano,

Milano, Italy2 Internal Medicine, Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico, Milano, Italy3 Center for Surgical Research, Fondazione IRCCS Ca’

Granda Ospedale Policlinico Milano, Milan, Italy4 Surgery, Fondazione IRCCS Ca’ Granda Ospedale

Policlinico Milano, Milan, Italy5 Department of Molecular and Clinical Medicine,

University of Gothenburg, Sweden

Introduction: We have recently shown that the rs641738 C>T

variant in Membrane bound O-acyltransferase domain-containing

7 gene (MBOAT7), involved in phosphatidylinositol acyl-chain

remodeling, increases the risk of developing nonalcoholic fatty liver

disease (NAFLD), inflammation and fibrosis due to lower protein

expression.

Aim: To evaluate the regulation of hepatic MBOAT7 and the

impact on hepatic fat accumulation.

Methods: We examined hepatic MBOAT7 in 119 obese patients,

and in experimental models. We silenced hepatic MBOAT7 by i.v.

administration of Morpholino antisense oligonucleotides (MPO) for

4 consecutive days in C57Bl/6 male mice (n = 5 per group).

Results: In obese patients, hepatic MBOAT7 mRNA levels

progressively decreased from normal liver to simple steatosis and

NASH (p < 0.05). At multivariate analysis, type 2 diabetes (p < 0.05),

necroinflammation (p < 0.01) and MBOAT7 genotype (p < 0.01)

were independently associated with MBOAT7 downregulation.

MBOAT7 expression was reduced in experimental models of

NAFLD, such as the methionine-choline deficient diet, but more so

in genetically obese ob/ob mice, and in insulin resistant mice with

Insulin receptor haplo-insufficiency, characterized by development

of hyperinsulinemia (p < 0.05). Furthermore, in wild-type male

mice MBOAT7 was downregulated by refeeding concomitantly

with the rise of insulin levels and activation of hepatic insulin

signaling through PI3 K and AKT. In keeping, insulin (330 nM)

downregulated MBOAT7 in primary mouse hepatocytes in a

PI3Kinase-depedent manner. Finally, MPO induced a 45% silencing


of hepatic MBOAT7 comparable to that associated with the

genetic risk variant, resulting in a 80% increase in hepatic triglyc-

eride content (p < 0.05 vs scramble) and in microvesicular steatosis

development, without altering circulating glucose, insulin and lipid

levels.

Conclusion: These data suggest that hyperinsulinemia causes

downregulation of hepatic MBOAT7, which both genetic and

experimental data indicate is causally implicated in steatosis

development. Further studies are necessary to investigate the

mechanisms linking reduced phosphatidyl-inositol desaturation by

MBOAT7 with the development of steatosis and hepatic inflamma-

tion.


OC-07

External validation of the ITA.LI.CA prognosticsystem for patients with hepatocellularcarcinoma: A multicenter cohort study

E. Dionigi 1, M. Borzio 1, A. Rossini 2,

M. Marignani 3, R. Sacco 4, I. De sio 5, E. Bertolini 6,

G. Francica 7, A. Giacomin 8, G. Parisi 9, S. Vicari 10,

A. Toldi 11, A. Salmi 12, S. Boccia 13,

A. Maringhini 14, F. Fornari 15

1 UOC Gastroenterologia ed Endoscopia Digestiva,

ASST Melegnano e della Martesana, Italy2 Dipartimento di Medicina, SSVD di Epatologia,

ASST Spedali Civili di Brescia, Italy3 UOS Malattie delle vie Biliari e del Fegato, UOC

Malattie dell’Apparato Digerente e del Fegato, AO

S.Andrea, Università “Sapienza” Roma, Italy4 UO Gastroenterologia e Malattie del Ricambio,

Azienda Ospedaliero Universitaria Pisana, Ospedale

Cisanello, Pisa, Italy5 Unità di Gastroenterologia. Ospedale Policlinico,

Napoli, Italy6 U.O. Medicina VI Epatologia e Gastroenterologia,

Ospedale San Paolo, Università degli Studi di Milano,

Italy7 Presidio Ospedaliero Pineta Grande – Unità di

Ecointerventistica – Castelvolturno, Italy8 Dipartimento di Scienze Chirurgiche e

Gastroenterologiche Ospedale Policlinico Padova,

Italy9 Dipartimento di Medicina, Ospedale Santa Maria

del Prato, Feltre, Italy10 UOS Gastroenterologia Ospedale di Bentivoglio,

Bologna, Italy11 UO Gastroenterologia Ospedale Valduce, Como,

Italy12 Dipartimento Medicina, Università di Verona, Italy13 UOC Gastroenterologia, Ospedale S.Anna, Ferrara,

Italy14 UO Medicina Interna I, Ospedale “Civico e

Benfratelli”, Palermo, Italy15 Unità di Gastroenterologia ed Epatologia,

Ospedale G. da Saliceto, Piacenza, Italy

Several staging systems for HCC patients have been developed.

BCLC classification is still considered the best in predicting survival,

but few limitations have emerged. Recently the Italian Liver Cancer

(ITA.LI.CA) new prognostic score, showing strong ability to predict

individual survival was proposed. Aim of our study is to provide an

external validation of the ITA.LI.CA system in an independent and

large Western cohort.

Methods: From September 2008 to April 2016, 1508 cirrhotics

with incident HCC were consecutively enrolled in 27 Italian insti-

tutions (EpaHCC cohort). Clinical, tumor and treatment-related

variables were collected, patients stratified according to BCLC,

ITA.LI.CA staging and prognostic score, HKLC, CLIP, JIS, and MESIAH

scores. Harrel’s C-index, Akaike Information Criterion and likeli-

hood ratio test were used to compare predictive ability of different

systems. A subgroup analysis for treatment category (curative vs

palliative) was performed.

Results: Median follow-up was 44 months (IQ 23–63) and

median overall survival was 34 (IQ 13–82). Patients enrolled had

a median age of 71 years, and were mainly males and hepatitis C

carriers. According to ITA.LI.CA stage 246 patients were in stage

0, 472 in stage A; 657 in the stages B1-3; 133 in stage-C. The

ITA.LI.CA prognostic system showed the best discriminatory ability

(C-index = 0.77) and monotonicity of gradients, compared to other

prognostic systems. The superiority of the score was also confirmed

after stratification of the population for treatment strategy.

Conclusions: This is the first study that externally validated

the ITA.LI.CA prognostic system for HCC in a large cohort of West-

ern patients with incident HCCs. ITA.LI.CA score system performed

better than other available systems, including BCLC, even after

stratification by curative or palliative treatment. This new system

including both a tumor staging and an integrated prognostic score

appears to be particularly useful in clinical practice to predict indi-

vidual HCC prognosis.


OC-08

The concept of therapeutic hierarchy forpatients with hepatocellular carcinoma: Amulticentre cohort study

A. Vitale 1, F. Farinati 1, T.L. Huo 2, F. Trevisani 3,

E.G. Giannini 4, F. Piscaglia 5, U. Cillo 1

1 Department of Surgery, Oncology and

Gastroenterology, University of Padua, Italy2 Department of Medicine, Taipei Veterans General

Hospital, Taipei, Taiwan3 Division of Semeiotics, Alma Mater Studiorum –

University of Bologna, Bologna, Italy4 Gastroenterology Unit, Department, University of

Genoa, Genoa, Italy5 Division of Internal Medicine, Alma Mater

Studiorum – University of Bologna, Italy

Background/aim: The ITA.LI.CA prognostic system for patients

with hepatocellular carcinoma (HCC) has been recently developed

and validated. Strict HCC treatment algorithms (i.e. BCLC or HKLC)

are poorly followed in clinical practice. We sought to develop

and validate ITA.LI.CA indications for treatment guidance in HCC

patients.

Methods: Prospective collected databases from 2002 to 2015 in

Italy (n = 4,627), and Taiwan (validation cohort, n = 2651) were used

for the analysis. Multivariable regression models including vari-

ables from the ITA.LI.CA prognostic system were used to calculate

the propensity score (PS, calculated by logistic regression), and the

predicted median survival (MS, calculated by parametric survival

model with stabilized inverse probability weight) for each therapy

(liver transplantation = LT, liver resection = LR, ablation = ABL, intra-

arterial therapy = IAT, Sorafenib = SOR, best supportive care = BSC).


Results: Multivariable logistic regressions showed that the PS

of loco-regional therapies (LR, ABL, IAT) was negligible (PS ≤ 1◦

quintile) in patients with impaired ITA.LI.CA functional score

(Child C, or PST > 2, or Child 8–9 + PST 1–2: only LT or BSC

available) or advanced tumor stage (extra-hepatic HCC dis-

ease, stage C: only SOR or BSC available). In all other ITA.LI.CA

tumor stages (0, A, B1, B2, and B3) with preserved liver func-

tion (functional score ≤ 2) survival benefit estimations showed

a fixed therapeutic hierarchy (i.e. LT [MS ≥ 120 months] > LR

[MS 24–102 months] > ABL [MS 40–77 months] > IAT [MS

18–64 months] > SOR [MS 15–25 months] > BSC [MS 5–7 months]).

All multivariable parametric models proved to give accurate

survival estimations (C-index > 0.7).

The concept of therapeutic hierarchy within ITA.LI.CA stages was

validated also in the Taiwanese cohort.

Conclusions: Based on weighted survival benefit estimations

the concept of therapeutic hierarchy was established within each

ITA.LI.CA stage in a large Italian population and validated in a large

Taiwanese cohort.


OC-09

Oncostatin M induces increased invasivenessand angiogenesis in hepatic cancer cellsthrough HIF1�-related release of VEGF-A

B. Foglia 1, S. Cannito 1, E. Morello 1, C. Turato 2,

G. Di Maira 3, E. Novo 1, S. Colombatto 4,

P. Pontisso 2, F. Marra 3, M. Parola 1

1 Department Clinical and Biological Sciences,

University of Torino, Turin, Italy2 Dept of Medicine, University of Padova, Padua, Italy3 Department Experimental and Clinical Medicine,

University of Firenze, Florence, Italy4 Dept of Oncology, University of Torino, Turin, Italy

Introduction: Oncostatin M (OSM) is overexpressed in cirrhotic

liver and can modulate hypoxia-dependent liver processes (devel-

opment, regeneration and angiogenesis) contributing to chronic

liver disease progression and hepatocellular carcinoma (HCC)

development. Recent data suggest that both hypoxia and OSM may

induce epithelial-to-mesenchymal transition (EMT) in cancer cells

by operating through hypoxia-inducible factors (HIFs).

Aim: In this study we investigated in vivo and in vitro the

relationships between OSM, vascular endothelial growth factor A

(VEGF-A) expression, and increased invasiveness.

Methods: EMT, invasiveness, angiogenesis and signal transduc-

tion pathways were investigated by integrating morphological,

molecular and cell biology techniques in: (a) HCC human spec-

imens, (b) HepG2 cells exposed to human recombinant OSM

(hrOSM) or stably transfected in order to overexpress OSM; (c)

murine xenografts.

Results: OSM was expressed in HCC specimens in areas positive

for HIFs and VEGF-A, with OSM expression correlating with early

recurrence in HCC patients. HepG2 cells exposed to hrOSM or OSM

overexpressing HepG2 cells show EMT-related changes, increased

invasiveness and metallo-proteinase-2 activity. OSM-dependent

invasiveness is due to the release of VEGF and involves activation

of PI-3 K, ERK1/2, and p38MAPK since: (1) OSM leads to an increase

of HIF1� and VEGF-A mRNA levels as well as release of VEGF-A in

culture medium; (2) the use of specific pharmacological inhibitors

against PI-3K, ERK1/2, p38MAPK signaling pathways, neutralizing

antibodies for Flk-1(VEGF receptor type 2) or specific inhibitors of

Flk-1 results in decrease of invasiveness induced by conditioned

medium collected by HepG2 cells treated with hrOSM for 48 h; (3)

OSM affects cell proliferation by blocking HepG2 cells in G0/G1

phase; (4) OSM promotes angiogenesis in vivo (xenograft model)

and in vitro (sprouting spheroid assay).

Conclusions: OSM, expressed in human HCC, can induce EMT

and increased invasiveness in human hepatic cancer cells through

a mechanism involving HIF1�-dependent release of VEGF-A.


OC-10

Impact of natural killer (NK) cells receptorsgene haplotypes on the development ofhepatocarcinoma in cirrhotic patients

S. Onali 1, R. Littera 4, M. Casale 1, F. Capraro 1,

C. Balestrieri 2, F. Figorilli 1, G. Serra 2,

E. Congeddu 3, P. Ragatzu 3, R. Maddi 3, M. Serra 3,

V. Loi 3, M. Trucas 4, C. Carcassi 3, L. Chessa 1,2

1 Dipartment of Medical Sciences and Public Health,

University of Cagliari, Cagliari, Italy2 Liver Unit, Department of Internal Medicine,

Azienda Ospedaliera-Universitaria di Cagliari,

Cagliari, Italy3 Medical Genetics, Department of Medical Sciences

“M. Aresu”, University of Cagliari, Cagliari, Italy4 Bone Marrow Transplantation Centre, Binaghi

Hospital, Cagliari, Italy

Introduction: Killer immunoglobulin-like receptors (KIRs) are

key regulators of NK-mediated immune responses and their

expression is regulated by different aplotypes.

Aim: to analyse the genetic pattern of KIRs and their human

leukocyte antigen (HLA) ligands in cirrhotic patients with and with-

out HCC in order to identify a correlation between the expression

of inhibitory/activating KIRs and presence of HCC.

Methods: Cirrhotic patients with and without HCC were

included. Their immunogenetic characteristics were compared to

healthy individuals extracted from the Sardinian bone marrow

donor registry. High resolution (4 digits) typing of HLA A, B, C and 14

KIRs gene loci was performed. Subjects were divided into 2 groups:

homozygosity for KIR haplotype A, heterozygosity or homozygos-

ity for KIR haplotype B (Bx). They were also stratified according to

the numbers of activating/inhibitory KIRs, the type of KIRs related

HLA-ligands and the combinations with their receptors.

Results: 113 patients were included:68% had HCC. Compared

to controls, cirrhotic patients showed higher frequency of HLA-

C*05 allele (27%vs17.5% p = 0.001), while HLA-A*02 allele was more

common among HCC patients compared to non-HCC (30%vs18%

p = 0.05). No difference was observed in the frequency of activat-

ing/inhibitory KIR genes and KIR aplotypes between patients and

controls. Conversely, non-HCC patients showed a higher frequency

of the inhibitory KIR gene 3DL1 compared to HCC patients (100%

vs 87% p = 0.03). The frequency of KIR2DS4, the only activating KIR

gene of aplotype A, was comparable between HCC and non-HCC.

However, homozygosis for the deletion variant of KIR2DS4 was

more common in HCC group (17% vs 3% p = 0.03) indicating that

a higher proportion of HCC patients with KIRs haplotype A did

not express any activating KIR genes compared to only 1 non-HCC

patient.

Conclusions: Loss of activating KIR2DS4 is more frequent

among HCC patients, suggesting a decreased cytotoxic function of

NK-cells and therefore a negative impact on immunosurveillance

and tumour control.



OC-11

Efficacy of oral direct acting antivirals fortreatment of advanced chronic hepatitis orcompensated cirrhosis due to hepatitis C virusinfection: The real-life experience of the Sicilyregistry

I. Cacciola, S. Petta, M. Distefano, M.R. Cannavò,

A. Davì, S. Madonia, V. Calvaruso, L. Larocca,

F. Di Lorenzo, A. Digiacomo, G. Bertino, A. Licata,

F. Latteri, F. Benanti, R. Volpes, L. Guarneri,

A. Averna, I. Scalisi, C. Iacobello, P. Colletti,

F. Cartabellotta, V. Portelli, M. Russello, G. Scifo,

G. Squadrito, G. Raimondo, A. Craxì, V. Di Marco,

on behalf of RESIST-HCV (Rete Sicilia Selezione

Terapia – HCV)

RESIST-HCV (Rete Sicilia Selezione Terapia – HCV),

Italy

Background and aims: The RESIST-HCV (Rete Sicilia Selezione

Terapia – HCV) is a network that registered patients with Hepatitis C

Virus (HCV) infection evaluated for Direct Acting Antivirals (DAAs).

We reported real-life effectiveness of DAAs in genotypes (G) 1b, 2

and 3 patients with F3 fibrosis (F3) or Child-A cirrhosis

Methods: We analyzed 2,106 patients who reached post-

treatment week 12 at October 2016. A rate of SVR12 by

intention-to-treat analysis higher than 90% was defined as

optimal. Evaluated regimens were Sofosbuvir plus Simepre-

vir (SOF + SIM) ± Ribavirin (RBV); Sofosbuvir plus Daclatasvir

(SOF + DCL) ± RBV; Sofosbuvir plus Ledipasvir (SOF + LDV) ± RBV;

Ombitasvir/Paritaprevir/Ritonavir (OBV/PTV/r) ± Dasabuvir

(DSV) ± RBV.

Results: SOF + LDV was optimal in G1b Child-A cirrhosis treated

for 24 weeks (208/230, 92%) or for 12 weeks plus RBV (100/107,

93.4%), while was suboptimal in G1b F3 (41/46, 89.1%) and Child-A

cirrhosis (33/42, 78.5%) treated for 12 weeks without RBV.

OBV/PTV/r/DSV for 12 weeks was optimal in G1b F3 (105/109,

96.4%), as well as in G1b Child-A cirrhosis treated with (196/211,

92.8%) or without (82/85, 96.4%) RBV.

SOF + DCL was optimal in G1b F3 treated for 12 weeks (10/10,

100%) and in G1b Child-A cirrhosis treated for 12/24 weeks with

RBV (49/51, 96.1%), while was sub-optimal in G1b Child-A cirrhosis

treated for 24 weeks without RBV (43/52, 82.7%).

SOF + DCL was also optimal in G2 Child-A cirrhosis treated for

12 weeks (20/22, 90.2%) and in G3 Child-A cirrhosis treated for 24

weeks with RBV (39/43, 90.6%), while was sub-optimal in G3 Child-

A cirrhosis treated for 24 weeks without RBV (27/32, 84.3%). Finally,

SOF + SIM was optimal in G1b Child-A cirrhosis treated for 12 weeks

with RBV (230/246, 93.5%), while was sub-optimal in G1b F3 (12/16,

75%) and G1b Child-A cirrhosis (34/46, 73.9%) treated for 12 weeks

without RBV.

Conclusions: Real-life data confirmed the efficacy of DAAs in

HCV advanced fibrosis or cirrhosis using carefully therapy time and

the addiction of RBV.


OC–12

Role of SerpinB3 in the stimulation ofmacrophage activation marker sCD163 in HCVinfected patients

A. Martini, A. Cappon, A. Biasiolo, C. Turato,

P. Pontisso

Clinica Medica 5, Department of Medicine,

University of Padua, Padua, Italy

Introduction: In chronic HCV infection, disease progression is

maintained by sustained necroinflammation and fibrosis in the

liver. Upon macrophage activation, the soluble marker CD163

(sCD163) is released in serum and its levels correlate with fibro-

sis and NASH in the liver. The serin protease inhibitor SerpinB3

(or SCCA1), has been shown to be involved in liver fibrogenesis and

the circulating SCCA-IgM complex has been depicted as a marker of

liver disease progression and of NASH in patients with chronic hep-

atitis C. Preliminary data suggest that SerpinB3 activates primary

monocytes through the Wnt canonical pathway.

Aim: The purpose of this study was to evaluate the relationship

between SCCA-IgM and sCD163 in serum and the possible effect of

SerpinB3 on sCD163 production in primary monocytes.

Materials and methods: In 91 patients with biopsy proven

chronic hepatitis C, serum samples were tested for sCD163 (ng/ml)

and SCCA-IgM (AU/ml) by ELISA. The results were analyzed in

relation with clinical and histological parameters. Primary mono-

cytes were isolated from healthy donors, treated with recombinant

SerpinB3 (200 ng/ml) and supernatants analyzed after 7 days.

Expression of sCD163 secreted in the supernatant was evaluated

by ELISA.

Results: In patients with chronic hepatitis C sCD163 was

found correlated with inflammatory and metabolic alterations

(AST, ALT, GGT, HOMA-IR, triglycerides), and was significantly

elevated in patients with more advanced histological fibrosis

stage (F1-F2 vs. F3–F4 s. Metavir: p < 0.04). Patients with levels of

SCCA-IgM > 200 AU/ml had more elevated serum levels of sCD163

(p < 0.05). When primary monocytes were stimulated with recom-

binant SerpinB3 “in vitro”, sCD163 expression increased of 2.5

times.

Conclusions: In chronic hepatitis C SerpinB3 is involved in

monocyte activation, leading to the release of sCD163. These results

support the correlation of these two molecules in serum of patients

with more severe liver fibrosis and metabolic alterations.



OC-13

Peripheral and intrahepatic virologicalphenotyping in HBeAg negative ChronicHepatitis B to evaluate risk of diseaseprogression and HCC in the “grey-zone” viralload cohort: Can grey-zone patients becandidate to treatment?

R. Salpini 1, L. Colagrossi 1, A. Battisti 1, N. Hansi 2,

C.F. Perno 1, U.S. Gill 2, P.T.F. Kennedy 2,

V. Svicher 1

1 Department of Experimental Medicine and Surgery,

Tor Vergata University, Rome, Italy2 Hepatology, Centre for Immunobiology, Blizard

Institute, Barts and The London SMD, QMUL, London,

United Kingdom

Introduction: HBsAg persistence is associated with an

increased risk for HCC-development in chronic hepatitis B (CHB)

and quantitative HBsAg (qHBsAg) has been proposed as a tool to

risk stratify patients for disease progression and HCC-development.

Limited data exist on the intrahepatic compartment and how accu-

rately qHBsAg reflects intrahepatic total HBV-DNA and cccDNA. We

studied liver tissue from eAg negative (eAg-) CHB patients, with 3

distinct disease profiles based on serum HBV-DNA: low-replicative

(LR) disease, “grey-zone” (moderate) and high viral-loads (VL).

Methods: To detect virological differences between periph-

eral and intrahepatic compartments, we quantified HBV-DNA and

HBsAg in serum and intrahepatic total HBV-DNA (itHBV-DNA)

along with cccDNA in biopsy specimens (n = 64). Patients were

divided as follows: low-replicative disease, HBV-DNA < 2000 IU/ml

(n = 22): Group 1; grey-zone VL, HBV-DNA 2000–20,000 IU/ml

(n = 18): Group 2; and high VL, HBV-DNA > 20,000 IU/ml (n = 24):

Group 3. Data on longitudinal ALT, Ishak fibrosis stage and

necroinflammatory (NI) scores were documented to establish

clinical correlations and determine any difference between the

groups.

Results: Patients in each group were age-matched; median

(IQR) age of 34(8–41); with no difference in ALT, Ishak fibrosis stage

and NI score. Overall, itHBV-DNA positively correlated with serum

HBV-DNA and qHBsAg (Rho = 0.53, p = <0.0001; Rho = 0.3, p = 0.02,

respectively). cccDNA positively correlated with serum HBV-DNA

(Rho = 0.39, p = 0.002), qHBsAg (Rho = 0.3, p = 0.02), and itHBV-DNA

(Rho = 0.56, p = <0.0001). We noted the amount of itHBV-DNA and

cccDNA progressively increased with increasing HBV-DNA, with

group 2 patients (grey-zone) displaying values more similar to the

high VL patients.

Conclusions: These data show that eAg-negative CHB patients

with HBV-DNA between 2000–20,000 IU/ml (grey-zone patients)

and those with HBV-DNA >20,000 IU/ml have a similar HBV

genomic reservoir; that is distinguishable from those with low-

replicative disease. Based on these data, a case could be made for

the earlier treatment of these grey-zone patients to avoid the devel-

opment of disease progression or HCC over the long-term.



OC-14

The challenge of HCV-retreatment afterDAA-failure: Italian real-life from VIRONET-Cnetwork

V. Cento 1, S. Barbaliscia 1, V.C. Di Maio 1,

C. Masetti 2, C. Minichini 3, C.F. Magni 4,

V. Micheli 5, S. Marenco 6, L.A. Nicolini 7,

B. Bruzzone 8, Y. Troshina 9, C. Baiguera 10,

C. Dentone 11, V. Calvaruso 12, S. Paolucci 13,

M. Melis 14, M. Aragri 1, A. Bertoli 1, I. Lenci 2,

S. Landonio 4, M. Schiavini 4, L. Sticchi 15,

T. Ruggiero 16, E. Polilli 17, V. Messina 18,

A. Pellicelli 19, L. Boglione 20, R. Cozzolongo 21,

M. Biolato 22, F. Morisco 23, M. Siciliano 24,

G. Parruti 17, G. Barbarini 25, A. Craxì 12,

S. Babudieri 14, M. Puoti 10, A. Ciancio 9,

G. Rizzardini 4, N. Coppola 3, M. Angelico 2,

C.F. Perno 1, F. Ceccherini-Silberstein 1, on behalf

of VIRONET-C


University of Rome Tor Vergata, Rome, Italy2 Hepatology Unit, Policlinic Foundation of Rome Tor

Vergata, Rome, Italy3 Infectious Diseases, Department of Mental and

Physical Health and Preventive Medicine, Second

University of Naples, Naples, Italy4 1st Division of Infectious Diseases, ASST

Fatebenefratelli Sacco, Milan, Italy5 Clinical Microbiology, Virology and Bioemergencies,

ASST Fatebenefratelli Sacco, Milan, Italy6 Division of Hepatology, University of Genoa-AOU

IRCCS San Martino-IST, Genova, Italy7 Infectious Diseases, Department of Health Sciences

(DISSAL), University of Genoa-AOU IRCCS San

Martino-IST, Genova, Italy8 Hygiene Unit, University of Genoa-AOU IRCCS San

Martino-IST, Genova, Italy9 Gastroepatology, Department of Medical Sciences,

City of Health and Science of Turin, University of

Turin, Turin, Italy10 Infectious Diseases, Hospital Niguarda Ca’ Granda,

Milan, Italy11 Infectious Diseases, Sanremo Hospital, Italy12 Gastroenterology, “P. Giaccone” University

Hospital, Palermo, Italy13 Molecular Virology, Policlinic Foundation San

Matteo, Pavia, Italy14 Infectious Diseases Unit, Department of Clinical

and Experimental Medicine, University of Sassari,

Italy15 Department of Health Sciences, University of

Genoa-AOU IRCCS San Martino-IST, Genova, Italy16 Infectious Diseases, “Amedeo di Savoia” Hospital,

Turin, Italy17 Infectious Disease Unit, “Spirito Santo” General

Hospital, Pescara, Italy18 Infectious Diseases Unit, A.O. S. Anna e S.

Sebastiano, Caserta, Italy19 Gastroenterology, San Camillo Hospital, Rome,

Italy20 Unit of Infectious Diseases, University of Turin,

Turin, Italy

21 Department of Gastroenterology, Scientific

Institute for Digestive Disease “Saverio de Bellis”

Hospital, Castellana Grotte, Bari, Italy22 Liver transplant unit, “Cattolica” University of

Rome, Rome, Italy23 Gastroenterology, University “Federico II”, Naples,

Italy24 Gastroenterology, “Cattolica” University of Rome,

Rome, Italy25 Division of Infectious and Tropical Diseases,

Policlinic Foundation San Matteo, Pavia, Italy

Background: In Italy, over 60,000 HCV-infected patients

received a direct-acting antiviral (DAA)-regimen. With a failure

rate of 5–10%, around 3000–6000 DAA-failures will need to be

retreated. Drug-class switch is generally recommended by inter-

national guidelines, as the performance of a reliable baseline (BL)

genotypic-resistance-testing (GRT). Few real-life data are available

on retreatment outcome.

Methods: Within the collaborative network VIRONET-C, we

analyzed patients retreated after failure of IFN-free regimens con-

taining a protease-inhibitor (PI, N = 23), and/or a NS5A-inhibitor

(N = 12), or only sofosbuvir (N = 55). GRT was performed by

population-sequencing.

Results: 84 patients infected with HCV GT1a/1b (N = 39), 2c

(N = 4), 3a (N = 31), and 4d (N = 10), 81.1% with compensated-

cirrhosis, were included. 74/84 (88.1%) patients performed a

BL-GRT, that disclosed resistance-associated-substitutions (RASs)

in 17/22 (77.3%) PI-failing, and in 8/11 (72.7%) NS5A-failing

patients.

75 patients were retreated with a NS5A-inhibitor (daclatasvir,

N = 42; ledipasvir, N = 29; ombitasvir, N = 4), including 5 NS5A-

experienced patients; 8 patients received simeprevir + sofosbuvir

after NS5A-failure. One GT4d patient was retreated with sofos-

buvir + ribavirin after simeprevir + daclatasvir failure. Ad interim

results on 40 patients showed a sustained-viral-response (SVR) in

27 (67.5%), including 3/4 (75%) receiving simeprevir + sofosbuvir,

11/18 (61.1%) receiving daclatasvir + sofosbuvir ± ribavirin, 12/15

(80%) receiving ledipasvir/sofosbuvir ± ribavirin and 1/2 (50%)

receiving paritaprevir/ombitasvir + dasabuvir + ribavirin.

SVR was low in GT3 (55.6%, N = 8) and GT2 (0/2), vs. 66.7% in GT4

(N = 6), 70% in GT1b (N = 10), 84.6% in GT1a (N = 13).

SVR to NS5A-retreatment was achieved in 18/21 (85.7%)

patients without BL NS5A-RASs, vs. 3/4 (75%) with 1 NS5A-RAS,

and 1/6 (16.7%) patients with >1 NS5A-RAS. Only 1/5 patients with

Y93H/C reached SVR.

13/11 patients who failed retreatment were cirrhotic; all 11

tested showed RASs, in 80.0% of cases on both NS3 and NS5A.

Conclusion: Preliminary results indicate that cirrhosis and pres-

ence of BL NS5A-RASs, especially Y93H, reduce retreatment efficacy

after DAA-failure in real-life. GRT-guided regimens may help to

select the natural candidates for future-generation DAAs, partic-

ularly for non-GT1.



OC-15

High rates of renal tubular damage in HBVmonoinfected patients long-term treated withtenofovir: A cross-sectional, single center,real-life study in 414 patients

G. Grossi 1, A. Loglio 1, F. Facchetti 1, E. Galmozzi 1,

M. Colombo 2, P. Lampertico 1

1 Division of Gastroenterology and Hepatology,

Fondazione IRCCS Cà Granda Ospedale Maggiore

Policlinico, Università degli Studi di Milano, Milan,

Italy2 Center for Translational Hepatology Research,

IRCCS Humanitas Hospital and University, Rozzano,

Italy

Background and aim: TDF is a popular treatment option for

patients with CHB, although a recent 48-week study showed sig-

nificant renal and bone toxicities in TDF but not in TAF-treated

patients. Aim of the study was to define the prevalence and risk

factors for such toxicities in HBV monoinfected patients long-term

treated with TDF.

Material and methods: All consecutive TDF treated patients

with CHB were enrolled in a cross-sectional single center, real-life

study. Renal safety was assessed by proteinuria, UPCR, UACR, UBCR,

and TmPO4/GFR ratio. Spine DEXA scans, FRAX, Vitamin D and PTH

levels were also recorded as well as the rs717620 of MRP2 (ABCC2

gene) by rtPCR.

Results: 414 patients (62 yr, 76% males, eGFRCG 69 mL/min)

treated with TDF for 82 (1–197) months were enrolled. Most

patients were Caucasians (94%), HBeAg negative (91%), GT D

(79%) undetectable HBV-DNA (90%) and normal ALT (92%), NUC-

experienced (60%). 45% had cirrhosis, 38% arterial hypertension

and 10% diabetes, 6% had Vit D levels <15 ng/ml, 20% had ele-

vated PTH. Fibroscan values were 5.4 Kpa (range 3–33). Osteopenia

and osteoporosis were observed in 42% and 14% patients at spine.

The 10-year probability of major and hip fractures by FRAX was

4.7% and 1.2%. As far as renal tubular safety, 37% of the patients

had low blood phosphate (<2.7 mg/dl), 59% had increased UBCR

(>300 mg/g), 66% hyperphosphaturia (<0.80 TmPO4/GFR ratio) and

53% hypercalciuria (>0.11 UCA/Cr ratio). By converse, significant

glomerular proteinuria was observed in few patients only. Overall,

41% of the patients had two markers of proximal tubular dam-

age. Patients with proximal tubular toxicity were older, previously

exposed to ADV, with lower eGFR, diabetes and arterial hyperten-

sion.

Conclusions: A significant proportion of CHB patients on

long-term TDF has proximal tubular damage associated with

hypercalciuria. These patients might benefit from a TDF to TAF

switch.


OC-16

Prothrombotic microparticles and risk of portalvein thrombosis in patients with HCV-relatedliver cirrhosis who underwent DAA antiviraltherapy

A. Zanetto 1, E. Campello 2, C.M. Radu 2,

S. Shalaby 1, E. Franceschet 1, A.M. Frigo 3,

A. Ferrarese 1, I. Bortoluzzi 1, M. Gambato 1,

G. Germani 1, M. Senzolo 1, A. Floreani 1,

F. Farinati 1, P. Burra 1, P. Simioni 2, F.P. Russo 1

1 Multivisceral Transplant Unit, Gastroenterology,

Department of Surgery, Oncology and

Gastroenterology, Padua University Hospital, Italy2 Hemorrhagic and Thrombotic Diseases Unit,

Department of Medicine, Padua University Hospital,

Italy3 Department of Cardiac, Thoracic and Vascular

Sciences, Biostatistics, Epidemiology and Public

Health Unit, Padua University Hospital, Italy

Background and aim: Prothrombotic microparticles (MP) have

been reported in cirrhosis. Since their ability of inducing the activa-

tion of coagulation cascade, high levels of MP have been associated

with a higher risk of portal vein thrombosis (PVT). Aim of this study

was to investigate the presence of MP in patients with HCV related

cirrhosis treated with DAA therapy as well as to correlate the MP

profile change with risk of PVT.

Methods: Patients with HCV related cirrhosis treated with

DAA were prospectively enrolled. Plasma levels of Annexin V-MP,

endothelial (E)-MP, platelet (P)-MP and tissue factor (TF) MP were

measured by cytofluorimeter at baseline (B-), at the end of therapy

(EOT) and 12 weeks (12 W) after EOT. During follow-up, PVT onset

was recorded. Fifty healthy subjects were enrolled as controls.

Results: 60 patients were enrolled (Child A/B 50/10). All of

them reached EOT. Twenty patients (33%) reached 12 W after

EOT follow-up. B-levels of Annexin V-MP (6640 MP/�L) and TF

bearing MP (32 MP/�L) were significantly higher than EOT lev-

els (4280 MP/�L, p < 0.05; 24 MP/�L, p < 0.01] and 12 W after

EOT-levels (2747 MP/�L, p < 0.01; 21 MP/�L, p < 0.01), respectively.

B-levels of P-MP (164 MP/�L) were higher than 12 W after EOT-

levels (125 MP/�L), however the difference was not significant

(p = 0.15). A statistically significant increase in E-MP was observed

after therapy (12 W after EOT: 1269 MP/�L in comparison to B-

levels 395 MP/�L; p < 0.05). Median follow-up was 12 months

(4–16). During follow-up, 1 PVT was recorded (incidence 2%).

Conclusions: Eradication of HCV is associated with significant

change in MP profile, related to reduction of inflammatory systemic

condition and to improvement of liver function. This ameliora-

tion may partially correct the disequilibrium of the hemostatic

imbalance of cirrhosis, leading to a reduction in the risk of PVT

development. Further studies are needed to confirm these results.



OC-17

Abnormal microvasculature in chronic viralhepatitis

S. Sarcognato 1, F. Farinati 2, R. Cardin 2,

F.P. Russo 2, M. Piciocchi 2, V. Guzzardo 1,

L. Giacomelli 1, M. Guido 1

1 Department of Medicine–DIMED, University of

Padua, Padua, Italy2 Department of Surgery, Oncology and

Gastroenterology, University of Padua, Padua, Italy

Background: Histological abnormalities of intrahepatic

microvasculature have been well described in both non-cirrhotic

and cirrhotic portal hypertension, but very little is known about

the prevalence of such lesions outside these settings.

Aim: The aims of this study were to investigate the type

and prevalence of morphological abnormalities of intrahepatic

microvasculature in chronic viral hepatitis B (CHB) and C (CHC)

and to correlate microvascular changes with fibrosis stage, tissue

markers of fibrogenesis, sinusoidal capillarization/angiogenesis,

and oxidative DNA damage.

Methods: Liver biopsies from 74 consecutive treatment-naive

patients with CHB or CHC were studied. No one had clinical signs

of portal hypertension or extra hepatic vascular alterations. The

evaluated microvascular changes included (i) phlebosclerosis, (ii)

aberrant vessels, (iii) portal angiomatosis, (iv) sinusoidal dilata-

tion, (v) thrombosis of small intrahepatic portal veins, vi) abnormal

parenchymal draining veins. Sections were stained with anti-CD34,

anti-CD105, and anti-alpha-smooth muscle actin (ASMA). Tissue

quantification of 8-OHdG adducts was performed as a marker of

oxidative DNA damage.

Results: Portal angiomatosis was the most frequent microvas-

cular change (46/74 cases; 62.1%), and it strongly correlated with

the HAI (p = 0.003), the stage of fibrosis (p = 0.00), the extension of

CD34 expression (p = 0.04), and with ASMA expression in both zone

1 (p = 0.0005) and 2/3 (p = 0.03). Aberrant vessels were detected

in 21.6% (16/74) of cases and correlated with the stage of fibrosis

(p = 0.008) and with the extension of ASMA immunoreactivity in

zones 2/3. Microvascular density in portal tracts was significantly

related to the number of 8-OHdG adducts. At the multivariate anal-

ysis, portal angiomatosis was an independent predictor of fibrosis

stage (p = 0.02).

Conclusions: Histological microvascular abnormalities are

common in CHB and CHC. Their correlation with fibrosis stage, sinu-

soidal capillarization, neoangiogenesis, and ongoing fibrogenesis

supports a role in disease progression. Systematic assessment of

microvascular changes in liver biopsies of chronic viral hepatitis

might provide prognostic informations.


OC-18

External validation of the HCC-MELD score forpatients with hepatocellular carcinoma waitingfor liver transplantation

A. Vitale 1, A.C. Frigo 2, P. Burra 1, P. Angeli 1,

G. Zanus 1, U. Cillo 1

1 Liver Transplant Center, Padua University, Padua,

Italy2 Biostatistic Unit, Padua University, Padua, Italy

Background and aims: We recently described a method for cal-

ibrating HCC and non-HCC patients according to survival benefit to

restore equity to the organ allocation system. The aim of this study

is to externally validate this method in a large cohort of US patients.

Methods: We modelled the post-transplantation survival of

adult, first-time liver transplant recipients with HCC (n. 9135) or

without (n. 25,890) from 2002 through 2013 using Cox propor-

tional hazards regression. We modelled waitlist survival of patients

listed for transplantation with HCC (n. 15,605) or without (n.

85,229) using competing risks analysis. MELD-related hazard ratios

obtained using these models were included in a Monte Carlo sim-

ulation and used to calculate 5-year survival benefit estimations

(i.e. the difference between post-transplantation and waitlist life

expectancy) in HCC and non-HCC populations.

Results: The 5-year survival benefit increased with actual MELD

score for patients with and without HCC, ranging from just a few

months in patients with low MELD scores (i.e., 6–8) to more than

48 months in patients with the highest MELD scores (i.e., 36–40).

As in the Italian study, the survival benefit of patients with

HCC was higher than that of patients without HCC who had the

same actual MELD score, irrespective of tumor burden or serum

level of a-fetoprotein. Median 5 year transplant benefit was 10.30

months (5.72–45.09) for the non-HCC patients, and 28.54 months

(10.66–44.88) for the HCC patients (p < 0.001).

Using our previously published method, we obtained the

equation “HCC-MELD US” = 1.73 * MELD − logAFP + 2.8 calculating a

numerical score for HCC patients, whereby their transplant benefit

is equal to that of non-HCC patients with the same numerical value

for MELD.

Conclusions: Our proposed method for calibrating HCC and

non-HCC patients according to survival benefit was validated in

a large US population.


OC-19

Entecavir or tenofovir monotherapy preventsHBV recurrence in liver transplant recipients: A5-year follow-up study after hepatitis Bimmunoglobulin withdrawal

M.A. Manini 1,2, M. Bruce 1, I. Carey 1,

G. Whitehouse 1, B. Wang 1, E. Gonsalkorala 1,

A. Considine 1, P. Lampertico 2, K. Agarwal 1

1 Institute of Liver Studies, King’s College Hospital,

London, United Kingdom2 A.M. and A. Migliavacca Center for Liver Disease,

Division of Gastroenterology and Hepatology,

Fondazione IRCCS CA’ Granda Ospedale Maggiore


Italy

Background/aims: Prophylaxis with HBIg + NUC remains the

standard-of-care to prevent HBV reinfection after LT. Recent data

suggest that 3rd generation NUC therapy may be effective as well.

We investigated the 5-year efficacy/safety of ETV or TDF monopro-

phylaxis after HBIG withdrawal.

Methods: Between 01/2010 and 01/2012, all HBV and HDV

transplanted patients followed in our centre withdrew HBIg + NUC

and started ETV or TDF monotherapy. Patients were followed every

3–6 months until 10/2016. HBsAg and HBV-DNA were monitored

at each follow-up visit.

Result: 77 patients with a post-transplant follow-up of 68

(range 6–237) months were included (55% TDF, 45% ETV). Group

A included 69 HBV monoinfected patients (80% male, 59 years, 58%

Caucasian) who underwent LT due to fulminant hepatitis (16%),

ESLD (38%), acute-on-chronic liver disease (6%) and HCC (40%).


Table 1

LTindication

HBVDNA atLT(IU/mL)

HBsAg atLT(IU/mL)

HBeAgat LT

HBIG + NUCpre-switch(mos)

NUC beforeHBIGwithdrawal

NUC afterHBIGwithdrawal

HBsAgrecurrence(mos)

AoCLF 800 3589 neg 31 LAM ETV 56HCC <12 43 neg 28 LAM ETV 19HCC 309 11391 pos 69 LAM TDF 22HCC 269 2281 neg 34 LAM ETV 47HCC <20 316 neg 8 TDF TDF 21

Group B included 8 HBV/HDV coinfected patients (50% male, 54

years, 75% Caucasian, ESLD in 88%, HCC in 12%).

Group A and B patients received oral therapy for a median of 69

(range 12–80) months and 61 (range 31–78) months, respectively.

No Group B patients had HBsAg or HBV DNA recurrence, while 5

(7%) Group A patients became HBsAg-positive, (see Table 1). The

cumulative 1-, 3- and 5-year rates of HBsAg recurrence were 0, 5%

and 8%. All 5 patients demonstrated undetectable HBV-DNA levels

and stable graft function at HBsAg seroreversion as well as during

follow-up. None experienced clinically relevant events.

Overall, 3 deaths occurred (1 for HCV recurrence and 2 for sep-

sis). The cumulative 5-year survival was 96%.

Conclusion: HBIG can be safely discontinued in HBsAg-positive

LT recipients and replaced by ETV or TDF monotherapy.


OC-20

A new strategy to improve the liverengraftment efficiency of transplanted humanbiliary tree stem/progenitor cells (hBTSCs): Cellcoating with hyaluronic acid

L. Nevi 1, G. Carpino 2, D. Costantini 1,

V. Cardinale 1, O. Riccioni 3, S. Di Matteo 1,

F. Melandro 4, P.B. Berloco 4, L. Reid 5, E. Gaudio 3,

D. Alvaro 1

1 Department of Medico-Surgical Sciences and

Biotechnologies, Sapienza University of Rome, Rome,

Italy2 Department of Movement, Human and Health

Sciences, Division of Health Sciences, University of

Rome “Foro Italico”, Rome, Italy3 Department of Anatomical, Histological, Forensic

Medicine and Orthopedics Sciences, Sapienza

University of Rome, Rome, Italy4 Department of General Surgery and Organ

Transplantation, University of Rome “Sapienza”,

Rome, Italy5 Department of Cell Biology and Physiology and

Program in Molecular Biology and Biotechnology,

University of North Carolina, Chapel Hill, NC, United

States

Human biliary tree stem/progenitor cells (hBTSCs) have been

used for cell therapy of patients with advanced liver cirrhosis.

Strategies to improve the liver engraftment of transplanted cells

are currently under evaluation. We aimed to investigate whether

coating hBTSCs with clinical-grade Hyaluronic Acid (HA) may

influence their liver engraftment efficiency, proliferation and

hepatocyte differentiation.hBTSCs were isolated, by EpCAM-

immunoselection, from the extrahepatic biliary tree of adult

liver donors and incubated with 0.1% HA. In vitro, HA-coated and

uncoated hBTSCs were analyzed for cell viability, colony formation,

proliferation and mRNA expression of CD44,ITG�1,ITG�4,CDH1.

In vivo, HA-coated and uncoated hBTSCs were injected into the

spleen of SCID mice. After 30 days, the liver engraftment and

ectopic distribution in distant organs were evaluated by immuno-

histochemistry. The human albumin mRNA into the mice liver

was measured by a de novo developed RT-qPCR method and the

human albumin concentration in the mice serum was evaluated by

ELISA.

Immunofluorescence analysis showed that HA homogeneously

coated more than 90% of hBTSCs. HA-coated hBTSCs showed

increased colony formation (p < 0.001), increased cell viability

(79.24 vs 70.06%; p < 0.05) and, increased proliferation rate (Pop-

ulation Doubling 2.03 vs 0.77 times/week; p < 0.05) with respect to

uncoated hBTSCs. HA-coating resulted into a significant increase

(p < 0.05) in gene expression of the adhesion molecules ITG�1 and

ITG�4 while, CDH1 and CD44 resulted into a significant decrease

(p < 0.05) genes expression was unchanged than uncoated cells. In

vivo, the engraftment efficiency of HA-coated hBTSCs was markedly

enhanced with respect to uncoated cells (11.02 vs 2.62%; p < 0.01).

HA improved the proliferation and hepatocyte differentiation of

hBTSCs engrafted into the mice liver. In keeping, the gene expres-

sion of human albumin in the liver and the human albumin serum

levels (117.62 vs 64.94 ng/dl; p < 0.05) were markedly higher in

mice transplanted with HA-coated than uncoated hBTSCs. Insignif-

icant or minimal ectopic distribution of transplanted hBTSCs in

distant organs was observed.

In conclusion, the easy and cheap procedure of HA-coating

markedly improved the effects of hBTSC transplantation and could

be rapidly turned in the clinical use.


OC-21

Parenchymal sparing vs. anatomic resection forhcc: A propensity score analysis

S. Famularo 1,3, A. Giani 1,3, S. Di Sandro 2,

M. Sandini 1,3, A. Giacomoni 2, E. Pinotti 1,3,

L. Nespoli 1,3, L. Gianotti 1,3, L. De Carlis 1,2,

F. Romano 1,3

1 School of Medicine and Surgery, University of

Milano-Bicocca, Milan, Italy2 Department of General Surgery and

Transplantation, Niguarda Ca’ Granda Hospital,

Milan, Italy3 San Gerardo Hospital, Department of Surgery,

Monza, Italy

Background: Although anatomic resection (AR) for hepatocel-

lular carcinoma (HCC) is advocated as the optimal approach for

curative intent, its superiority over parenchyma-sparing resection

(PSR) has not been consistently proven. The purpose of this study

was to compare the impact of AR vs. PSR on disease recurrence and

patient survival.

Methods: We retrospectively analyzed patients suffering from

HCC who underwent liver resection from January 2001 to August

2015 in two hospitals. Patients receiving AR or PSR were directly

compared by a propensity score analysis (caliper of 0.1) using 9

variables. Thus, patients were stratified also for number of nod-

ules, presence of cirrhosis, size of the nodule, and ALBI grade. The

primary outcome measures were disease-free (DFS) and overall

survival (OS) rates. The secondary outcome was to identify vari-

ables related to disease recurrence.

Results: 455 consecutive patients were retrospectively ana-

lyzed. Propensity score matching was run on: age, cirrhosis, HCV

infection, number and size of nodules, bilobar disease, extension

of hepatectomy, radical resection, microvascular invasion, pres-

ence of satellitosis and ALBI grade. After matching 354 patient were

enrolled, 177 pairs for both groups. The median follow-up was 30


months. Median OS was 47.5 months (95% CI: 30.03–65.9) for AR

group and 56.48 months (95% CI: 33.2–79.6) for PSR (p: 0.169).

Median DFS was 29.2 months (95% CI: 17.6–40.8) for AR and 24.8

months (95% CI: 15.2–34.2) for PSR (p: 0.337). At univariate and

multivariate analyses PSR was not associated with an higher risk of

intra-hepatic or extra-hepatic recurrence or tumor-related death.

Microvascular invasion and satellitosis were the predominant risk

factors for recurrence.

Conclusions: Overall survival and disease recurrence seem to

be independent from the type of resection. PSR may be safely used

to preserve liver function and reduce the impact of hepatectomy.


OC-22

The survival benefit of laparoscopic ablationover trans-arterial chemoembolization inpatients with hepatocellular carcinomaineligible for liver resection or percutaneousablation

A. Bertacco 1, A. Marchini 1, A. Vitale 1, C. Ungaro 1,

F. D’Amico 1, E. Gringeri 1, D. Neri 1, D. Bassi 1,

G. Zanus 1, R. Carandina 2, C. Aliberti 2, U. Cillo 1


Gastroenterology, Hepatobiliary Surgery and Liver

Transplantation, Padua University, Padua, Italy2 Oncology Radiodiagnostics, Oncology Institute of

Veneto, Institute for the Research and Treatment of

Cancer (IRCCS), Padua University, Padua, Italy

Background: Different options are available for hepatocellular

carcinoma (HCC) treatment according to tumor characteristics and

patients liver function. Trans-arterial-chemioembolisation (TACE)

is the first-line treatment for patients ineligible for liver resection or

percutaneous ablation. Aim of our study was to compare outcome

of patients with HCC treated with laparoscopic ablation versus

patients treated with TACE.

Methods: Two HCC patients populations were used for the anal-

ysis: 485 patients treated with laparoscopic ablation (LA) as first

therapy in the period 2004–2015 and 410 patients that received

TACE as first treatment in the period 2008–2015. After propensy

score analysis we obtained two comparable groups (n = 175 for

each) to evaluate the overall survival. A simulation analysis was

also used to define survival benefit between the groups in different

BCLC stages.

Results: Laparoscopic ablation showed a significantly superior

long-term survival compared with TACE in unmatched patients

(median survival 47 vs 30 months, p < 0.05) but after sample size

reduction due to propensity score analysis (175 vs. 175 patients) the

difference between groups became not significant (median survival

46 vs. 32 months, p = 0.117). With the application of the median

survival simulation (995 patients undergoing LA vs. 995 undergo-

ing TACE) we showed a significant survival benefit of LA over TACE

in each BCLC stage (48 months in stage 0, 17 in stage A, 7 in stage B).

The variables that most influenced the survival benefit were MELD

score and patient age.

Conclusions: In HCC patients ineligible for percutaneous abla-

tion or liver resection, LA should be evaluated as potential

therapeutic strategy before considering TACE, whenever BLCL

stage.


OC-23

Outcome of liver transplant recipients after thefirst episode of bacterial infection

A. Ferrarese 1, A. Zanetto 1, G. Germani 1,

M. Gambato 1, F.P. Russo 1, U. Cillo 2, P. Angeli 3,

P. Burra 1, M. Senzolo 1

1 Multivisceral Transplant Unit, Department of

Surgery, Oncology and Gastroenterology, Padua

University Hospital, Italy2 Hepatobiliary Surgery and Liver Transplant Center,

Padua University Hospital, Italy3 Internal Medicine, Padua University Hospital,

Padua, Italy

Introduction: Bacterial Infections (BI) represent a major cause

of decompensation and death in patients with cirrhosis. However,

the outcome during and after infection, and subsequently prioriti-

zation and drop-out from the waiting list for Liver Transplantation

(LT) remain still poorly understood.

Aim: To prospectively evaluate, in a single center cohort of

cirrhotic patients awaiting LT, the prevalence of BI; the 1-, and 12-

month outcome after the first episode of BI; the change of liver

function during and after resolution of BI, and the consequent pri-

oritization for LT.

Materials and methods: All patients who experienced BI while

in the WL for LT at Padua University Hospital since 2006–2014

were prospectively evaluated. MELD score, type of infection were

assessed before, during BI, and 1 and 12 months thereafter, together

with recipients’ outcome. Data were compared with a control group

matched for severity of liver disease without episodes of BI.

Results: 1794 patients were evaluated, of which 114 (6.4%)

were enrolled (M/F 79/35, age 57.2 ± 7.8 years, HCV 29.8%, HCC

19.3%). Spontaneous bacterial peritonitis was the prevalent BI(36%),

without any impact on short term mortality (p = 0.09). One month

mortality was significantly higher after BI than controls (p < 0.001);

indeed, considering survivors, there was a trend towards an

higher 12 month drop-out rate (p = 0.08). MELD score significantly

increased during BI in the whole cohort (20 ± 6 to 22 ± 6; p = 0.001),

and in those who survived (17.5 ± 5 vs 19.6 ± 5; p = 0.01). In the lat-

ter subgroup, MELD after resolution of BI was higher than before

(18.1 ± 4.9 vs 19.2 ± 5; p = 0.02).

Conclusions: BI represents a common cause of decompensation

and death in patients awaiting LT, determining a poorer outcome.

BI was associated with a significant short-term worsening of liver

function according to MELD score, also in those LT recipients who

recovered from BI. Thus, in this specific window time, personalized

scores for prioritization of patients awaiting LT should be advisable.



OC-24

Identification of Twinfilin-1 as a key regulatorof cholangiocyte biological response to injury:Evidence for a possible role of ageing in theprogression of cholangiopathies

L. Maroni 1, C. Pinto 1, D.M. Giordano 1,

S. Saccomanno 1, C. Rychlicki 1, L. Trozzi 1,

M.C. Albertini 2, F. Orlando 3, E. Melum 4,

J. Banales 5, A. Benedetti 1, G. Svegliati Baroni 1,

M. Marzioni 1

1 Dipartimento di Gastroenterologia e Epatologia,

Università Politecnica delle Marche, Ancona, Italy2 Dipartimento Scienze Biomolecolari, Università

degli Studi di Urbino “Carlo Bo”, Urbino, Italy3 Servizio di Allevamento Sperimentazione

Animale, Polo Scientifico Tecnologico, Falconara,

Italy4 Norwegian PSC Research Center, Division of

Surgery, Inflammatory Medicine and

Transplantation, Oslo University Hospital,

Rikshospitalet, Oslo, Norway5 Department of Liver and Gastrointestinal Diseases,

Biodonostia Health Research Institute – Donostia

University Hospital, Ikerbasque, CIBERehd,

University of the Basque Country (UPV/EHU), San

Sebastian, Spain

Introduction: Disorders of the biliary tree such as PBC, PSC or

cholangiocarcinoma develop and progress differently according to

the patient age. Similarly, biliary injury after liver transplantation

is affected by donor age. It is not known yet whether the ageing

process plays any role in the pathophysiology of biliary disorders.

The aim of the study was to identify molecular pathways associ-

ated to the ageing process and to verify their role in cholangiocyte

response to injury.

Materials and methods: Expression of a number of age-related

microRNAs (miRs) were evaluated in cholangiocytes of 2-month

old (young) and 22-month old (old) mice, either subjected or not

to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-treatment, a

model of sclerosing cholangitis. Common intracellular pathways

and molecular targets of elevated miRs were identified by in silico

analysis. Proliferation was assessed by sulforhodamine B (SRB)

assay; senescence and senescence-associated secretory phenotype

(SASP) markers (p16INK4a, p21WAF1/Cip1, Il-1, Il-6, Igf-1, Pai-1) were

evaluated in vitro by qPCR.

Results: Ageing-related miR-1a, miR-30e, miR-93, miR-34a,

miR-146b and miR-20a were up-regulated in cholangiocytes from

DDC-treated mice compared to controls. In silico analysis identi-

fied Twinfilin-1 (Twf1) as a common target of the up-regulated

miR-1a, miR-30e and miR-20a. Young mice subjected to DDC and

old-untreated mice showed similar expression of Twf1 and related

miRs in cholangiocytes, which was markedly increased as com-

pared to young untreated ones. Twf1 and miRs expression was

further increased in DDC-treated old mice. By immunofluores-

cence, intrahepatic cholangiocytes of PSC patients were positive

for Twf1 expression. Knock-down of Twf1 by siRNAs in cultured

cholangiocytes significantly reduced cell proliferation. In parallel,

senescence and SASP markers were increased in Twf1-deficient

cholangiocytes.

Conclusions: Twf1 is as an important mediator of both cholan-

giocyte adaptation to ageing processes and response to injury. Our

data suggest that disease and ageing might share common path-

ways, which may unveil novel markers of disease progression.


OC-25

Metformin reduces cell migration anddown-regulates epithelial to mesenchymaltransition (EMT) by AMPK/Foxo3a pathway inhuman intrahepatic cholangiocarcinoma (CCA)

S. Di Matteo 1, D. Costantini 1, L. Nevi 1, A. Lustri 1,

C. Napoletano 3, J. Faccioli 1, F. Giulitti 1,

E. Manzi 2, A.M. DeRose 4, M.C. Bragazzi 1,

G. Grazi 2, P.B. Berloco 5, F. Giuliante 4,

V. Cardinale 1, G. Carpino 6, D. Alvaro 1

1 Medico-Surgical Sciences and Biotechnologies,

Sapienza University of Rome, Rome, Italy2 Gastroenterology Unit, Regina Elena National

Cancer Institute, Rome, Italy3 Department of Experimental Medicine, Sapienza

University of Rome, Rome, Italy4 Hepatobiliary Unit, Catholic University of the

Sacred Heart School of Medicine, Rome, Italy5 Department of General Surgery and Organ

Transplantation, Sapienza University of Rome, Rome,

Italy6 Department of Health Science, University of Rome

“Foro Italico”, Rome, Italy

CCA is an aggressive cancer resistance to chemotherapeutics.

We demonstrated that CCA is enriched of cancer stem cells express-

ing EMT traits associated with aggressiveness and drug resistance.

We established primary cell cultures from human IHCCA sub-

types (mucin and mixed). Treatment with the anti-diabetic drug

metformin has been associated with reduced cancer incidence. In

immortalized cancer cell lines, metformin showed EMT inhibitory

effects by up-regulating Foxo3a signaling.

We aimed evaluating the effects of metformin on proliferation,

apoptosis, cell migration and expression of EMT traits in primary

cultures of CCA subtypes.

CCA were treated with acute increasing metformin concentra-

tions (5–1000 �M, 1–4 days) and chronically at 10 �M Metformin.

We evaluated proliferation by MTS assay; apoptosis by Flow

cytometry analysis of Annexin V-FITC/Propidium Iodide; and cell

migration by wound-healing assay. The expression of Vimentin,

E-Cadherin, SNAIL1/2, TWIST1, Cytokeratin19, FOXO3a and AMPK

genes were analyzed by RT-qPCR, whereas FOXO3a, Cytokeratin19

and Vimentin were analyzed by Immunofluorescence Assay.

Metformin significantly inhibited cell proliferation and induced

apoptosis in primary cultures ofmucin- and mixed-IHCCA; the

effects were dose- and time-dependent. The migration of IHCCA

cells, from both mucin and mixed CCA subtypes, was also signifi-

cantly reduced by acute treatment. The effects of metformin were

associated with enhanced gene expression of the epithelial marker

E-Cadherin and decreased expression of Vimentin and EMT specific

genes, SNAIL1/2 and TWIST1. Metformin also increased the AMPK

and FOXO3a mRNA levels. FOXO3a gene expression was negatively

correlated with the expression of SNAIL1 and Vimentin genes. The

FOXO3a protein migrates from cytoplasm to nucleus in metformin

treated cells. After chronic treatments the Mucin-IHCCA showed

a high expression of Cytocheratin19 and a very low expression of

Vimentin.

In conclusion, we demonstrated that metformin inhibits cell

proliferation, enhances apoptosis and impairs EMT traits by activat-

ing Foxo3a in primary cultures of human CCA. Therefore, metformin

could play anticancer effects against human CCAs with relevant

therapeutic implications.



OC-26

Microgravity maintains stemness and enhanceglycolytic metabolism in human hepatic andbiliary tree stem/progenitor cells

D. Costantini 1, V. Cardinale 1, L. Casadei 2,

G. Carpino 3, L. Nevi 1, S. Di Matteo 1, A.M. Lustri 1,

S. Safarikia 1, F. Melandro 4, P. Berloco 4,

C. Manetti 2, D. Alvaro 1

1 Department of Medico-Surgical Sciences and

Biotechnologies, Sapienza University of Rome, Rome,

Italy2 Department of Chemistry, Sapienza University of

Rome, Rome, Italy3 Department of Health Science, University of Rome

“Foro Italico”, Rome, Italy4 Department of General Surgery and Organ

Transplantation, Sapienza University of Rome, Rome,

Italy

Gravity plays a key role in regulating cell processes such as pro-

liferation, differentiation and cell function.

The aim of the study was to evaluate the effects of microgravity

on differentiation and exo-metabolome profile of human hepatic

and biliary tree stem/progenitor cells.

Simulated weightless conditions were obtained by the RCCS

(Synthecon). Primary cultures of human biliary tree stem cells

(hBTSCs) and immortalized human hepatic cell line (HepG2)

were cultured in microgravity or in normogravity conditions.

Self-replication and differentiation toward mature cells were

determined, respectively, by culturing in Kubota’s Medium and

hormonally defined medium tailored for hepatocyte differentia-

tion. RT-qPCR was used to evaluate gene expression and NMR to

analyze the cell exo-metabolome profile.

Microgravity determined an increase of stemness genes (OCT4,

SOX17, PDX1) in hBTSCs (p < 0.05 vs normogravity). hBTSCs cul-

tured in microgravity showed an impaired capacity to differentiate

toward mature hepatocytes, since the expression of hepatocyte

lineage genes (ALB, ASBT and CYP3A4) was significantly lower

with respect to normogravity (p < 0.05). In HepG2, the microgravity

caused a lower (p < 0.05 vs normogravity) expression of CYP3A4,

a terminal differentiation gene expressed in lobular zone 3. The

NMR PCA of the exo-metabolome cell profile evidenced that, in

microgravity, both cell lines presented higher glucose consumption

and lower consumption of pyruvate and glutamate with respect

to normogravity (p < 0.05), with formation of fermentation and

ketogenesis products. Interestingly, while in normogravity the

differentiation of hBTSCs toward mature hepatocytes was associ-

ated with increased oxidative phosphorylation (p < 0.05), this was

prevented by microgravity in association with the impaired cell

differentiation.

Our results demonstrated significant combined biologic and

metabolomic effects of microgravity on hepatic stem/progenitor

cells with several implications. From one side, these effects of

microgravity should be taken into consideration for space medicine

programs but, from the other side, they could be interesting for the

generation of devices based on stem/progenitor cells.


OC-27

Epidemiology of primary biliary cholangitis inItaly: evidences from a real world database

M. Marzioni 1, C. Bassanelli 2, B. Marini 2,

C. Ripellino 3, D. Urbinati 3, D. Alvaro 4

1 Clinic of Gastroenterology and Hepatology,

Università Politecnica delle Marche, Ancona, Italy2 Intercept Pharmaceuticals, Milan, Italy3 IMS Health, Milan, Italy4 Department of Medical-Surgical Sciences and

Biotechnologies, “La Sapienza” Rome University,

Rome, Italy

Introduction and aim: Primary biliary cholangitis (PBC) is a

rare chronic autoimmune liver disease. Orphanet estimates that

the global prevalence of PBC is 21.0/100,000 with an incidence

of 3.0/100,000/year. The only available data concerning PBC epi-

demiology in Italy, specifically in the Lombardy region, report a

prevalence of 29.5/100,000 and an incidence of 1.6/100,000/year

based on administrative databases. The aim of this analysis was to

investigate the epidemiology of PBC in Italy and describe the main

characteristics of this patient population.

Materials and methods: IMS Health analyzed longitudinal

databases of 900 General Practitioners and selected patients with

a 571.6 diagnosis code (ICD9, Biliary Cirrhosis) from 1/2014 to

12/2015. Demographics and treatment were registered at the time

of first evidence of PBC diagnosis. Comorbidities were collected up

to twelve months prior to diagnosis.

Results: 1,204,216 inhabitants >14 years old, homogenously

distributed throughout Italy were analyzed: 412 patients had

a diagnosis of PBC according to the ICD9 code 571.6. In

2015, the prevalence was 28.0/100,000 while the incidence was

5.3/100,000/year. The female to male ratio was 4:1. The most

common comorbidities were osteoporosis (21.5%), and diabetes

(12.7%). Diseases of the connective tissue, rheumatoid arthritis and

thyroiditis primarily affected female patients. 13 patients had cir-

rhosis and 3 patients had primary liver cancer. 364 patients (88.4%)

received a pharmacologic treatment for PBC, 92% of whom received

UDCA. Within six months of follow up, 1 (0.24%) patient underwent

liver transplantation and 5 (1.20%) patients died.

Conclusions: The estimated prevalence of PBC based on a real

world database analysis was consistent with a previous Italian

study based on administrative databases and with Orphanet data,

while the incidence was slightly higher. Despite limitations, data

collected through the IMS longitudinal database provides unique

and valuable insight into the current epidemiology of PBC in Italy,

key PBC patient’s characteristics and medications.



OC-28

Characterisation of the immune response inpatients with drug induced liver injury

C. Bergamo 1, G. Germani 1, D. Bizzaro 1,

C. Frasson 2,3, G. Basso 2, A. Ferrarese 1,

A. Zanetto 1, S. Shalaby 1, I. Bortoluzzi 1,

M. Gambato 1, M. Senzolo 1, F.P. Russo 1, P. Burra 1


Surgery, Oncology and Gastroenterology, Padova

University Hospital, Padova, Italy2 Haemato-Oncology Laboratory, Department of

Woman and Child Health, University of Padova,

Padova, Italy3 Fondazione Città della Speranza, Istituto di Ricerca

Pediatrica, Padova, Italy

Introduction and aim: Drug Induced Liver Injury (DILI)

represents the leading cause of acute liver failure and liver trans-

plantation in Western countries. The aim of the study was to assess

the clinical presentation, outcome and modification of the immune

pattern in patients with DILI.

Methods: Patients admitted at Multivisceral Transplant Unit of

Padova University Hospital for suspected DILI from 2013 to 2016

were included. Demographic and clinic characteristics and trans-

plant free survival were evaluated in all patients.

In a subgroup of patients with DILI, isolated mononuclear cells

from peripheral blood were analyzed by flow cytometry for: mono-

cytes, B-lymphocytes, T-helper and T-cytotoxic lymphocytes. Data

were compared with healthy controls.

Results: 31 DILI patients were evaluated, 55% women with a

median age of 46.7 years (range 33–70). The most frequent drugs

involved in DILI were antimicrobials (42%). Transplant free sur-

vival rate at 1 year was 73%, with 16% patients who underwent

liver transplantation. The cytofluorimetric analysis performed in 7

DILI patients compared to 4 healthy controls showed a significant

decrease of B-lymphocytes in DILI patients (2.4% ± 0.9 vs. 7.9 ± 0.5%,

p = 0.01). Patients with DILI due to antimicrobials, compared to con-

trols, showed a more evident decrease of B-lymphocytes (0.6 ± 0.4%

vs. 7.9 ± 0.4%; p = 0.004), of T-Helper lymphocytes (8.3 ± 7.7% vs.

20.9 ± 12.2%; p = 0.05) and a significant decrease of T-Helper

compared to the other DILI patients (8.3 ± 7.7% vs. 26.6 ± 12.2%,

p = 0.04). Male patients showed a higher percentage of immature

(12.9 ± 3.3% vs. 2.7 ± 2.7%, p = 0.007), early monocytes with pro-

inflammatory properties (9.7 ± 1.6% vs. 3.0 ± 2.9%, p = 0.03) and a

higher percentage of memory T-cells (22.5 ± 2.8% vs. 3.8 ± 1.7%,

p < 0.001) compared with female patients.

Conclusions: The most frequent agents involved in DILI were

antimicrobials, which seem to induce a marked immunodeficiency,

especially towards B-lymphocytes, suggesting a possible cytotoxic

T-cell-mediated damage. Despite the incidence of DILI was higher

in women, males seem to have a more enhanced pro-inflammatory

status.


OC-29

In-hospital mortality and length of stay incirrhotic patients with sepsis treated withnon-selective beta-blockers

A. Facciorusso, R. Villani, F. Bellanti, R. Bruno,

G. Fioravanti, G. Vendemiale, G. Serviddio

Department of Internal Medicine, University of

Foggia, Foggia, Italy

Introduction: Non-selective beta-blockers (NSBBs) have been

suggested to be associated with decreased rate of bacterial infection

and reduced severity of systemic inflammation in cirrhotic patients.

Aim: To test whether low doses NSBBs ameliorate short-term

outcomes in cirrhotic patients with sepsis.

Methods: Out of 854 cirrhotics admitted to our hospital

between 2006 and 2016, 107 patients with sepsis were included

in the analysis and grouped into 2 cohorts: 48 patients under

NSBB treatment (Group 1) and 59 NSBB non-users (Group 2). Uni-

variate/multivariate logistic regression analysis was performed to

identify the factors influencing in-hospital mortality, and results

were expressed as odds ratios (OR) and 95% confidence intervals

(CI). Duration of hospital stay, severity of septic events, and tem-

poral trend of MELD score were analyzed too.

Results: The two cohorts resulted balanced for clinical and

demographical characteristics. NSBB-users experienced milder

septic events, although not significantly (72.9% of septic events reg-

istered in group 1 were not severe vs 54.2% in group 2, p = 0.12). This

trend was paralleled by inflammatory lab markers [white blood cell

count: 9.2 (3.4–16.3) in NSBB-users vs 12.1 (4.2–19.8) in NSBB non-

users (p = 0.004); and plasma C-reactive protein: 47.4 (1.55–172)

and 65.5 (2.3–248) in the two groups, respectively (p = 0.24)]. In-

hospital mortality was significantly lower in group 1 (18.7% versus

42.3%, p = 0.01) and duration of hospital stay was shorter among

NSBB users (15 days, range 2–37 versus 18.5, 2–60; p = 0.03).

Comorbidity index (OR: 4.14, p = 0.03) and NSBB use (OR: 0.29,

p = 0.02) resulted significantly associated with in-hospital mortal-

ity in multivariate analysis. MELD score resulted significant higher

in group 2 from the sixth day since sepsis occurrence onwards.

Conclusions: Our study is the first report on the efficacy of low

doses of NSBB in reducing mortality and hospital stay in cirrhotics

with sepsis. NSBB may exert these effects through the modulation

of systemic inflammatory responses.



OC-30

Local prothrombotic state in portal venoussystem in cirrhosis

S. Shalaby 1, P. Simioni 3, E. Campello 3,

S. Gavasso 3, A. Zanetto 1, F. D’Amico 2,

E. Gringeri 2, U. Cillo 2, M. Battistel 4, P. Burra 1,

M. Senzolo 1



University Hospital, Padua, Italy2 Hepatobiliary Surgery and Liver Transplantation

Unit, Department of Surgery, Oncology and

Gastroenterology, Padua University Hospital, Padua,

Italy3 Hemorrhagic and Thrombotic Diseases Unit,

Department of Medicine (DIMED), University of

Padua Medical School, Padua, Italy4 University Radiology, Department of Medicine,

University Hospital of Padua, Padua, Italy

Introduction: Cirrhosis is characterized by both bleeding

and thrombotic complications due to underlying procoagulative

haemostatic imbalance. Among thrombotic-events, portal-vein

thrombosis (PVT) is the most common with annual incidence ran-

ging between 4.6% and 12.8%. Demonstrated associated risk-factors

are severity of portal-hypertension and slowed portal-flow. How-

ever, data regarding haemostasis in the portal venous-system of

cirrhotics are lacking.

Aims and methods: To evaluate peripheral and portal

venous haemocoagulative-state in patients with cirrhosis in

comparison with controls, through thrombin generation-test

(TGT), rotational-thrombelastometry (ROTEM) along with evalu-

ation of endothelial-dysfunction by quantification of circulating

endothelial-microparticles (MP). Correlate these results with

activity-levels of local pro and anticoagulant factors. Compare

peripheral and portal venous districts in cirrhotics in terms of

haemostatic-balance.

We consecutively enrolled cirrhotic patients undergoing liver-

transplantation (LT) or TIPS. Non-cirrhotic patients awaiting

liver-surgery or deceased liver-donors were enrolled as controls.

On citrated peripheral and portal venous blood we performed: TGT

with/without thrombomodulin (TM), ROTEM, dosage of pro and

anticoagulant factors and endothelial-MP.

Results: 25 cirrhotics (15 LT and 10 TIPS) and 6 controls

(2 undergoing hepatic-resection for benign liver-lesions and 4

liver-donors) were enrolled. Peripheral-blood in cirrhotics showed

resistance to activation of PC-pathway at TGT (ETP with/without

TM 0.89 (0.78–0.92) vs 0.6 (0.3–0.74), p < 0.001), lower clot sta-

bility at ROTEM (MCF-NATEM mm: 43.5 (36–51) vs 63 (53–69),

p = 0.042), and significant increase of endothelial-MP (CD62E-

MP/�L: 1391 (651–2301) vs 582 (380–1161), p = 0.046), indicative

of higher endothelial-damage compared to controls. Similar results

were obtained comparing portal-blood of cirrhotics and controls

(ETP with/without TM 0.89 (0.78–0.92) vs 0.63 (0.33–0.75),

p = 0.001; MCF-NATEM mm: 46 (39–51) vs 62 (49–66), p = 0.056;

CD62E-MP/�L: 1606.5 (680–1885) vs 529.5 (266–781), p = 0.069).

There was a significant correlation between diminished levels of

PC, PS, AT-III, FII and either TGT or ROTEM parameters. Comparing

portal and peripheral blood of cirrhotics, we detected endogenous

heparinoids in portal blood (ɑ-angle NATEM 51◦ (46–57) vs HEP-

TEM 57◦ (50–59), p = 0.05). This finding, together with a decreased

concentration of endothelial-MP carrying TM (TM-MP/�L:

232 (190–287) vs 377 (218–493), p = 0.002) and endothelial-PC

receptor (EPCR/CD65E-MP/�L: 16 (14–25) vs 37 (24–70), p < 0.001),

demonstrated a local greater endothelial damage in cirrhotics.

Conclusion: In cirrhotics, venous hypercoagulability and por-

tal site-specific endothelial damage, associated with hampered

antithrombotic properties, may be important local risk-factors in

the pathogenesis of PVT along with the documented venous stasis.


OC-31

In experimental ascitic cirrhosis reduction ofadrenergic function by means of �2Aadrenergic receptor agonists has considerableaquaretic effects

G. Sansoè 1, M. Aragno 2, R. Mastrocola 2,

M. Ayoubi 1, M. Parola 2

1 Division of Gastroenterology, Humanitas Gradenigo

Hospital, Torino, Italy2 Department of Clinical and Biological Sciences,

University of Torino, Italy

Introduction: Catecholamines trigger proximal tubular fluid

retention and decrease Na+ and water delivery to the diluting

segment of the Henle’s loop, thereby reducing renal excretion

of solute-free water. In advanced cirrhosis, non-osmotic hyper-

secretion of vasopressin (ADH) has a role in causing dilutional

hyponatremia, but the advantage of ADH V2 receptor antagonists

is somewhat controversial in the treatment of ascites.

Aims: By means of the use of sympatholytic agents (�2A adren-

ergic receptor agonists), we assessed the hypothesis that adrenergic

hyperfunction might contribute to water retention in experimental

ascitic cirrhosis.

Methods: Hormonal status, renal function ad tubular free-water

reabsorption (TFWR) were evaluated in six groups of rats with

ascitic cirrhosis: rats with cirrhosis due to 13 weeks of CCl4 (group

G1); cirrhotic rats receiving, from 11th to 13th CCl4 week, daily

diuretics alone (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate)

(G2), or diuretics plus guanfacine oral prodrug (�2A adrener-

gic receptor agonist and sympatholytic agent) 2 (G3), 7 (G4), or

10 mg/kg (G5). Group G6 received diuretics plus SSP-004240F1 (V2

receptor antagonist) 1 mg/kg.

Results: Compared to G2, low-dose guanfacine plus diuret-

ics (G3) reduced serum norepinephrine from 423 ± 22 to

211 ± 41 ng/mL and plasma renin activity from 35 ± 8 to

9 ± 2 ng/mL/h (all P < 0.03). Compared to G1 and G2, TFWR was

significantly reduced, and to the same extent, with low-dose guan-

facine plus diuretics (G3) and with V2 antagonist plus diuretics (G6)

(all P < 0.03). TFWR correlated with plasma aldosterone (r = 0.51,

P < 0.01) and urinary potassium excretion (r = 0.90, P < 0.001).

Conclusions: In ascitic cirrhosis, reduced volaemia and adren-

ergic hyperfunction, especially when exacerbated by potassium-

depleting diuretics (furosemide), contribute to tubular retention of

water and dilutional hyponatremia. In this case, suitable doses of

sympatholytic agents are as effective as V2 antagonists when the

aquaretic effect is needed.



OC-32

Extracellular vesicles induce renal tubular cellsapoptosis, oxidative stress and functionalabnormalities in patients with an acutedecompensation of cirrhosis

A. Brocca 1, D. Medica 2, S. Piano 1, A. Romano 1,

A. Sticca 1, V. Cantaluppi 3, P. Angeli 1

1 Unit of Internal Medicine and Hepatology,

Department of Medicine – DIMED, University of

Padua, Padua, Italy2 Department of Medical Sciences, University of

Torino, Azienda Ospedaliera “Città della Salute e

della Scienza-Molinette”, Torino, Italy3 Nephrology and Kidney Transplant Unit,

Department of Translational Medicine, University of

Eastern Piedmont, Novara, Italy

Introduction: Extracellular vesicles (EVs) are involved in bio-

logical processes as well as in disease pathogenesis. The origin and

the role of EVs in the pathogenesis of liver disease is poorly recog-

nized. The aims of this study were to: (a) characterize plasma EVs

isolated from patients with compensated cirrhosis (CC), AD, ACLF

and healthy subjects (CTRL), (b) study the in vitro effects of EVs on

renal tubular cells (RTCs).

Methods: 12 CC, 13 AD, 11 ACLF patients and 12 CTRL were

enrolled. Plasma EVs were characterized by Nanosight analysis.

Detection of EVs surface proteins, ROS productions in RTCs, pro-

tein expression in RTCs was performed by FACS analysis. Cytotoxic

effects of plasma EVs on RTCs were assayed.

Results: Plasma EVs isolated from ACLF patients were more

concentrated and bigger compared to CTRL (p = 0.002). Plasma

EVs were mainly derived from platelets activated endothelium, as

shown by the expression of CD62E. CD62E levels were significantly

higher in ACLF patients compare to CC patients and CTRL (p = 0.011

and p = 0.004, respectively). Platelet derived and monocytes derived

EVs, as assessed by CD41, CD42b and CD14, were not found. CD40L

levels, a receptor involved in lymphocytes T activation, were sig-

nificantly higher in CC, AD and ACLF groups than in CTRL (p < 0.02).

Plasma EVs from patients with AD and ACLF exerted a higher cyto-

toxic effects than EVs from CTRL and CC patients on RTCs (p < 0.001).

Cells incubated with EVs from AD and ACLF patients showed an

increase in apoptosis (p < 0.001) and ROS production (p < 0.001),

loss of albumin intake capabilities (p < 0.001) and reduction of ZO-1

expression (p = 0.017) compared to CTRL and CC patients.

Conclusions: EVs derived from activated endothelium may

exerts an important role in the pathogenesis of acute kidney injury

in patients with AD of cirrhosis and ACLF.


OC-33

Non-invasive tools to ruling out large varices:RESIST-HCV vs Baveno VI criteria in a largecohort of patients with HCV cirrhosis

V. Calvaruso, I. Cacciola, A. Licata, S. Madonia,

R. Benigno, F. Bronte, S. Petta, G. Malizia,

G. Bertino, M. Distefano, R. Volpes, A. Montineri,

A. Digiacomo, G. Alaimo, B. Cacopardo, A. Davì,

L. Guarneri, I. Scalisi, G. Mazzola, F. Cartabellotta,

V. Portelli, M. Russello, G. Squadrito,

G. Raimondo, A. Craxì, C. Cammà, V. Di Marco, On

behalf of RESIST-HCV (Rete Sicilia Selezione

Terapia-HCV)

RESIST-HCV (Rete Sicilia Selezione Terapia-HCV),

Italy

Background: Patients with cirrhosis should undergo to endo-

scopic variceal screening to identify large esophageal varices

(LEV-F2/F3) requiring primary prophylaxis. Recently, Baveno

VI consensus suggested criteria to avoid esophagogastroduo-

denoscopy (EGD) in patients with liver stiffness by Transient

elastography (TE) 150,000/mm3.

Aims: To validate the performance of Baveno VI criteria and to

assess the ability of RESIST-HCV (REte SIcilia Selezione Terapia-

HCV) criteria in predicting LEV in patients with HCV cirrhosis

included in a single-centre cohort (Palermo – training cohort) and

from the other 21 centres of the RESIST-HCV (validation cohort).

Methods: We evaluated 1381 patients with HCV cirrhosis who

had endoscopy within 1 year of TE. By multivariate logistic analy-

sis we selected laboratory variables independently associated with

LEV to create RESIST-HCV criteria.

Results: PLT and Albumin were independently related with LEV.

Best-cut off values were >120000 mmc (sensitivity: 87.4%, negative

predictive value (NPV) 97.2%) for PLT and >3.6 g/dl (sensitivity: 65%,

NPV: 94.7%) for albumin and together define RESIST-HCV criteria.

Patients of the training cohort were 326 (100% of EGD according

to guidelines), only 53 (16.2%) met Baveno VI criteria and among

them 1 patient had LEV. Thus Baveno VI allow to reduce the rate

of EGD to 83.8% (273 patients) with a false negative rate (FNR) of

1.9% (NPV: 98.1%). 119 patients (36.5%) met RESIST-HCV criteria

and among them 1 patients had LEV (FNR: 0.8%, NPV: 99.2%) allow-

ing a reduction of EDS to 63.5% (207 patients). In the validation

cohort (1055 patients), 169 (16%) and 315 (29.9%) met BAVENO VI

and RESIST HCV criteria respectively and among them 5 (FNR: 3.0%,

NPV: 97.0%) and 6 (FNR: 1.9%, NPV: 98.1%) had LEV. According to

BAVENO VI and RESIST-HCV criteria the rates of EDS to perform are

84% and 70.1% respectively.

Conclusions: RESIST-HCV criteria include only routine labora-

tory data and allow to avoid endoscopies in more of 30% of patients

in comparison of 16% of saved EDS by Baveno VI criteria, further

improving the negative predictive value.



OC-34

Assessment of Sepsis-3 criteria in patients withcirrhosis and bacterial infections

S. Piano, G. Chies, M. Tonon, A. Romano,

E. Vettore, M. Stanco, C. Pilutti, A. Brocca,

S. Fasolato, P. Angeli

Unit of Internal Medicine and Hepatology,

Department of Medicine – DIMED, University of

Padua, Padua, Italy

Introduction: Patients with cirrhosis have a high risk of sepsis,

which confers a poor prognosis. SIRS criteria has several limitations

in cirrhosis. Recently, new criteria for sepsis have been suggested

in general population. Sepsis was defined an increase of Sequen-

tial Organ Failure Assessment(SOFA) ≥2 points from baseline in

patients with infections (Sepsis-3). Outside the ICU, the Qsofa (at

least 2 among: alteration in mental status, systolic blood pres-

sure ≤100 mmHg, or respiratory rate ≥22/min) was suggested to

screen sepsis. These criteria have never been evaluated in cirrhotic

patients. The aim of our study was to assess the ability of sepsis-3

criteria in predicting in hospital mortality in patients with cirrhosis

and bacterial infections.

Methods: From 2012 to 2016 consecutive patients with cirrho-

sis and bacterial infections were included. Demographic, laboratory

and microbiological data were collected at diagnosis of infection.

Preadmission SOFA was assessed using preadmission data as pro-

vided for acute kidney injury criteria. Patients were followed-up

until death, liver transplantation or discharge.

Results: 259 patients were included (Age = 61 ± 12 years, MELD-

score = 20 ± 7). The most common infections were urinary tract

infection (33%), SBP (23%) and pneumonia (14%). SIRS, qSOFA

and Sepsis-3 criteria were found in 34, 23 and 76% of patients,

respectively. During the hospitalization 19% of patients died. In

multivariate analysis CLIF-AD score (OR = 1.06; p < 0.01), C-reactive

protein (OR = 1.64; p = 0.01), qSOFA (OR = 3.37; p < 0.01), Sepsis-3

criteria (OR = 5.81; p = 0.02) and nosocomial infections (OR = 2.16;

p = 0.05), but not SIRS, were found to be independent predictors of

mortality. Patients with Sepsis-3 criteria had a higher incidence of

onset of acute-on-chronic liver failure (50 vs 19%; p < 0.01), were

more likely to be transferred in ICU (14 vs 2%; p = 0.01) and to die

(22 vs 3%; p < 0.01) during the hospitalization than those without

Sepsis-3 criteria. Similar findings were found for qSOFA.

Conclusions: Sepsis-3 criteria are accurate in predicting the

severity of bacterial infections in patients with cirrhosis. qSOFA

is a useful bedside tool to assess risk for worse outcomes in these

patients. Patients with Sepsis-3 criteria and positive qSOFA deserve

more intensive management and a strict surveillance.








Selected Posters Thursday

T-01

Ang-2 polymorphisms in relation to outcome inadvanced HCC patients receiving sorafenib

G. Marisi 1, M. Scartozzi 2, L. Faloppi 2,

M. Iavarone 3, F.G. Foschi 4, G. Lauletta 5,

M. Valgiusti 6, S. Cascinu 7, G.L. Frassineti 1,

G. Ercolani 7,8, A. Dino 6, A. Casadei Gardini 6

1 Biosciences Laboratory, Istituto Scientifico

Romagnolo per lo Studio e la Cura dei Tumori (IRST)

IRCCS, Meldola, Italy2 University of Cagliari, Cagliari, Italy3 A.M.&A. Migliavacca Center for Liver Disease, 1st

Division of Gastroenterology, Fondazione IRCCS Ca’

Granda Maggiore Hospital, University of Milan,

Milan, Italy4 DPT Internal Medicine, Faenza Hospital, AUSL

Romagna, Faenza, Italy5 Department of Biomedical Sciences and Human

Oncology, Internal Medicine “G. Baccelli”, University

of Bari “A. Moro”, Bari, Italy6 Department of Medical Oncology, Istituto

Scientifico Romagnolo per lo Studio e la Cura dei

Tumori (IRST) IRCCS, Meldola, Italy7 University of Modena, Italy8 Department of General Surgery,

Morgagni-Pierantoni Hospiatal, AUSL Romagna,

Forli, Italy

Background: Sorafenib represents the standard care for

advanced hepatocellular carcinoma. Angiopoietin-2 (Ang-2) is a

crucial angiogenic factor. By binding to its receptor Tie2, Ang-2

cooperates with the VEGF pathway to maintain normal physi-

ological functions. In the presence of VEGF, Ang-2 destabilizes

blood vessels and promotes vascular sprouting. In cancers, Ang-2

is linked to not only angiogenesis but also invasive and metastatic

phenotypes. Although sorafenib exerts no significant activity

against Tie2, the predictive value of Ang-2 has been explored in 2

studies. Llovet et al conducted a large biomarker study based on

SHARP study. The authors found that a high baseline plasma Ang-2

level was an independent factor for poorer OS but not for reduced

sorafenib efficacy. Conversely, in a small retrospective study, a high

serum Ang-2 level was associated with a lower DCR and poorer

PFS. The actual role of Ang-2 in predicting sorafenib efficacy war-

rants further investigations. Polymorphism analysis seems to have

more advantages than protein or gene expression analysis. Gene

expression analysis is performed on biological material collected at

a specific time in the natural history of the disease. It is also subject

to the influence of a number of laboratory biases. In our study we

analysed the role of ANG-2 polymorphisms in relation to clinical

outcome in patients with hepatocellular carcinoma treated with

sorafenib.

Methods: We analyzed 135 patients with hepatocellular car-

cinoma treated with sorafenib. Peripheral blood samples were

available for DNA extraction and genotyping analysis. Nine Ang-

2 polymorphisms were analyzed by direct sequencing or Real Time

PCR method. With regard to Ang4rs55633437 was observed that

patients carrying the allele GG were associated with a better PFS

and OS. The variants GG were associated with a median OS of 16.9

months vs 6.5 months of variants GT and TT (p = 0.016). The vari-

ants GT and TT were associated with a median PFS of 2.94 months

vs 4.67 months of variants GG (p = 0.03). These data were confirmed

by multivariate analysis.

Conclusions: Ang4rs55633437 could represent prognostic

markers in patients with advanced hepatocellular carcinoma

treated with sorafenib.


1590-8658/


T-02

Impact of multidisciplinary team approach toliver tumors: 5-Years experience

S. Okolicsanyi 1,2, V. Pontecorvi 1, G. Bonato 1,

A. Ciaccio 1,2, R. Perego 3, F. Romano 1,2,

F. Uggeri 1, D. Leni 3, F. Vacirca 3, A. Gambini 3,

A. Mariani 3, M. Ratti 3, M. Acquati 4, N. Zucchini 5,

G. Bovo 5, R. Corso 3, M. Strazzabosco 1,2,6

1 Department of Surgery and Translational Medicine,

University of Milano-Bicocca, Milan, Italy2 International Centre for Digestive Health,

University of Milan-Bicocca, Milan, Italy3 Department of Radiology, San Gerardo Hospital,

Monza, Italy4 Oncology Unit, San Gerardo Hospital, Monza, Italy5 Department of Pathology, San Gerardo Hospital,

Monza, Italy6 Liver Center & Section of Digestive Diseases,

Department of Internal Medicine, Yale University

School of Medicine, New Haven, CT, USA

Background: Multidisciplinary team (MDT) approach is a major

requirement to guarantee a fair access to treatment to heteroge-

neous patients with liver neoplasms and to improve the quality

of care provided. This work retrospectively analyzes the impact of

MDT experience at our tertiary center.

Methods: Between 2011 and 2016, 490 consecutive patients

with a liver mass were discussed at standardized meetings involv-

ing hepatologists, radiologists, surgeons, pathologists, oncologists.

Patients with HCC were assigned a BCLC stage, treated accordingly

BCLC recommendation whenever possible and followed-up as per

AASLD/EASL guidelines (median f-up: 26 months).

Results: Out of 490 patients, 70% had a HCC diagnosis, 5% cholan-

giocarcinoma or metastasis and 25% benign liver nodules. Among

341 HCC patients, 55% were BCLC 0/A, 29% BCLC B and 15% BCLC

C. Of them, 80% received treatment after the first MDT discus-

sion. Patients with BCLC B stage had significantly more treatments

(2.5 ± 0.9 treatments per patient), compared to BCLC 0/A (1.3 ± 0.1)

and to BCLC C (1.2 ± 0.5, both p < 0.05). First-line BCLC recommen-

dations for therapy were followed in 67%, 59%, 32% of cases for

BCLC 0/A, B, C respectively. In 274 HCC patients managed until

February 2015 (median f-up: 30 months), median survival from

first MDT discussion was 37 months. Main predictors of outcomes

were BCLC stage (5-years survival in BCLC 0/A 54%, B 21%, C 23%,

p < 0.0001), CHILD score (5-years survival CHILD A 42%, B 20%, C 0%,

p < 0.0001) and first treatment applied (survival at 5 years from

OLT 90%, resection 49%, ablation 40%, TACE 28%, sorafenib 15%,

p < 0.0001)

Conclusions: A MDT approach to HCC patients allowed a ratio-

nal revision of treatments suggested by BCLC recommendations in

30% to 70% of cases; this discrepancy did not affect survival out-

comes, indicating that the difficulties related to the applicability of

the current guidelines in the clinical practice could be overcome by

a MDT approach.


T-03

In experimental liver cirrhosis impairedsecretion of renalase into blood may lead toorgan damage and sympathetic overactivity






Introduction: Sympathetic overactivity and generation of per-

oxidant molecules are crucial in liver fibrogenesis and functional

renal failure of advanced cirrhosis. Renalase (REN), 38 kDa amine

oxidase with just 13% aminoacid identity with monoamine oxidase

A, is secreted into the blood and clears plasma from excess cat-

echolamines. Isomers of �-NAD(P)H are also substrates for tissue

REN, a reaction leading to H2O2 and �-NAD(P)+ production in liver

and kidney.

Aims: To study plasma and tissue content and function of REN

in experimental preascitic and ascitic cirrhosis.

Methods: In normal rats (group G1), rats with CCl4-dependent

liver cirrhosis without ascites (G2) and with ascites (G3) we eval-

uated: REN levels and activity in plasma, liver and kidney; REN

gene transcription and immunohistochemical localization in both

organs; liver histology and matrix deposition, hormonal status and

kidney function.

Results: In plasma, mature (38 kDa) REN and REN activity, well

detected in normal rats, were virtually absent in rats with com-

pensated or ascitic cirrhosis (P < 0.01 vs. G1). In G2 and G3 rats, but

not in G1, we found large amount of enzymatically active high-

molecular weight (78 kDa) REN and very little 38 kDa protein in

hepatocytes of regenerative nodules of the cirrhotic liver and in

kidney tubules. RT-PCR confirmed higher levels of REN gene tran-

scription in both liver and kidney of G2-3 (P < 0.03 vs. G1). Rats with

preascitic liver damage showed increased plasma catecholamines,

normal renin-angiotensin system activation and subtle sodium

retention, while ascitic rats had both secondary aldosteronism and

increased adrenergic activation.

Conclusions: Active 78 kDa REN accumulates in diseased liver

and kidney and generates H2O2 and other pro-oxidant molecules,

but release of mature (38 kDa) REN into the circulation is almost

absent, leading to increased levels of catecholamines and early

sodium retention in preascites.


T-04

A novel role for heparanase in the onset of liverfibrosis

M.F. Secchi 1, M. Crescenzi 2, F.P. Russo 2,

M. Onisto 1, A. Floreani 2

1 Department of Biomedical Science, University of

Padua, Padua, Italy2 Department of Surgery, Oncology and

Gastroenterology, University of Padua, Padua, Italy

Introduction: Activation of both Kupffer cells and hepatic stel-

late cells (HSCs) plays a fundamental role in fibrosis process.

Heparanase (HPSE) is the only mammalian endoglucuronidase

capable of cleaving heparan sulfate (HS) chains of HS proteogly-

cans. The involvement of HPSE in chronic liver disease has not been

demonstrated so far.


Aims: (a) To investigate the HPSE expression in chronic liver

injury and (b) to study its effects on the fibrosis process.

Materials and methods: 1. Experimental design: CCl4 model

for fibrosis was utilized in 20 BALB/cJ mice. 2. In vitro studies: HPSE

expression was assayed on macrophages (U937 cell line) by real

time RT-PCR and western blot analyses. Furthermore, we evaluated

the HPSE activation of HSCs (LX-2 cell line). Finally, the migration

of macrophages (RAW 264.7 cell line) was assayed by treatment

with HPSE.

Results: HPSE expression in liver tissue of CCl4-treated mice

increased after 1 and 2 weeks of treatment but not after 8 and 12

weeks. Immunostaining analyses revealed that HPSE was restricted

in the centrilobular areas with both necro-inflammatory damage

and fibrosis, and co-localized with macrophage markers F4/80

and CD68. TNF-� treatment of U937 macrophages significantly

increased HPSE mRNA and protein expression, as well as HPSE

secretion. Using the conditioned medium of TNF-�-pre-treated

U937, we found that macrophage-secreted HPSE regulated the

expression of both �-SMA and fibronectin in LX-2 cells. Finally,

macrophages with latent HPSE significantly increased the cell

migration rate.

Conclusions: Overall, HPSE is involved in early stages of fibrosis

process. Inflammatory macrophages could be an important source

of HPSE. In this context, HPSE may play a role in the macrophage-

mediated activation of HSCs and in migration of macrophages

themselves.


T-05

Local renin–angiotensin system in the kidney ofascitic cirrhosis: An innocent bystander or amajor protagonist?






Introduction: In liver cirrhosis, kidney local renin–angiotensin

system (RAS) deserves scrutiny and includes: conversion of

angiotensin I into angiotensin II (Ang-II) by ACE and chymase;

binding of renin and prorenin to their tissue receptor (RPRr),

and hence local generation of angiotensin I and Ang-II; conver-

sion of Ang-II by ACE2 into angiotensin1-7; degradation of the

latter to angiotensin1-4 by neprilysin. Changes in expression of

these enzymes and receptors affect renal levels of sodium-retentive

(Ang-II) and natriuretic (angiotensin1-7) peptides.

Aims: To assess, in ascitic rats’ kidney, expression and

immunolocation of major components of RAS and their hormonal

consequences.

Methods: Healthy rats (group G1) and rats with ascitic cirrho-

sis due to CCl4 (G2) were studied. Kidney content of ACE, chymase,

RPRr, ACE2, neprilysin, Ang-II, angiotensin1-7 and plasma levels of

Ang-II, direct renin (DR), plasma renin activity (PRA) were mea-

sured. DR is quantified through monoclonal antibodies that bind

both active renin and prorenin, and therefore plasma concentra-

tions of prorenin can be derived from the ratio DR/PRA.

Results: DR/PRA ratios were 3.3 ± 0.8 and 7.9 ± 1.6 in healthy

and ascitic rats, respectively (P < 0.03), showing more prorenin in

ascitic rats. In G2, Ang-II was higher than normal in plasma (P < 0.01)

but especially in renal tissue (1150 ± 199 vs. 78 ± 22 pg/mg kid-

ney protein, P < 0.001). Kidney content of ACE, chymase, ACE2 and

neprilysin was significantly higher, but RPRrs significantly lower,

in ascitic than in healthy rats. The ratio Ang-II/Angiotensin1-7 in

kidneys rose from 1.3 ± 0.2 in G1 to 5.3 ± 0.4 in G2 (P < 0.03).

Conclusions: In ascitic cirrhosis: (a) the contribution of ACE

and chymase to renal Ang-II synthesis seems stronger than that

of RPRrs, despite increased plasma prorenin; (b) the kidney shows

an imbalance in favour of the production of anti-natriuretic Ang-II

because overexpressed neprilysin finally degrades ACE2-generated

angiotensin1-7.


T-06

Durable response in the markers of cholestasisthrough 24 months of open-label extensionwith obeticholic acid in Italian patients withprimary biliary cholangitis

P. Andreone 1, A. Floreani 2, P. Invernizzi 3,

G. Mazzella 1, J. Owens-Grillo 4,

E. Smoot Malecha 4, L. MacConell 4

1 Dipartimento di Scienze Mediche e Chirurgiche,

Universtiy of Bologna, Bologna, Italy2 Department of Surgery, Oncology and

Gastroenterology, University of Padova, Padova, Italy3 Program for Autoimmune Liver Disease,

International Center for Digestive Health,

Department of Medicine and Surgery, University of

Milan-Bicocca, Milan, Italy4 Intercept Pharmaceuticals, Inc., San Diego, CA,

United States

Introduction and aim: Obeticholic acid (OCA) is a potent and

selective farnesoid X receptor (FXR) agonist under investigation

for the treatment of primary biliary cholangitis (PBC). This anal-

ysis evaluated the long-term efficacy and safety of OCA in Italian

patients with PBC.

Material and methods: POISE was a Phase 3, 12-month,

double-blind, placebo-controlled study followed by an ongoing

open-label extension (OLE). Patients with an alkaline phosphatase

(ALP) >1.67× ULN and/or bilirubin >ULN to <2× ULN, on a stable

ursodeoxycholic acid (UDCA) dose or unable to tolerate UDCA, were

randomized to daily Placebo, OCA 5–10 mg, or OCA 10 mg.

Results: Thirty-two of 216 patients were treated at Italian

sites (Placebo, n = 11; OCA 5–10 mg, n = 11; OCA 10 mg, n = 10).

In Italian patients, both OCA groups demonstrated significant

reductions in ALP (U/L) after 12 months of double-blind treat-

ment (Placebo: 43 ± 108; OCA 5–10 mg: −114 ± 86, p < 0.01; OCA

10 mg: −132 ± 104, p < 0.01). This response was durable through

an additional 24 months of treatment during the OLE (Placebo:

−105 ± 86, p < 0.05; OCA 5–10 mg: −140 ± 78, p < 0.01; OCA 10 mg:

−122 ± 110, p < 0.05). After 12 months of double-blind treatment,

total bilirubin (�mol/L) increased in the Placebo group (2.1 ± 2.5),

but remained stable in OCA 5–10 mg and OCA 10 mg groups

(−0.6 ± 3.5, p < 0.05 and −1.1 ± 1.9, p < 0.05). The change from Base-

line in total bilirubin at month 24 of the OLE remained relatively

stable (Placebo: 1.1 ± 5.4; OCA 5-10 mg: −0.3 ± 4.5; OCA 10 mg:

0.4 ± 5.7). Five (45%) of the Placebo patients in the double-blind

phase and 8 (80%) of the Placebo patients initiating OCA in the OLE

experienced pruritus.

Conclusions: OCA given to Italian patients resulted in signifi-

cant improvements in markers of cholestasis and hepatic damage.

A durable response was evident throughout the OLE demonstrating

the safety and efficacy of long-term OCA treatment.



T-07

Impairment of coronary microvascular functionin patients with Primary Biliary Cholangitis

N. Cazzagon 1, C. Dal Lin 2, I. Franceschet 1,

L. Perini 1, G. Famoso 2, F. Tona 2, A. Floreani 1


Gastroenterology, University of Padova, Italy2 Department of Cardiac, Thoracic and Vascular

Sciences, University of Padova, Italy

Background: Primary biliary cholangitis (PBC) is characterized

by a long natural history and a low incidence of cardiovascu-

lar events despite high serum cholesterol levels. Coronary flow

reserve (CFR) is widely used to examine the integrity of coronary

microvascular circulation and it is well recognized as a predictor of

cardiovascular outcome.

Aim: To evaluate the risk of coronary microvascular dysfunction

in patients with PBC without metabolic syndrome.

Methods: 37 PBC patients (4 males and 33 females, aged 57 ± 12

years) without clinical evidence of heart disease and without

metabolic syndrome, and 37 sex- and age-matched healthy con-

trols underwent CFR by transthoracic Doppler echocardiography

(TDE). Coronary flow velocity in the left anterior descending coro-

nary artery was detected by TDE at rest and during iv. adenosine

infusion. CFR was calculated as the ratio of hyperemic diastolic

flow velocity (DFVh) to resting DFVr. Correction of DFV and CFR

for cardiac workload was also performed.

Results: The mean time between the onset of symptoms and

CFR assessment was 10 ± 5 yrs. In PBC patients CFR and corrected

CFR (cCFR) were significantly lower than in controls (3.1 ± 0.4

vs 3.7 ± 0.7, and 2.8 ± 0.7 vs 3.7 ± 0.7 respectively, p < 0.0001).

Stratifying PBC population according to a cCFR value of 2.5, 26

patients (70%) showed a cCFR >2.5 (PBC1) and 11 patients (30%)

a cCFR < 2.5 (PBC2). Corrected DFVr resulted significantly higher

in PBC2 patients, indicating the presence of a higher flow velocity

at basal condition, otherwise the other hemodynamic parameters

were significantly higher in PBC1 patients; cCFR resulted not cor-

related to any of the characteristics of liver diseases, comorbidities

(both autoimmune and cardiovascular) and Framingham risk score.

Conclusions: PBC patient had an impairment of coronary

microvascular function correlated to an increased diastolic flow

velocity at rest, suggesting a possible impairment of bioenergetics

of cardiomyocytes.


T-08

CEUS LI-RADS are effective in predicting the riskhepatocellular carcinoma of liver nodules

E. Terzi, L. De Bonis, S. Leoni, F. Benevento,

A. Granito, F. Tovoli, P. Pini, L. Bolondi, F. Piscaglia

Division of Internal Medicine, Department of

Digestive Disease and Internal Medicine,

Sant’Orsola-Malpighi Hospital, University of

Bologna, Bologna, Italy

Introduction: American College of Radiology (ACR) – Liver

Imaging Reporting and Data System (LI-RADS) for CEUS is an algo-

rithm that, on the basis of CEUS patterns, categorizes patients

in different classes of risk of HCC (HepatoCellular Carcinoma),

and accounts for the characteristics differentiating HCC from CC

(CholangioCarcinoma) based on timing and intensity of contrast

changes.

Aim: Validate CEUS LI-RADS to stratify patients with different

risk of HCC focusing on LR-3 (intermediate probability for HCC),

LR-4 (high probability HCC) and LR-5 (definitely HCC) and LR-M

(probable malignancy not specific for HCC), to test the rate of HCC

in each class.

Methods: We retrospectively evaluated CEUS pattern of 146

patients with a total of 350 nodules (2005–2015) for all of whom the

diagnostic reference standard had been performed Results. A total

350 consecutive nodules were investigated. CC were 2.2%. The risk

of having HCC increases from LR-3 to LR-5. In particular, 45/75 LR-3

nodules (60%) were HCC, 90/102 (88%) LR-4 were HCC and 150/152

LR-5 (99%) were HCC (n = 149) or mixed HCC-CC (n = 1) (p < 0.001).

LR-M were 15 (4.3%) of which 6 HCC, 2 mixed HCC-CC, 7 CC.

Conclusions: CEUS LI-RADS classes are effective in predicting

the risk of HCC, with LR-5 class definitely diagnostic for HCC at

practically no risk of misdiagnosis for CC. The present algorithm

may be useful for restoring CEUS for the diagnosis of HCC and for

guiding the diagnostic approach of “atypical” nodules, all of which

remain at relatively significant risk of HCC (>50% if LR-3 or LR-4).


T-09

Platelet count, spleen length and plateletcount/spleen length ratio for the diagnosis ofoesophageal varices in patients with hepaticcirrhosis. A systematic review andmeta-analysis

A. Colli 1, M. Fraquelli 2, D. Prati 3, D. Conte 2,

G. Casazza 4

1 Department of Internal Medicine, Ospedale A.

Manzoni, Lecco, Italy2 Gastroenterology and Endoscopy Unit, Fondazione

Ca’ Granda, Ospedale Maggiore Policlinico, Milano,

Italy3 Department of Transfusion Medicine and

Hematology, Ospedale A. Manzoni, Lecco, Italy4 Department of Biomedical and Clinical Sciences,

Ospedale Luigi Sacco, Università degli Studi di

Milano, Italy

Background: Current guidelines recommend endoscopy in cir-

rhotic patients at diagnosis to screen for esophageal varices (EV)

despite half patients having no identifiable EV. We aimed to

assess the diagnostic accuracy of platelet count, spleen length, and

platelet/spleen length ratio (Plt/s) as alternative noninvasive tests

for the diagnosis of EV.

Methods: We searched and included studies assessing the diag-

nostic accuracy of platelet count, spleen length, and Plt/s for the

diagnosis of EV using upper endoscopy as the reference- standard

in patients with cirrhosis. We followed the available guidelines

provided in the Cochrane Handbook for Diagnostic Test of Accu-

racy Reviews for search, data collection and analysis. No language

restrictions were applied.

Results: We included 67 studies performed in a secondary-

tertiary care-setting. Only one was at low risk of bias, as most of

them derived a posteriori the best cut-off values overestimating

accuracy.

EV of any size: indirect comparison of the three index tests,

showed that Plt/s is the most accurate. In the 17 studies with 2637

participants, using the predefined cut-off value of 909, sensitivity

was 0.93 (95% CI 0.83 to 0.97), specificity 0.84 (95% CI 0.75 to 0.91).

EV at high risk of bleeding: Plt/s was the most accurate index test

and with 909 as cut-off value (7 studies 642 participants) showed a


sensitivity of 0.85 (95% CI 0.72 to 0.93), and specificity of 0.66 (95%

CI 0.52 to 0.77).

Conclusions: A simple test such as cPlt/s could be used to stratify

the risk of having EV. Using 909 as cut off value, the presence of any

size EV can be excluded halving the number of useless endoscopic

procedures. However, this test is not accurate enough to replace

endoscopy for the identification of EV at high risk of bleeding that

require primary prophylaxis.


T-10

Clinical presentation and outcomes ofhepatocellular carcinoma in elderly patientsreferred to a tertiary center: 5-Years experience

S. Okolicsanyi 1,2, G. Bonato 1, V. Pontecorvi 1,

A. Ciaccio 1, M. Gemma 1, M. Strazzabosco 1,2,3

1 Department of Medicine and Surgery, University of

Milano-Bicocca, Milan, Italy2 International Center for Digestive Health,

University of Milano-Bicocca, Milan, Italy3 Liver Center & Section of Digestive Diseases,

Department of Internal Medicine, Yale University

School of Medicine, New Haven, CT, USA

Background: An emerging cohort of elderly patients with

hepatocellular carcinoma (HCC) shows age-significant morbidities

without receiving optimal therapy for malignancies, mainly due to

reduced life expectancy and the current lack of strategies according

to age. This study retrospectively analyzes age-specific disparities

in patients with HCC managed in our tertiary center between 2010

and 2015 according to Barcelona Clinic Liver Cancer (BCLC) recom-

mendation and individual case discussion by a multidisciplinary

team (median f-up: 25 months).

Methods: A total of 239 consecutive patients with first diagnosis

of HCC was divided in group A below 70 years old (n = 89), group B

between 70 and 79 years (n = 100), group C above 80 years (n = 50).

Gender, etiology, Child-Pugh (CP), BCLC score and alpha fetoprotein

(AFP) level at diagnosis, type of first treatment, time to recurrence

after therapy were compared using Cochran-Mantel-Haenszel test

for ordinal variable among the 3 groups. Overall and disease specific

survival were calculated with Kaplan–Meier estimator.

Results: Patients older than 70 years were significantly more

female (34–48% in B-C vs 5.6% in A, p < 0.0001), and had more fre-

quent viral etiology (68–76% in B-C vs 59% in A, p < 0.05). Main

characteristics at diagnosis were CP score A (75%), BCLC 0/A (64%)

and AFP <20 U/L (62%), without significant difference in 3 groups.

A lower percentage of older patients received treatment (58% vs

85–83% in group A-B, p < 0.05), and this was mostly chemoem-

bolization (45%), with significant less patients undergoing surgery

(14% vs 40% in A, 34% in B, p < 0.05) and no difference in time to

recurrence, overall and disease specific survival (median 38 ± 16

months).

Conclusions: Male gender lost its predominance and viral eti-

ology was significantly increased with aging. The multidisciplinary

team approach allowed to evaluate and treat with loco-regional

therapies elderly patients, with survival outcomes not different

respect to younger patients, permitting to move the boundary of

treatment over 80 years.


T-11

Ruling-in and ruling-out significant fibrosis andcirrhosis using a shear wave measurementmethod

G. Ferraioli 1, L. Maiocchi 1, R. Lissandrin 1,

C. Tinelli 2, A. De Silvestri 2, C. Filice 1

1 Infectious Diseases Department, Fondazione IRCCS

Policlinico S. Matteo, Medical School University of

Pavia, Pavia, Italy2 Clinical Epidemiology and Biometric Unit,

Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

Aims: This study aimed at prospectively assessing the cutoff

values of a point shear wave measurement (SWM) method for

ruling-in and ruling-out significant fibrosis and cirrhosis using tran-

sient elastography (TE) as the reference standard.

Materials and methods: Consecutive patients with chronic viral

hepatitis were enrolled. Liver stiffness was assessed with the SWM

method of the HI VISION Ascendus ultrasound system (Hitachi Ltd,

Japan) and with the TE method of the FibroScan®

device (Echosens,

France). For staging significant fibrosis (F ≥ 2), and cirrhosis (F = 4)

we used the TE cutoffs of 7.0 and 12.0 kiloPascal (kPa), respectively.

The diagnostic performance of the SWM method was assessed by

calculating the area under the receiver operating characteristic

(AUC) curve. To rule-in or rule-out F ≥ 2 and F = 4 the cutoffs with

specificity or sensitivity >90% were chosen.

Results: 411 individuals [218 males, 193 females; mean age,

61.2 (13.2) years] were studied. 382 (92.9%) of them were affected

by chronic hepatitis C. 179 (43.5%) individuals were in F0-F1 stage,

75 (18.2%) in F2, 41(10.0%) in F3, and 116 (28.2%) in F4.

For ruling-in F ≥ 2 the SWM cutoff was 6.95 kPa [sensitivity,

76.3% (69.7–82.0); specificity, 90.4% (84.9–94.4)] and for ruling-

out it was 5.58 kPa [sensitivity, 90.4% (85.4–94.1); specificity, 73.6%

(66.3–80.2)]. For ruling-in F = 4 the SWM cutoff was 9.15 kPa [sen-

sitivity, 83.5% (74.3–90.5); specificity, 90.1% (86.0–93.4)] and for

ruling-out it was 8.41 kPa [sensitivity, 90.1% (82.1–95.4); speci-

ficity, 82.5% (77.5–86.8)]. AUCs were 0.92 (0.89–0.94) for F ≥ 2 and

0.94 (0.91–0.96) for F = 4.

Conclusions: We propose to use a dual cutoff of SWM in order to

rule-in or rule-out significant fibrosis and cirrhosis. In the clinical

contest, this may increase the confidence in staging liver fibrosis

with non-invasive shear wave elastography technique.



T-12

Liver stiffness fibrosis thresholds of Fibroscancannot be adopted by all new elastographymachines: A comparative study

V. Salvatore 1, L. Mulazzani 1, V. Cantisani 2,

A. Colecchia 1, R. Di Donato 1, C. Felicani 3,

A. Ferrarini 1, N. Gamal 1, V. Grasso 3, G. Marasco 1,

E. Mazzotta 3, F. Ravaioli 1, G. Ruggieri 4, I. Serio 1,

J.F. Sitouok Nkamgho 1, C. Serra 3, D. Festi 1,

C. Schiavone 5, L. Bolondi 1, F. Piscaglia 1

1 Department of Medical and Surgical Sciences,

University of Bologna, Italy2 Department of Radiological Sciences, Policlinico

Umberto I, University Sapienza, Rome, Italy3 Unit of Internal Medicine and Organ Insufficiency,

S. Orsola-Malpighi Hospital, Bologna, Italy4 Division of Infectious Disease, G. d’Annunzio

University, Chieti, Italy5 Unit of Internistic Ultrasound, Dept of Medicine

and Science of Aging, G. d’Annunzio University,

Chieti, Italy

Introduction: Whether shear wave elastography techniques

provide liver stiffness results comparable to Fibroscan to an extent

that the Fibroscan thresholds can be immediately adopted has not

been tested for many of the machines recently introduced onto the

market.

Aim: The aim of the present study was to test the concordance

of the findings obtained from 7 of the most recent ultrasound elas-

tography machines having various elastography technologies with

respect to Fibroscan as a reference method.

Methods: A total of 16 hepatitis C virus (HCV)-related patients

with chronic liver disease and significant fibrosis, and having

reliable results at Transient Elastography with Fibroscan were

investigated in two intercostal spaces using 7 different elastog-

raphy machines. Both precision (an index of data dispersion) and

accuracy (an index of bias correction factors expressing different

magnitude of changes in stiffness values in comparison to the ref-

erence) were calculated for each comparison.

Results: Median stiffness values differed among the different

machines as did both precision (range 0.54–0.72) and accuracy

(range 0.28–0.87). When the average of measurements of two,

rather than the predefined intercostal space, was considered, pre-

cision significantly increased with all machines (range 0.72–0.90)

whereas accuracy improved more haphazardly and by a smaller

degree (range 0.40–0.99).

Conclusions: The present results showed the significant lack

of concordance of the majority of elastography machines with

the Fibroscan results; the moderate values of accuracy prevented

the possibility of the immediate universal adoption of Fibroscan

thresholds for defining liver fibrosis staging for all new machines.


T-13

Autoimmune hepatitis in children and adults:A single centre experience

L. Perini 1, E. Nicoletto 2, E. Salami 1, P. Gaio 2,

C. Mangini 1, N. Cazzagon 1, V. Baldo 3,

M. Cananzi 2, A. Floreani 1


Gastronterology University of Padova, Padova, Italy2 Department of Pediatrics, University of Padova,

Padova, Italy3 Department of Hygiene and Public Health,

University of Padova, Italy

Autoimmune hepatitis (AIH) can be diagnosed in both children

and adults.

Aim: To compare the clinical features of AIH in a pediatric group

(GA) and in an adult population (GB).

Methods: GA included 33 patients (M:F = 12:21), mean age

8 ± 4.5 years, range 1–16; GB included 149 patients (M:F = 20:129),

mean age 45 ± 19.8 years, range 19.8–89. The mean follow-up was

57 ± 41 months in GA and 97 ± 91 months in GB. Patients were

treated with a first line therapy with prednisone ± azathioprine

and when needed with a second line therapy with mycophenolate

mofetil (MMF) + prednisone.

Results: An acute onset at presentation was recorded in 4% of

cases in GA and in 4.9% in GB, an acute liver failure onset was

recorded in 10% in GA only, an acute on chronic onset in 36% in

both groups. At onset, children showed significantly higher lev-

els of AST (1035.3 ± 1086.2 vs 534.5 ± 508.4 UI/l, p = 0.004), ALT

(1075 ± 1030 vs 675.8 ± 679.2 UI/L, p = 0.02) and lower levels of GGT

(121.6 ± 116.3 vs 181.4 ± 151.3 UI/L, p = 0.013) compared to adults.

An higher prevalence of anti-LKM positivity was observed in chil-

dren than in adults (24.5% vs 3.8%). No differences between the

two groups were observed regarding: ANA and ASMA positivity,

autoimmune comorbidities, response to the immunosuppression

after 1 year (complete response = 76.4% in GA vs 78.4% in GB, partial

response = 20.9% vs 19.6% respectively, non-responders 2.7% vs 2%

respectively). Relapse was more frequent in GB, although not sta-

tistically significant (36.2% vs 27.8%). Three patients (9%) in GA and

4(3%) in GB were treated with MMF+ prednisone. Liver transplanta-

tion was performed in 1 child and in one adult patient. Liver-related

death was observed in 1case in GA and in 5 cases in GB.

Conclusions: Children had a more severe AIH in terms of

biochemical alterations at presentation but the natural history

appeared comparable in children and adults.


T-14

Effectiveness of HCV antiviral treatment inpatients with cirrhosis or advanced fibrosis andend-stage kidney disease on dialysis

F.R. Ponziani 1, M. Siciliano 1, R. Lionetti 2,

C. Pasquazzi 3, L. Gianserra 3, L. Lambiase 3,

G. D’Offizi 2, A. Gasbarrini 1, M. Pompili 1

1 Internal Medicine and Gastroenterology, Agostino

Gemelli Hospital, Rome, Italy2 Infectious and Liver diseases, IRCCS Lazzaro

Spallanzani, Rome, Italy3 Infectious Diseases, S. Andrea Hospital, Rome, Italy

Introduction: Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir

(PROD) is one of the recommended antiviral regimens for patients


with hepatitis C and severe renal impairment (creatinine clearance

<30 mL/min). Little is known about the safety and efficacy of PROD

in subjects with advanced fibrosis or cirrhosis undergoing dialysis.

Patients and methods: Consecutive patients with advanced

fibrosis or cirrhosis and chronic kidney disease (CKD) on dialysis

undergoing antiviral treatment were included in the study. HCV-

RNA quantification was performed at 4-week intervals; SVR was

defined as serum HCV-RNA <15 IU/mL at 4 (SVR4) or 12 (SVR12)

weeks after the end of therapy.

Results: Ten patients with CKD on dialysis (median age 55

(39–76) yrs) were treated for HCV infection (8 genotype 1b, 1

genotype 1a and 1 genotype 4d). Among them, 8 had evidence

of cirrhosis (Child – Pugh A) and 2 of advanced fibrosis (F3

Metavir) according to clinical, ultrasound or elastosonographic

parameters. Five patients were treatment experienced (PEG-

IFN ± ribavirin), and 4 had previously undergone to unsuccessful

kidney transplantation. Genotype 1b patients received PROD regi-

men without ribavirin for 12 weeks, the patient with genotype 1a

PROD + ribavirin 200 mg/d for 24 weeks, the patient with genotype

4d PRO + ribavirin 200 mg/d for 12 weeks. Grade 1 and 2 fatigue

was reported by all patients, reaching grade 3 in one of them;

grade 2 anemia was reported in the two patients receiving riba-

virin. One patient with mild ascites required an increased number

of dialysis sessions/week during therapy. Reported AEs resolved

spontaneously after the end of treatment. All patients completed

the prescribed treatment. All subjects achieved the SVR12.

Conclusions: PROD is an effective and well-tolerated HCV

antiviral regimen in patients with cirrhosis and CKD undergoing

dialysis. Strict monitoring is advisable to promptly recognize and

manage adverse events related to treatment.


T-15

Validation of the Bolondi stratification forintermediate stage hepatocellular carcinoma(HCC). Clinical and therapeutical implications

A. Mega 1, M. De Giorgio 2, H. Zoller 3,

A. Finkenstedt 3, M. Felder 1, S. Fagiuoli 2,

M. Haefner 1

1 Department of Gastroenterology, Central Hospital,

Bolzano, Italy2 Department of Gastroenterology & Hepatology,

Ospedale Papa Giovanni XXIII, Bergamo, Italy3 Gastroenterologie und Hepatologie, University

Klinik fuer Innere Medizin, Innsbruck, Austria

Background: The treatment of HCC is according to the Barcelona

Clinic Liver Cancer algorithm (BCLC). HCC BCLC-B should be treated

with trans-arterial chemoembolization (TACE). Considering clinical

and tumoral aspects, many centers have adopted other treatments.

In 2012, Bolondi and colleagues, suggested a stratification of BCLC-

B patients in 4 sub-groups (B1–B4) and applying other therapeutic

strategies (transplantation, resection, radiofrequency, TACE plus

ablation, radioembolization, antitumoral therapy with Sorafenib©)

with the aim to improve overall survival (OS).

Aims: To retrospectively test whether the use of the Bolondi

stratification of BCLB patients, would have altered OS in a multi-

centric cohort of HCC patients.

Methods: The study involved 276 HCC BCLC-B patients, treated

between 2000 and 2015 in 2 large hospitals in Italy (Bolzano and

Bergamo) and in one large Austrian Hospital (Innsbruck). The OS of

patients treated according to the EASL and AASLD guidelines was

compared with the OS obtained using the Bolondi stratification.

Results: The median follow up was 6.4 yrs, with an OS of

37% at 5 yrs. Analyzing the stratification of patients in 4 sub-

groups as suggested by the Bolondi Model, there was a significative

difference in OS between B1 vs B2, B2 vs B3 and B3 vs B4

(log rank overall p < 0.001). OS analysis for type of treatment

(Bolondi model vs TACE proposed by EASL and AASLD guidelines),

was better when the Bolondi stratification was used (log rang

p < 0.001, Ranyi type test p < 0.001). In the multivariate analysis

the B1–B4 stratification is the factor which influences OS with

B2 patients performing better (p < 0.05). Patients stratified in B3

and B4 Bolondi group would have had a better outcome if treated

with liver transplantation, TACE or antitumoral therapy with

Sorafenib.

Conclusions: Our study confirms the validity of the Bolondi

stratification, which allows a more “tailored therapy” and a better

OS.


T-16

Impact of direct-acting anti-HCV treatmentsbefore liver transplant on virological andclinical outcomes of HCV patients at one yearafter surgery

S. Martini 1, M. Sacco 1, S. Strona 1, A. Ottobrelli 1,

F. Tandoi 2, S. Mirabella 2, D. Cocchis 2,

M. Salizzoni 2, G.M. Saracco 1, R. Romagnoli 2

1 Gastrohepatology Unit, AOU Città della Salute e

della Scienza di Torino, University of Torino, Turin,

Italy2 Liver Transplant Center, General Surgery 2U, AOU

Città della Salute e della Scienza di Torino, University

of Torino, Turin, Italy

Introduction: In HCV-positive recipients who are viremic at

liver transplant (LT), viral recurrence is universal and biliary com-

plications occur in 25–40% of the cases. Liver stiffness (LS) ≥8.7

kilopascal (kPa) at one year after LT, was associated with all cause-

related graft loss. We evaluated the impact of pre-LT direct-acting

antivirals (DAAs) on virological and clinical outcomes at one year

after LT.

Methods: Between 07-2014 and 10-2016, 64 patients, who

received DAAs plus ribavirin before-LT, underwent LT in our Center

from brain-dead, HCV-negative donors. Sixteen patients bridged

DAAs and ribavirin from pre to post-LT to achieve/maintain HCV

RNA negativization.

Results: Median recipient age was 57 years, males 84%, BMI

26 kg/m2, 80% hepatocellular carcinoma, median MELD at LT 12

(range 6–30), genotype 1b: 44%, 3: 23%; median donor age 66 years;

median donor risk index 1.9. Five patients died within 90 days of

LT due to multi organ failure. 54/55 (98.2%) recipients reached a

sustained virological response at week 12 after LT/therapy. During

a median follow-up after LT of 377 days (range 35–839) for sur-

viving patients, we recorded: 15.6% biliary complications and 4.7%

treated acute cellular rejections. Twenty-four patients underwent

liver elastography at 1 year after LT: median LS was 6.8 kPa, with

18 (75%) patients having a LS < 8.7 kPa; 3 patients had LS > 9.5 kPa, 2

of them underwent liver biopsy, which showed mild portal inflam-

mation and focal reticular fibrosis; the third patient was cholestatic

at liver elastography.

Conclusions: DAAs pre or peri-LT achieved HCV eradication in

98% of the patients after LT; early post-LT management was sim-

plified by the absence of viremia and resulted in a low rate of acute

rejections and biliary complications. Despite a LT activity mostly


relying on elderly donors, three-fourths of the cured patients

showed a LS corresponding to absent/mild fibrosis at 1 year after LT.


T-17

Worsening of serum lipid profile after directacting antiviral treatment

S. Gitto 1, A.F.P. Cicero 2, E. Loggi 1,

M. Giovannini 2, F. Conti 1, E. Grandini 1,

V. Guarneri 1, A. Scuteri 1, G. Vitale 1, C. Cursaro 1,

C. Borghi 2, P. Andreone 1

1 Hepatology Unit, Department of Medical and

Surgical Sciences, University of Bologna and Azienda

Ospedaliero Universitaria di Bologna, Policlinico di

Sant’Orsola, Bologna, Italy2 Internal Medicine Unit, Department of Medical and

Surgical Sciences, University of Bologna and Azienda

Ospedaliero Universitaria di Bologna, Policlinico di

Sant’Orsola, Bologna, Italy

Introduction: Hepatitis C virus and host lipid metabolism show

complex interactions since lipids influence both viral replication

and lifecycle.

Aim: Our aim was to evaluate changes of glucose and lipid

metabolism in patients with chronic hepatitis C after therapy with

direct acting antivirals (DAA).

Materials and methods: All patients consecutively treated from

January to November 2015 were considered. We recorded labora-

tory and clinical data at baseline and week 24 of follow-up. Frozen

serum samples were used to assay apolipoprotein A1 (apoA1), B

(apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to esti-

mate trends and logistic regression for predictors of lipid changes.

Results: We analyzed 100 patients, mostly cirrhotic (81%) and

with genotype 1b (59%). Ninety three patients achieved sustained

virological response (SVR) while 7 relapsed. From baseline to week

24 of follow-up, any modification of drugs, life-style and body

mass index was registered. However, insulin and Homeostasis

Model Assessment of Insulin Resistance declined (from 16.5 ± 7.3

to 11.6 ± 5.8 �IU/ml and from 3 to 2.7, p = 0.000). Non-High Density

Lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35

(p = 0.000) and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dl (p = 0.000).

Rise of both Low Density Lipoprotein/HDL and apoB/apoA1 ratio

was registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18

to 0.53 ± 0.18 mg/dl, p = 0.000). Notably, any change in lipid profile

was recorded in patients with relapse. At univariate test for Lp(a)

increase, male gender, advanced fibrosis and ribavirin use showed

p < 0.1 but at multivariate analysis only ribavirin appeared as inde-

pendent predictor (OR 3.982, 95% CI 1.206–13.144, p = 0.023).

Conclusions: DAA led to decrease of insulin-resistance. How-

ever, relevant pro-atherogenic lipid changes were registered in

patients with SVR. Ribavirin emerged as independent predictor of

Lp(a) increase. Further studies will be necessary to evaluate cardio-

vascular balance between negative change of lipid profile and both

amelioration of glucose metabolism and viral clearance.


T-18

The immunomodulatory activity of SerpinB3 anprotease-inhibitor in vivo and in vitro

A. Cappon 1, G. Villano 1, S. Quarta 1, A. Biasiolo 1,

C. Turato 1, M. Ruvoletto 1, S. Sutti 2, S. Bruzzi 2,

E. Novo 3, E. Morello 3, S. Cannito 3, E. Albano 2,

M. Parola 3, P. Pontisso 1

1 Department of Medicine, University of Padua,

Padua, Italy2 Department of Health Sciences and

Interdisciplinary Research Centre for Autoimmune

Diseases, University of East Piedmont, Novara, Italy3 Department of Clinical and Biological Sciences,

University of Turin, Turin, Italy

Introduction: NASH is associated with a higher risk of overall

mortality and HCC development. The serin protease inhibitor Ser-

pinB3 is not expressed in normal liver, but its level increases in

relation with the extent of liver damage. To date, only few data are

available on this serpin in the setting of NASH.

Aim: Aim of this study was to assess the role of SerpinB3 in a

murine model of NASH, with particular respect to inflammatory

response.

Materials and methods: Wild-type and SerpinB3 trangenic

C57BL/6 mice were fed on MCD diet for 8 weeks. At the end of the

study, mice were sacrificed and the liver was used for further anal-

ysis. Immunohistochemistry for macrophage detection was carried

out using F4/80 antibody, while inflammatory cytokines were eval-

uated on total RNA by molecular amplification techniques. Primary

mononuclear cells were isolated from healthy donors and treated

with or without SerpinB3 (200 ng/ml) for 2, 8, 24, 72 and 168 h.

Gene expression was evaluated by Q-PCR, and Real-time cell pro-

liferation was measured using the xCELLigence instrument.

Results: After 8 week of MCD diet, SerpinB3 transgenic mice

showed a significantly increased inflammatory cells infiltration in

the liver, with higher F4/80 positive cells staining, compared to wild

type mice. These findings were supported by a marked increase of

CD11b and TNF-alpha. Interestingly, the expression of IL-12, CXCL-

10 and IL-1-beta, markers associated with M1 macrophage profile,

were significantly up-regulated in the liver of treated transgenic

mice, as compared to controls. Primary monocytes treated with

SerpinB3 showed increased survival and proliferation, associated

with higher levels of TNF-alpha, IFN-alpha, IL-12 and CXCL-10.

Conclusions: These data suggest for first time that SerpinB3 may

have a direct pro-inflammatory and immunomodulatory role on

monocytes in vitro and in vivo in the contest of NASH.



T-19

Hypoxia-inducible factor 2� drives theprogression of experimental non-alcoholic fattyliver disease by stimulating hepatocyteproduction of histidine rich glycoprotein

S. Sutti 1, E. Morello 2, S. Cannito 2, E. Novo 2,

C. Bocca 2, B. Foglia 2, S. Bruzzì 3, E. Bugianesi 1,

E. Albano 3, M. Parola 2

1 Department Medical Sciences, University of Torino,

Turin, Italy2 Department Clinical and Biological Sciences,

University of Torino, Turin, Italy3 Department Health Sciences, A. Avogadro

University, Novara, Italy

Introduction: Hypoxia and hypoxia inducible factors (HIFs) are

believed to significantly affect fibrogenic progression of chronic

liver diseases (CLD). Recently, we showed that HIF-2� expression

is up-regulated in parenchymal cells in either experimental or

human non-alcoholic fatty liver disease (NAFLD) and contributes

in sustaining liver fibrogenesis in the methionine/choline-deficient

(MCD) diet model of NAFLD.

Aims: In the present study, we provide further insides in the

mechanisms by which HIF-2� promotes the progression of exper-

imental NAFLD.

Methods: NAFLD was induced by feeding in mice with

hepatocyte-specific conditional deletion of HIF-2� (HIF-2�fl/fl/Alb-Cre mice) and control littermates with MCD and choline-

deficient l-amino acid refined (CDAA) diets. In vitro studies have

been performed using HepG2 cells overexpressing HIF-2�.

Results: In both the dietary models of NAFLD hepatocyte

deletion of HIF-2� resulted in: (i) a decrease in fatty liver

and parenchymal necrosis; (ii) amelioration in lobular inflam-

mation and in the hepatic expression of pro-inflammatory

cyto/chemokines (TNF-�, IL-12, CCL2, CXCL10); (iii) a significant

decrease in the expression of pro-fibrogenic genes (collagen 1A1,

TGF-�1, �-SMA) as well as in extracellular matrix deposition (Sir-

ius Red staining) and in the number of activated myofibroblasts.

Such an improvement in NAFLD evolution in HIF-2� deficient mice

was associated with a selective lowering of the hepatic produc-

tion of Histidine-Rich Glycoprotein (HRGP), a hepatocyte-derived

protein recently implicated in sustaining macrophage M1 activa-

tion. Accordingly, flow cytometry showed a decreased production

of IL-12 by macrophages isolated from HIF-2� fl/fl/Alb-Cre mice

receiving the MCD diet. Furthermore, in vitro experiments con-

firmed that up-regulation of HIF-2� resulted in enhanced HRGP

expression by HepG2 cells.

Conclusions: These results indicate that activation of HIF-2�in hepatocytes stimulates the progression of experimental NAFLD

through the up-regulation of HRGP production.


T-20

TERT promoter and CTNNB1 gene mutationsrepresent cancer signatures specific forhepatitis B and hepatitis C relatedhepatocellular carcinoma

F. Pezzuto 1, F. Izzo 2, L. Buonaguro 1,

C. Annunziata 1, F. Tatangelo 3, G. Botti 3,

F.M. Buonaguro 1, M.L. Tornesello 1

1 Molecular Biology and Viral Oncology Unit, Istituto

Nazionale Tumori “Fondazione G Pascale” – IRCCS,

Napoli, Italy2 Hepatobiliary Surgery Unit, Istituto Nazionale

Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy3 Department of Pathology, Istituto Nazionale

Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy

Introduction and aim: Recurrent somatic mutations in the pro-

moter region of telomerase reverse transcriptase (TERT) gene and

in the exon 3 of CTNNB1 gene have been recognized as common

events in hepatocellular carcinoma (HCC) with variable frequen-

cies depending on etiology and geographical region. We analyzed

the distribution of such mutations in a cohort of hepatitis B (HBV)

and hepatitis C (HCV) related HCC patients from Southern Italy.

Materials and methods: Our cohort consisted of 122 cases of

hepatitis B (HBV) and hepatitis C (HCV) related HCCs and 7 cases of

cholangiocarcinoma and hepatocholangiocarcinoma (CC/HCC-CC).

TERT promoter and CTNNB1 gene mutations were searched in all

tumor biopsies and in autologous cirrhotic tissues.

Results: Overall, 50.4% and 26% of HCC as well as 14.3% and

none of CC/HCC-CC were mutated in TERT promoter and in CTNNB1

exon 3, respectively. TERT and CTNNB1 mutations were found more

frequently in HCV related (53.6% and 26.4%, respectively) than

HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in

57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1

were not associated with the functional promoter polymorphism

rs2853669. No mutations were detected in the 129 non-HCC cir-

rhotic tissues.

Conclusions: Mutations in TERT promoter and in CTNNB1 gene

represent specific cancer signatures in the pathogenesis of viral

related HCC and could be promising early biomarkers as well as

targets for tailored therapies.



T-21

Minimal increases of alpha-fetoprotein stronglypredict HCC development in caucasiancompensated HBV cirrhotics treated byentecavir or tenofovir: A 7-year longitudinalcohort study in 225 patients

A. Loglio 1, G. Grossi 1, M. Iavarone 1, M. Viganò 2,

A. Sangiovanni 1, M. Colombo 3, P. Lampertico 1




Italy2 Division of Hepatology, Ospedale San Giuseppe,

Università degli Studi di Milano, Milan, Italy3 Center for Translational Hepatology Research,


Italy

Background and aims: As the diagnostic accuracy of alpha-

fetoprotein (AFP) in long-term NUC treated patients with

HBV-related compensated cirrhosis remains debated, aim of the

study was to assess the sensitivity and specificity of AFP values for

HCC diagnosis.

Methods: 225 HBsAg-positive monoinfected HCC-free compen-

sated cirrhotics HCC starting ETV/TDF were consecutively enrolled

in this longitudinal cohort study (age 60 (21–81) years, AFP 2

(1–296) ng/ml, 80% males, 97% Caucasian, 88% HBeAg negative, 76%

GT D, 73% normal ALT, 65% NUC-treated). Patients were regularly

followed-up till HCC development or July 2016 with blood tests

comprehensive of AFP (≤7 ng/ml) assessed every 3-6 months and

HCC surveillance every 6 months.

Results: Overall, 5338 AFP measurements were collected during

89 (7–109) months of follow-up; 31 (13.8%) patients developed an

HCC after 48 (7–88) months (1.9% per year). Among the 212 (96%,

group A) patients who maintained persistently normal AFP levels

throughout the follow-up, 20 (9.4%) developed HCC after 48 (7–75)

months. Among the 9 (4%, group B) patients in whom AFP increased

>7 ng/ml at least at one-time point (after 53 months, range 13–82),

8 (89%) developed an HCC within 3.6 (0.3–12.3) months after AFP

increase. The only case with an AFP of to 14 ng/ml but no evidence

of HCC had lung cancer multiple hepatic metastases. Among the

remaining 4 NUC-naïve patients (group C) who maintained AFP >7

(range 18–310), HCC occurred in 3 (75%) after 48 (20–87) months.

Overall, AFP increase >7 ng/m had 71.4% sensitivity and 99.5% speci-

ficity in diagnosing HCC, with a 88.9% PPV and 90.6% NPV.

Conclusions: An AFP increase >7 ng/ml strongly predicts HCC

development in long-term NUC suppressed compensated HBV cir-

rhotic patients.


T-22

MiR-122 targets SerpinB3 and is involved inSorafenib resistance in hepatocellularcarcinoma

D. Pollutri 1, F. Fornari 2, C. Turato 3, G. Villano 3,

S. Quarta 3, M. Ruvoletto 3, L. Bolondi 2,

L. Gramantieri 1, P. Pontisso 3

1 Centro di Ricerca Biomedica Applicata (CRBA),

Azienda Ospedaliero-Universitaria Policlinico S.

Orsola-Malpighi, Bologna, Italy2 Department of Medical and Surgical Sciences,

University of Bologna, Bologna, Italy3 Department of Medicine, University of Padova,

Padova, Italy

Introduction: The only first-line treatment approved for

advanced hepatocellular carcinoma (HCC) is Sorafenib. However,

many patients experience drug resistance and more effective ther-

apeutic strategies are still an unmet clinical need. In HCC MiR-122,

the most abundant liver-specific miRNA, is downregulated, while

SerpinB3 is upregulated. This serpin displays oncogenic properties,

since it increases cell death resistance, proliferation, invasion and

drug resistance.

Aims: To assess the possible relationship between miR-122 and

SerpinB3 and their influence on cell phenotype and Sorafenib resis-

tance in HCC.

Methods: HCC-derived cell lines and a di-ethyl-nitrosamine

(DEN)-induced HCC rat model were studied. QPCR and Western

blot were used to quantify miR-122, SerpinB3 and stem markers

expression. Sorafenib resistance in miR-122 transfected cells was

evaluated by cell viability and caspase-3/7 activity assays. A cohort

of 35 resected HCCs was tested to assay any correlation between

miR-122, SerpinB3 and stem cell markers expression.

Results: A bioinformatics analysis showed SerpinB3 among

miR-122 hypothetical targets. In HepG2 cells stably transfected

to over-express SerpinB3, miR-122 over-expression determined a

decrease of SerpinB3 mRNA and protein levels, whereas miR-122

inhibition caused SerpinB3 increase. Luciferase assay demonstrated

a direct interaction between miR-122 and SerpinB3 mRNA. In the

rat HCC model, high miR-122 levels were associated with nega-

tive SerpinB3 expression, while low miR-122 levels were associated

with SerpinB3 positivity. A negative correlation between miR-122

and SerpinB3 or stem cell markers was found in human HCCs. MiR-

122 over-expression determined a decrease of cell viability and an

increase of caspase activity in Sorafenib-treated HepG2 and Hep3B

cells. On the contrary, anti-miR-122 treatment caused an increase

of cell viability in Huh-7 cells following Sorafenib treatment.

Conclusions: MiR-122 targets SerpinB3 and its downregulation

associates with SerpinB3 overexpression and stem-like phenotype

in HCC. MiR-122 replacement therapy deserves attention as a pos-

sible therapeutic strategy in combination with Sorafenib for the

treatment of HCC.



T-23

Genetic variations in PD-1 and STAT4 genes donot predict off-treatment functional cure in IFNtreated genotype D, HBeAg-negative patientswith chronic hepatitis B

E. Galmozzi, F. Facchetti, G. Grossi, A. Loglio,

P. Lampertico

A.M. and A. Migliavacca Center for Liver Disease,



Policlinico, Università degli Studi di Milano, Milano,

Italy

Introduction and aim: Single-nucleotide polymorphisms

(SNPs) in programmed cell death-1 (PD-1) (rs10204525) and STAT4

genes (rs7574865) have been associated with hepatitis B infection.

Aim of the study was to assess if these SNPs could improve the

predictive power of other genetic signatures such as IFNL4 vari-

ants on response to interferon (IFN)-based treatment in genotype

D HBeAg-negative chronic hepatitis B (CHB) patients.

Methods: 126 HBeAg-negative CHB patients with compensated

disease that received pegylated-IFN alfa for 22 (6–48) months and

followed for 11 (1–23) years were analyzed by either TaqMan SNP

Genotyping Assays (PD-1, STAT4) and Sanger sequencing (IFNL4).

Results: The genotype distribution in the 126 patients was as

follows: GG in 106 (84%), GA in 19 (15.2%) and AA in 1 (0.8%) for

PD-1 rs10204525 (MAF 0.08); GG in 85 (68%), GT in 37 (29%) and

TT in 4 (3%) for STAT4 rs7574865 (MAF 0.18); TT/TT in 62 (49%),

TT/�G in 51 (40%), �G/�G in 13 (11%) (MAF 0.31) and CC in

107 (85%), CT in 18 (14.2%), TT in 1 (0.8%) (MAF 0.08) for IFNL4

rs368234815 and rs117648444 respectively. Twenty-eight patients

(22%) ultimately cleared HBsAg with a 15-year cumulative proba-

bility of 30%. In univariate analysis, PD-1 and STAT4 variants did

not predict the 15-year cumulative incidence of HBsAg loss (dom-

inant model, rs10204525, HR = 0.89, 95%CI = 0.31–2.6, p = 0.838;

rs7574865, HR = 1.13, 95%CI = 0.52–2.50, p = 0.745). At multivariate

analysis including also all the canonical pretreatment predictors of

response (age, gender, Cirrhosis, ALT, HBV-DNA and HBV genotype),

the only independent baseline predictors of HBsAg seroclearance

were the combined IFNL4 rs368234815 and rs117648444 geno-

types (HR = 3.95, 95%CI 1.4–11.4, p = 0.011) and the pretreatment

serum HBV-DNA levels (HR = 0.62, 95%CI 0.44–0.88, p = 0.007).

Conclusions: ThePD-1 rs10204525 and STAT4 rs7574865-

polymorphisms do not further improve the predictivity of IFNL4

variants on IFN-induced functional cure in the setting of genotype

D HBeAg-negative CHB patients.


T-24

Validation of the Baveno VI criteria forscreening of esophageal varices in patients withmetabolic and alcohol related compensatedadvanced chronic liver disease

N. Mezzina 1, M. Viganò 1, T. Giulia 2, S. Labanca 1,

R. Lombardi 3, V.L. Mainardi 1, A.L. Fracanzani 3,

P. Lampertico 2, M. Rumi 1, M. Primignani 2

1 Hepatology Division, San Giuseppe Hospital,

University of Milan, Milan, Italy2 Gastroenterology and Hepatology Division,

Fondazione IRCCS Ca’ Granda Ospedale Maggiore

Policlinico, University of Milan, Milan, Italy3 Internal Medicine, University of Milan and IRCCS

Ca’ Granda Maggiore Hospital Foundation, Milan,

Italy

Introduction: According to the Baveno VI criteria, patients with

virus-related compensated advanced chronic liver disease (cACLD)

having transient elastography (TE) values <20 kPa and platelet (PLT)

count >150.000/mmc have a very low risk of esophageal varices

(EV) needing prophylactic treatment (VNT) and can avoid screening

endoscopy.

Aims: To evaluate the Baveno VI criteria in patients with cACLD

due to alcohol-related (ALD) and non-alcoholic fatty liver disease

(NAFLD).

Materials and methods/Results: All consecutive patients with

cACLD (LS≥10 kPa or histologically proven) due to NAFLD and/or

ALD, without ascites, hepatitis C/B infection, hepatocellular carci-

noma, portal-vein thrombosis, previous gastro-intestinal bleeding

or endoscopic band ligation, non-selective beta-blockers use were

included if TE was performed within 6 months from the screening

endoscopy. Sensitivity (Sn), specificity (Sp), positive (PPV) and neg-

ative (NPV) predictive values, positive/negative likelihood ratio

[LR(+), LR(−)] were calculated. Eighty-two cases were included

(43 NAFLD, 27 ALD, 12 mixed). Nineteen (23%) had EV of which 4

(5%) had VNT. Among the 15 patients fulfilling the Baveno criteria,

none presented VNT, and one (7%) had small-sized EV, thus result-

ing in Sn = 100% and Sp = 19% in ruling-out VNT, with a PPV = 6%,

NPV = 100%, LR(+) = 1.24 and LR(−) = 0. Sn, NPV and the LR(−) were

100%, 100% and 0 in NAFLD and ALD patients, respectively, whereas

Sp was 17% and 24%. These results were still reproducible using

a less conservative threshold values for PLT (>125.000/mmc) and

TE (<30 kPa) which correctly identified 32 patients without VNT,

resulting in Sn = 100%, Sp = 41%, PPV = 8%, NPV = 100%, LR(+) = 1.7

and LR(−) = 0 with the same accuracy among sub-groups.

Conclusions: Baveno VI criteria ruling-out VNT could be safely

applied in cACLD patients due to NAFLD/ALD, thus sparing 18% of

screening endoscopy without missing VNT. In addition, the use of a

less conservative threshold of PLT and TE could increase the number

(39%) of spared endoscopy, but needs further confirmation.



T-25

Inherited prothrombotic risk factors in childrenwith extrahepatic portal veinobstruction(EHPVO). A case–control study

M. Primignani 1, I. Martinelli 2, G. Tosetti 1,

M. Cheli 3, P. Bucciarelli 2, M. Colusso 3,

D. Alberti 3,4



Policlinico, Milano, Italy2 A. Bianchi Bonomi Hemophilia and Thrombosis

Center, Fondazione IRCCS Ca’ Granda Ospedale

Maggiore Policlinico, Milano, Italy3 UOC Chirurgia Pediatrica – Ospedale Papa

Giovanni XXIII, Bergamo, Italy4 UOC di Chirurgia Pediatrica – Dipartimento di

Scienze Cliniche e Sperimentali, Università di Brescia,

Italy

Background: In children, EHPVO is the commonest cause of

upper gastrointestinal bleeding. Although umbilical vein catheter-

ization or omphalitis are frequently reported causes, most

cases remain unexplained. Inherited thrombophilia has not been

extensively evaluated. We investigated thrombophilia in EHPVO

children, as compared with EHPVO in adults (without solid tumors

or cirrhosis) and in adult controls. The two groups were compared

with controls in terms of odds ratios and 95% CI.

Methods: DNA analysis for factor V Leiden (FVL) and G20210A

prothrombin gene mutation (PTG20210A) and functional/antigenic

assays for antithrombin, protein C, S were performed.

Results: 53 EHPVO children, 65 EHPVO adult and 700 controls

were studied. Thirty children (57%) had umbilical vein catheteriza-

tion. FVL and PTG20210A were found in 3 (6%) and one (2%) children

and in 2 (3%) and 14 (22%) adults, respectively: OR 2.4 (0.7–8.5) for

FVL and 0.6 (0.1–4.2) for PTG20210A in children, and 0.8 (0.1–6.4)

for FVL and 8.1 (3.8–17.5) in adults. 53% of children and 28% of

EHPVO adult had one or more deficiency of antithrombin, protein

C or S but the inheritance could be excluded in all children and in

14 of 18 adults.

Myeloproliferative disorders were excluded in children, but

caused EHPVO in 35% of adults. One risk factor for EHPVO was iden-

tified in 57% children and 40% adults. Two or more risk factors were

recognized in 15% children and 37% adults (c2 = 7.14, p = 0.028),

whereas no risk factors were identified in 28% of children and 23%

adults

Conclusions: Umbilical vein catheterization is the commonest

cause of EHPVO in children. Differently from adults, who have a high

rate of PTG20210A, inherited thrombophilia has no role in children.

The occurrence of multiple risk factors is significantly lower in chil-

dren. However, up to 30% of paediatric EHPVO occur in the absence

of any recognized risk factor.


T-26

Increase in transporter MATE-1 expressioninduced by obeticholic acid correlates withhigher biliary excretion of asymmetricdimethylarginine during hepaticischemia/reperfusion injury

L.G. Di Pasqua 1, C. Berardo 1, V. Siciliano 1,

R. Viscusi 1, V. Rizzo 2, L. Adorini 3, P. Richelmi 1,

A. Ferrigno 1, M. Vairetti 1

1 Department of Internal Medicine and Therapeutics,

University of Pavia, Pavia, Italy2 Department of Molecular Medicine, IRCCS

Policlinico San Matteo, University of Pavia, Pavia,

Italy3 Intercept Pharmaceuticals, San Diego, CA, USA

Introduction and aim: We demonstrated that asymmetric

dimethylarginine (ADMA), inhibitor of nitric oxide synthases,

is excreted by bile and its clearance increases after hepatic

ischemia/reperfusion (I/R). Further biliary ADMA increase occurs

in sham and I/R groups following administration of farnesoid-X-

receptor (FXR) agonist obeticholic acid (OCA) and this increase

seems CAT-2-transporter-indipendent. In this study, we evaluated

the OCA effect on other ADMA transporters including CAT-1, OCT-1

and MATE-1 after hepatic I/R.

Methods: Male Wistar rats received orally 10 mg/kg/day of OCA

(Intercept Pharmaceuticals) or vehicle for 5 days and were sub-

jected to 60-min partial hepatic ischemia or sham-operated. After a

60-min reperfusion, serum, tissue and bile ADMA levels and hepatic

mRNA expression of CAT-1, OCT-1, MATE-1 and FXR were mea-

sured. Liver iNOS and eNOS content was evaluated.

Results: Serum ADMA levels were higher in sham rats treated

with OCA compared with vehicle. OCA administration induced

an increase in biliary ADMA levels both in sham-operated and

I/R groups, without significant changes in hepatic ADMA con-

tent. A reduction in CAT-1 expression was found in OCA-treated

sham-operated rats compared with vehicle. In I/R groups, OCA

administration did not change CAT-1 but a marked decrease in

OCT-1 was observed. An increase in MATE-1 was detected both

in sham-operated and I/R groups treated with OCA. OCA induced

an increase, although not significant, in eNOS and a significant

decrease in iNOS expression after I/R, compared with vehicle-

treated animals. A decrease in mRNA expression of FXR was found

in OCA-treated sham-operated rats compared with vehicle.

Conclusions: Since ADMA transporters such as CAT-1 and OCT-

1 were markedly downregulated and MATE-1 was upregulated in

the I/R group treated with OCA, we suggest that MATE-1 proteins,

involved in the biliary excretion of intoxicants, are also responsible

for the biliary excretion of ADMA as they provide an alternative

elimination route.



T-27

Clinical effectiveness of enhanced surveillancein “super-high risk” cirrhotics as evaluated inthe ITA.LI.CA database

M. D’Elia 1, G. Peserico 1, F. Pelizzaro 1,

A. Meneghetti 1, A. Imondi 1, E. Giannini 2,

F. Trevisani 3, F. Farinati 1


Gastroenterology, Section of Gastroenterology,

University of Padua, Padua, Italy2 Department of Internal Medicine, Gastroenterology

Unit, University of Genoa, Genoa, Italy3 Unità di Semeiotica Medica, Dipartimento di

Scienze Mediche e Chirurgiche, Alma Mater

Studiorum, Università di Bologna, Bologna, Italy

Background: Surveillance of cirrhotics in the secondary pre-

vention of HCC is mandatory but the ideal surveillance interval is

still under discussion. The Japanese guidelines consider HCV/HBV-

related cirrhotics as “super-high risk” patients, with shorter

doubling time, and indicate an enhanced surveillance (3–4

months).

Aims of the study: Were to evaluate the impact of a three-

months enhanced surveillance (3MS) in patients with viral cirrhosis

in terms of tumor stage, survival and direct costs.

Patients and methods: The multicenter ITA.LI.CA database

(5849 HCC patients) was used. Inclusion criteria were: cirrhosis,

viral etiology and diagnosis under surveillance (3MS versus 6MS).

Overall 1576 cirrhotics met the definition of “super-high risk”: 194

underwent 3MS, 1382 6MS. The survival analysis took into account

the lead time bias (LTB) (by Schwartz’s algorithm, Cancer 1961).

Results: The 3MS did not increase the proportion of lesions diag-

nosed as “very early” (p = 0.622) or within Milan Criteria (p = 0.067).

In the 3MS patients a greater portion of HCC were multifocal

(p = 0.025), probably due to an increased likelihood of the 3MS

to diagnose more aggressive tumors. The survival of the 3MS

patients was not significantly different, also when corrected for LTB

(p = 0.987), with actually a shorter survival in the 3MS group (35

months, 95% CI 32–38, vs 42 months, 95% CI 37–43). These results

were confirmed in the multivariate analysis. Micro-economic anal-

ysis estimated an increase of 1447D in the costs for each HCC while

the cost for year of life saved was not computable.

Conclusions: In patients at “super-high risk” an enhanced 3MS

does not improve tumor stage, feasibility of curative treatments

and patients’ survival, with an increase in direct costs. It can be

concluded that “super-high risk” patients should be managed as all

the population at risk, as indicated by the European guidelines.


T-28

Lobe-specific oxidative stress and matrixmetalloproteinase activation in two animalmodels of non-alcoholic fatty liver disease(NAFLD)

V. Siciliano 1, L.G. Di Pasqua 1, C. Berardo 1,

V. Rizzo 2, P. Richelmi 1, S. Perlini 1, A. Ferrigno 1,

G. Palladini 1, M. Vairetti 1

1 Department of Internal Medicine and Therapeutics,

University of Pavia, Pavia, Italy2 Department of Molecular Medicine, IRCCS

Policlinico San Matteo, University of Pavia, Pavia,

Italy

Introduction and aim: We previously demonstrated that in

models of ischemia/reperfusion and obstructive cholestasis a lobar

functional heterogeneity of the liver exists indicating that different

events occur in the different hepatic lobes (Palladini et al., 2012;

Ferrigno et al., 2014). In this study we evaluated the liver hetero-

geneity in two animal models of non-alcoholic fatty liver disease

(NAFLD).

Methods: NAFLD was induced in male Wistar rats by 4–8 week

MCD diet administration; 12-week old Obese (fa/fa) and Lean

(fa/−) male Zucker rats were also used. Serum hepatic enzymes

and TNF-alpha were quantified. Reactive oxygen species (ROS) and

malondialdehyde (MDA), index of oxidative stress, and matrix met-

alloproteinase activation (MMP-2, MMP-9) were evaluated using

liver samples from left lobe (LL), median lobe (ML) and right lobe

(RL).

Results: Liver injury in MCD and Zucker obese rats was con-

firmed by the increased hepatic enzymes release; an increase

in serum TNF-alpha occurred in MCD rats when compared with

Zucker obese rats. A lower MDA level was observed in the RL as

compared with the LL and ML in the MCD animals; the difference

was time dependent and more evident after 8 weeks. In Zucker rats,

higher MDA levels was found in LL both in Lean and Obese Zucker

rats. The same trend occurred in ROS formation both in MCD and

Zucker rats. A marked MMP-2 and MMP-9 activation occurred in

RL compared with LL and ML in MCD rats.

Conclusions: A lobar difference was detected for ROS, MDA and

MMPs activity both in MCD and Zucker rats, with higher oxida-

tive stress in the LL for all groups considered. On the contrary an

higher MMPs activation was found in RL when compared with LL

and ML. This study supports the growing evidence of a functional

heterogeneity among the liver lobes, also occurring in NAFLD rats.


T-29

Vitamin D deficiency is an independent riskfactor and is predictor of infections in patientsaffected by HCV-related liver cirrhosis

A.R. Buonomo, E. Zappulo, R. Scotto, B. Pinchera,

A.E. Maraolo, F. Borrelli, G. Di Filippo, G. Borgia,

I. Gentile

Department of Clinical Medicine and Surgery,

Section of Infectious Disease, University of Naples,

Naples, Italy

Introduction: Vitamin D has other biological effects than

calcium-fosforus omeostasis. Among these effects, it plays a keyrole

in native immunity stimulation and adaptive immunity regulation.


Material and methods: A total of 291 patients affected by HCV-

related liver cirrhosis were prospectively enrolled between 2013

and 2015 at the Infectious Disease Section of the University of

Naples “Federico II”. Cirrhosis was defined by clinically, histolog-

ically or by the means of transient elastography ≥13 kPa. Serum

vitamin D levels were dosed at enrolment. A clinical evaluation

was performed at baseline and during follow-up (three months) to

diagnose the presence of an infection.

Results: Vitamin D deficiency (VDd) (25-OH-Vitamin D

<20 ng/mL) was detected in 68.3% of patients. Overall, 102 infec-

tions were detected and urinary tract infections were the most

common one (47.1%). VDd significantly correlated with the sever-

ity of Child-Pugh classification scores (p = 0.008 Bonferroni test).

The presence of infection was significantly associated with VDd

(p < 0.001), MELD >15 (p < 0.05), hospitalization (p < 0.05), diabetes

mellitus (DM) (p < 0.05), Child-Pugh class B/C versus A (p < 0.001)

and the presence of active HCC (p < 0.001).

At multivariate analysis, VDd (p < 0.01), HCC (p < 0.05) and hos-

pitalization (p < 0.001) were independent predictors of infection at

enrolment in a model that included also Child-Pugh class B/C versus

A, MELD > 15 and DM (these three variables were not significantly

associated with infections).

In patients who did not showed signs and symptoms of an infec-

tion at enrolment (n = 226), VDd (p = 0.034), Child-Pugh class B/C

versus A (p < 0.01) and hospitalization (p < 0.001) were predictive of

a higher incidence of new infections in the following three months.

Conclusions: VDd is associated with a higher risk of infections in

patients with liver cirrhosis. Preventive strategies employing vita-

min D supplementation in this setting should be evaluated in a

randomized controlled trial. This study has been funded by “Borsa

di Studio in Epatologia 2014” provided by FIRE ONLUS.


T-30

Direct acting antiviral (DAA) therapy of HCV,effects on the cryoglobulinemic vasculitis:A multi center open label study

E. Mauro 1, L. Quartuccio 2, M. Ghersetti 1,

M. Lenzi 3, S. Gitto 3, P. Andreone 3, P. Casarin 1,

S. De Vita 2, G. Pozzato 4, C. Mazzaro 5

1 Department of Internal Medicine, Pordenone

General Hospital, Pordenone, Italy2 Rheumatology Clinic, University of Udine, Udine,

Italy3 Department of Internal Medicine and Surgical

Sciences DIMEC, University of Bologna, Bologna, Italy4 Department of Clinical and Surgical Sciences,

University of Trieste, Trieste, Italy5 Clinical of Experimental Onco-Haematology Unit,

CRO Aviano National Cancer Institute IRCCS, Aviano

(PN), Italy

Background: Hepatitis C virus (HCV) is the major etiologic agent

of mixed cryoglobulinemia (MC). Prognostic effects on HCV-related

MC of (DAA) in combination with ribavirin have been shown in

some reports.

Aim: To verify efficacy and safety of interferon-free therapy in

MC.

Methods: In five Italian centers, 27 patients (14 women and 13

men, median age 69 years, range 39–74) were enrolled in 2015.

Treatment was administered according to AISF recommendations.

Results: HCV genotypes 1a were reported in 3 cases, 1b in 15

cases, genotypes 2 in 6 cases, 3 in 2 cases, 4 in 3 cases. MC was Type

II in 22 cases (81%) and Type III in 5 cases (19%). The extra-hepatic

manifestations were: purpura in 14 cases, arthralgias in 13 cases,

peripheral neuropathy in 11 cases. Metavir fibrosis score: F1 7

cases, F2 4 cases, F3 2 cases, F4 14 cases and Indolent low-grade

Non Hodgkin Lymphoma (NHL) in 3 cases. After four weeks DAA

therapy, undetectable HCV viremia was achieved in all patients

and maintained in 95% of cases after 12 or 24 week treatment.

Moreover, regression of purpura (6 cases) and reduction of cryocrit

(17 cases) were observed, but only 2 cases showed undetectable

levels of cryoglobulins at the end of treatment. The median level

of rheumatoid factor is decreased, while C4 remained low at the

Sustained Virological Response (SVR) 24. Peripheral neuropathy

improved in five cases at the end of therapy and maintained in SVR

12 and SVR 24 week. No NHL patients achieved haematological

response. Most common side effects were: fatigue, insomnia, itch

and anemia, in five cases ribavirin dose was reduced for anemia.

Conclusions: DDA plus ribavirin is safe and effective to eradi-

cate HCV, it seems to be associated with good clinical response in

vasculitis but not with response in B-NHL.


T-31

Dynamic risk prediction in Primary BiliaryCholangitis using the UK-PBC cohort

M. Carbone 1,2, A. Nardi 3, H.F. Ainsworth 3,

M.A. Heneghan 3, G.M. Hirschfield 3,

D. Thorburn 3, A. Bathgate 3, M. Aldersley 3,

J.M. Neuberger 3, D.D. Stocken 3, H.J. Cordell 3,

G.J. Alexander 3, R.N. Sandford 3, D.E.J. Jones 3,

G.F. Mells 3

1 Academic Department of Medical Genetics,

University of Cambridge, Cambridge, UK2 Division of Gastroenterology, University of Milan

Bicocca, Milan, Italy3 UK-PBC Research Group, UK

Background and aims: The accurate identification of patients

with adverse long-term outcome is of key importance in primary

biliary cholangitis (PBC), particularly with the advent of novel ther-

apies. Current prognostic tools are based on Cox models that make

the assumption of proportional hazards, i.e. the hazard ratio of

each variable remains constant over time. In PBC, however, this

assumption may be unreliable for long-term prediction. Detecting

and modeling time-dependent effects may improve accuracy com-

pared with time-fixed (time-independent) models. The aim of this

study was to identify time-dependent variables in PBC that might

improve the accuracy of long-term prognostication by using data

from the UK-PBC Research Cohort.

Methods: Data on 3062 patients from the UK-PBC Research

Cohort treated with ursodeoxycholic acid (UDCA) were analyzed.

We performed Cox’s proportional hazards regression analysis of

diverse explanatory variables to derive the best-fitting Cox model.

The endpoint was a composite outcome (liver transplantation and

overall death). Where detected, non-linear effects of continuous

covariates were investigated using spline functions or fractional

polynomials. A smoothed plot of scaled Schoenfeld’s residuals pro-

vided a first crude estimate of time-varying parameters.

Results: The median follow-up was 7.4 years (interquartile

range: 4.2, 10.8). During follow-up, 306 patients (10.0%) suffered

an event: 119 patients (3.9%) underwent LT and 187 patients (6.1%)

died, of whom 97 (3.2%) of liver-related causes. The overall event-

free survival rate was 96% at 5 years, 88% at 10 years, and 74% at

15 years. The most important predictors were as follows: alkaline

phosphatase at baseline (hazard ratio [HR] = 1.12, confidence

interval [CI]: 1.08–1.16), albumin (abnormal vs normal; HR = 2.37,


Fig. 1.

CI: 1.73–3.24), platelets count (abnormal vs normal; HR = 2.45,

CI: 1.72–3.5), ‘delta ALP’ after twelve months of treatment with

UDCA and bilirubin (log-scale). Only for ‘delta ALP’ and bilirubin a

time dependent effect was detected and estimated together with

a confidence band (Fig. 1).

Conclusions: We identified the time-dependent effect of pre-

viously known predictive variables. Elevated bilirubin strongly

predicts adverse outcome but the risk conferred declines with time.

The risk of ‘delta ALP’ after treatment with UDCA has a slight

increase over the time. Accounting for time-dependency we can

improve the accuracy of existing prognostic models. Dynamic pre-

diction modelling represents a high-performance statistical tool to

support decision-making in patients with PBC in need of intensive

monitoring and care.


T-32

Established cirrhosis at the time of diagnosispredicts adverse outcome in autoimmunehepatitis: A retrospective cohort study

A. Gerussi 1,2, N. Halliday 3, D. Roccarina 1,

F. Saffioti 1,4, P. Polly 1, M. Pinzani 1, A. Marshall 1,

D. Thorburn 1

1 UCL Institute for Liver and Digestive Health, The

Royal Free Sheila Sherlock Centre, Royal Free

Hospital, London, United Kingdom2 Department of Experimental and Clinical Medical

Sciences, Liver Unit, Clinica Medica, Udine, Italy3 Institute of Immunity and Transplantation, UCL,

London, United Kingdom4 Department of Clinical and Experimental Medicine,

Division of Clinical and Molecular Hepatology,

University of Messina, Messina, Italy

Introduction: Autoimmune hepatitis (AIH) can lead to cirrhosis,

hepatic failure and death.

Aim: To identify those clinical parameters which, when present

at diagnosis, predict liver transplant (LT) or death in AIH patients.

Materials and methods: Data from a retrospective database of

all patients with AIH, attending a tertiary liver unit since 1980, were

used. Patients who did not meet IAIHG diagnostic criteria or had

other concomitant liver diseases, acute liver failure at onset, incom-

plete data or less than 1 month follow up were excluded. Cases were

censored at the endpoint of death or LT.

Results: 137 patients were included, of which 39 had

histologically-proven cirrhosis, 16 reached the endpoint of death

or LT. Only 3 non cirrhotic patients reached the endpoint. Median

follow up since diagnosis was 62 months (IQR 121). Univariate

Cox regression analysis identified that histologically-proven cir-

rhosis (HR 12.2, p < 0.0001) correlated with adverse outcome, while

higher ALT (HR 0.012, p < 0.027) was associated with reduced risk

of adverse outcomes. Histological cirrhosis significantly increased

the risk of death or LT on multivariate Cox regression analysis (HR

14.6, p < 0.001) and was associated with reduced LT-free survival

(159 months vs 354 months respectively, p < 0.0001, log rank). On

univariate analysis, lower ALT, albumin and INR at diagnosis were

significantly associated with histological cirrhosis. Lower serum

albumin (OR 0.905, p < 0.013) and ALT (OR 0.998, p < 0.001) showed

a significant independent association with cirrhosis on binary logis-

tic regression.

Conclusions: Histological cirrhosis at diagnosis was a significant

independent predictor of all-cause death or LT. Patients with cir-

rhosis at presentation had lower ALT levels and lower albumin than

those without cirrhosis. The degree of elevation of transaminases

and hepatic synthetic dysfunction was not associated with adverse

outcomes, suggesting that presence of cirrhosis is the predominant

factor in determining patient outcomes.


T-33

Cirrhosis regression does not preventhepatocellular carcinoma in patients with asustained virological response to IFN

R. D’Ambrosio 1, A. Aghemo 1, E. Degasperi 1,

A. Sangiovanni 1, M.G. Rumi 2, M. Fraquelli 3,

R. Perbellini 1, P. Bedossa 4, M. Colombo 5,

P. Lampertico 1

1 A.M. and A. Migliavacca Center for Liver Disease,




Italy2 Department of Hepatology, Ospedale San Giuseppe,

Università degli Studi di Milano, Milan, Italy3 Department of Gastroenterology and Endoscopy,



Italy4 Department of Pathology and INSERM U773,

Beaujon Hopital, Universitée Paris-Diderot, Clichy,

France5 Center for Translational Hepatology Research,


Italy

Introduction: Sustained virological response (SVR) to anti-

HCV treatments is associated with fibrosis re-absorption, cirrhosis

regression (CR) and reduced risk of cirrhosis-related complications.

Whether the histological changes associated with SVR have any

impact on the incidence of cirrhosis complications is still unknown.


Aim: To prospectively assess the incidence of liver-related

events in a cohort of HCV cirrhotic SVR patients with an SVR and

post-SVR histological assessment.

Methods: We followed-up with 6-month HCC surveillance and

clinical evaluation a previously published cohort of 38 cirrhotics

with paired pre- and post-SVR liver biopsies (D’Ambrosio R, Hep-

atology 2012). At post-SVR liver biopsy (LB), 15 (39%) achieved CR

(METAVIR).

Results: After 69 (7–88) months of follow-up after LB, no

episodes of clinical decompensation or GI-bleeding were recorded

in our cohort, whilst 5 (13%) patients developed hepatocellular

carcinoma (HCC). The rates of HCC were similar in patients with

and without CR (3/21 vs. 2/15: 14% vs. 13%, p = 1.0). Histological

findings didn’t differ between patients who developed or didn’t

develop HCC. In fact, among them rates of residual cirrhosis (40%

vs. 40%, p = 1.0), collagen content [2.4 (1.7–5.9) % vs. 2.3 (0.6–15.1%),

p = 0.48] METAVIR activity (p = 0.34), residual portal inflammation

(p = 0.06) and steatosis (40% vs. 12%, p = 0.17) were similar. Sim-

ilarly, we observed no difference in immunochemistry (CK7, GS,

ASMA, CD34, CYP2E1). Clinical features and biochemical param-

eters were similar in patients with and without HCC; only gGT

remained higher in the former group [median 46 (21–57) U/l vs.

23 (14–142) U/l, p = 0.05]. The 5-year survival rates were the same,

independently on CR (96% vs. 100%, p = 1.0) or HCC development

(100% vs. 97%, p = 1.0). One CR patient died of non-liver related

complications, whilst no cases of cirrhosis-related deaths were

recorded.

Conclusions: Post-SVR histological assessment in HCV compen-

sated cirrhotics does not predict HCC risk within 5 years.


T-34

Impact of von Willebrand factor andADAMTS-13 on the pro-coagulant imbalance ofpatients with cirrhosis

V. La Mura 1,2, A. Tripodi 3, N. Bitto 1, G. Tosetti 2,

V. Chantarangkul 3, L. Baronciani 3, C. Valsecchi 3,

F. Peyvandi 3, F. Salerno 1, P. Lampertico 2,

M. Colombo 2, M. Primignani 2

1 Internal Medicine-IRCCS San Donato, Department

of Biomedical Sciences for Health, University of

Milan, Milan, Italy2 Division of Gastroenterology and

Hepatology-IRCCS Ca’ Granda Maggiore Hospital

Foundation, University of Milan, Milan, Italy3 Angelo Bianchi Bonomi Hemophilia and Thrombosis

Center-IRCCS Ca’ Granda Maggiore Hospital

Foundation, Department of Clinical, Sciences and

Community Health, University of Milan, Milan, Italy

Introduction: Von Willebrand factor (VWF) is an independent

predictor of clinical outcome in cirrhosis confirming the potential

pathogenic role of hemostasis on liver damage.

Aim: The study explored: 1 – the association between VWF and

thrombomodulin-resistance (TM-R), 2 – the impact of ADAMTS-13

on VWF along with the severity of the liver disease.

Material and methods Results: Prospective collection of clin-

ical and laboratory data of 79 patients (n◦Child A/B/C = 29/35/15)

consecutively admitted for endoscopic band ligation of esophageal

varices/paracentesis. All patients were in stable hemodynamic

conditions and without clinical evidence of bacterial infection.

Examinations included VWF (antigen, VWF:Ag, and activity,

VWF:RCo) (VWF:RCo/VWF:Ag was an estimate of highly active

VWF), ADAMTS-13 activity, the main pro-(FVIII, FII) and anti-

coagulants (antithrombin, protein C). ETP-ratio (Endogenous

thrombin Potential) with/without thrombomodulin defined the

degree of TM-R and was used to explore the influence of VWF on

pro-coagulant imbalance. Liver dysfunction correlated with high

VWF:Ag, VWF:RCO and low ADAMTS-13 (p < 0.05). FVIII was the

factor with the highest degree of association with VWF:Ag and

VWF:RCO independently from MELD or Child-Pugh (multiple lin-

ear regression; p < 0.001) in accordance with the biological role

of VWF protecting FVIII from degradation. ADAMTS-13 negatively

correlated with VWF:RCO/VWF:Ag ratio, an indirect estimation of

VWF multimers. The thrombin generation curve of patients with

high VWF:Ag disclosed the lowest lag-time and time-to-peak sug-

gesting high reactivity for thrombin generation. VWF positively

correlated with the degree of TM-R independently from the sever-

ity of liver disease. Furthermore, it identified the highest proportion

of patients with TM-R over 0.78 units, the threshold of risk for

thrombosis and severe clinical outcome recently described in a ret-

rospective study of patients with cirrhosis. By contrary ADAMTS-13

was not associated with TM-R.

Conclusions: VWF/ADAMTS-13 axis is impaired along with the

severity of liver dysfunction. VWF significantly influences the pro-

coagulant imbalance detected in cirrhosis through high levels of

FVIII.


T-35

DAA-based regimens in HBsAg/anti-HCVpositive patients: The need to control HBVreplication to avoid HBV reactivation

M. Macera 1, M. Stanzione 1, V. Messina 2,

G. D’Adamo 3, V. Sangiovanni 4, L. Fontanella 5,

S. De Pascalis 1, G. Stornaiuolo 1, G. Piai 6,

G.B. Gaeta 1, I. Gentile 7, N. Coppola 1

1 Public Medicine, Second University of Naples,

Naples, Italy2 AO Caserta, Caserta, Italy3 AO Nocera, Nocera, Italy4 AO Cotugno, Naples, Italy5 AO Fatebenefratelli, Naples, Italy6 Gastroenterology, AO Caserta, Italy7 Infectious diseases, Federico II University, Naples,

Italy

Background: The aim of the present study was to evalu-

ate the efficacy of Direct Antiviral Agents (DAA)-based regimen

in HBsAg/anti-HCV/HCV-RNA-positive patients (pts) with chronic

liver disease in terms of sustained virolgical response for HCV and

of reactivation of HBV infection.

Methods: We enrolled 16 HBsAg-positive pts with anti-

HCV/HCV-RNA positive-related chronic liver diseases, treated with

DAA [median age 61 years (IQR 44–65), 11 males, 10 with cir-

rhosis (Child A in 9), only 1 post-liver transplant]. Regarding the

HBV infection, only one patient was HBeAg-positive, all anti-HDV-

negative. At the time when DAA was started, 11 pts were treated

with Entecavir from 1-36 months (all HBV-DNA negative; NUC-tx

group) and 5 pts not [NUC-sparing group: HBV-DNA was negative

in 4 and positive in 1 (577 IU/ml)]. All patients were monitored for

HCV-RNA and HBV-DNA every month during the treatment and for

6 months after the stop.

Result: Of the 16 patients enrolled, 14 (87.5%) showed a HCV-

SVR and 2 a relapse. In NUC-tx group, all pts remained HBV-DA

negative. Of the 5 pts in NUC-sparing group, 2 pts remained HBV-


DNA negative and 3 showed a HBV reactivation (2 at first month of

DAA treatment and one at the stop of DAA). Because of NUC-rescue

Tx quickly started in all these 3, HBV-DNA became negative in 2.

Instead, in a 77-years old HBeAg negative/HBV DNA positive patient

treated with SOF + ledipasvir for a HCV-1b cirrhosis, although the

NUC-rescue therapy, HBV DNA became negative at day 90 of DAA

and a severe biochemical and clinical reactivation was observed.

Conclusion: Because of the reciprocal viral interaction between

HBV and HCV, HBV reactivation after the negativization of HCV is

possible in the pts not treated with NUC. Thus, a NUC treatment

may be hypothesized in all HBsAg positive patients before the start

of DAA.


T-36

Liver microRNA hsa-miR-125a-5p may exert anoncosuppressor effect on HCC

L. Onorato 1, N. Coppola 1, G. de Stefano 2,

M. Panella 3, V. Iodice 2, C. Minichini 1, N. Mosca 3,

L. Desiato 3, N. Farella 2, M. Starace 1, G. Liorre 2,

N. Potenza 3, E. Sagnelli 1, A. Russo 3

1 Department of Mental Health and Public Medicine,

Second University of Naples, Italy2 IX Interventional Ultrasound Unit for Infectious

Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy3 Department of Environmental, Biological and

Pharmaceutical Sciences and Technologies, Second

University of Naples, Caserta, Italy

Aims: To evaluate the hsa-miR-125a-5p concentration and the

expression levels of 4 of its validated oncogenic targets in neoplastic

and in non-neoplastic liver tissue of patients with HCC.

Methods: All consecutive patients who underwent a diagnostic

liver biopsy for HCC were enrolled. For each patient, real-time PCR

was used to quantify miR-125a-5p and its targeted transcriptsin

relation to RNU6B and GAPDH, respectively, in HCC and non-HCC

liver tissue.

Results: 55 patients were included in the study; the mean age

was 70.3 ± 6.0 years and 58.1% of patients were males. The etiologic

agent was HCV in 41 patients, HBV in 10 and 4 had NASH-related cir-

rhosis (Child-Pugh class A in 89.1% of casesand classes-B/C in 10.9%).

According to the Barcelona Clinic Liver Cancer (BCLC) class, 47

(85.4%) had class A, 5 (9.1%) class B and 3 (5.5%) class C. Lower levels

of hsa-miR- 125a-5p were observed in HCC tissue than in non-HCC

liver tissues (M ± SD 4.08 ± 2.87 vs. 8.25 ± 4.53 A.U., p < 0.00001).

This difference was highly significant to statistical analysis in the

41 HCV-patients, 3.75 ± 2.8 vs. 7.97 ± 4.85 AU (p < 0.00001) and

still significant although at a lower level in the 10 HBsAg posi-

tive patients, 5.47 ± 3.13, vs. 8.94 ± 3.46AU (p = 0.036), and in the 4

patients with NASH-related cirrhosis, 4.65 ± 2.84 vs. 10.9 ± 1.16AU

(p = 0.015). When patients were stratified according to the epi-

demiological and clinical characteristics of HCC, no difference was

observed between the mean fold-regulation of the miRNA in HCC

vs. non-HCC tissue. The analysis of the expression patterns of four

validated targets showed an up-regulation of MMP11, SIRT7 and c-

Raf, with mean fold regulation values of 3, 2.1 and 1.7, respectively.

Conclusions: These data suggest an oncosuppressor effect of

microRNA hsa-miR-125a-5pon HCC; this effect could be exerted

through the regulation of its oncogenic targets MMP11, SIRT7 and

c-Raf, an observation deserving further investigation.


T-37

Prognostic role of vascular endothelial growthfactor and hypoxia inducible factor in HCCpatients after conventional and DEB-mediatedchemoembolization

A. Meneghetti 1, G. Peserico 1, F. Pelizzaro 1,

C. Pozzan 1, V. Iurilli 2, R. Vezzaro 2, R. Cardin 1,

M. Piciocchi 1, D. Paccagnella 3, F. Farinati 1


Gastroenterology, Padua University, Padua, Italy2 Department of Radiology, Azienda Ospedaliera di

Padova, Padua, Italy3 Department of Gastroenterology, Ospedale

Sant’Antonio ULSS 16, Padua, Italy

Introduction/aims: Transcatheter arterial chemoembolization

(TACE) is the conventional treatment for the BCLC “intermediate”

stage HCC. TACE treatment prompts a neo-angiogenic reaction to

ischemia that probably affects its impact. Our study sought signif-

icant differences, if any, in the levels of two circulating markers of

neo-angiogenesis, Vascular Endothelial Growth Factor (VEGF) and

Hypoxia-Inducible Factor (HIF), after conventional TACE (cTACE)

and DC-Beads mediated TACE (DEB-TACE).

Methods: 170 HCC intermediate stage patients (pts) underwent

TACE (95 c-TACE, 75 DEB-TACE). VEGF and HIF (ELISA) were deter-

mined in sera/plasma, respectively, before (t0) and 4 weeks after

TACE (t1). Tumor vascularization was evaluated at t0 (angiography)

and response to treatment at t1 (CT/NMR scan, mRECIST criteria).

Results: VEGF t0 levels overall significantly correlated with

age (p = 0.031), etiology (p = 0.047), number of lesions (p = 0.001),

BCLC stage (p = 0.008) and progressive disease after treatment

(p = 0.0001). VEGF was significantly higher in non-naïve pts with

previous TACE (p = 0.017). HIF t0 levels significantly correlated

with previous TACE (p = 0.041) and response (p = 0.044). In C-TACE

pts VEGF significantly increased from t0 to t1 (overall p = 0.0001,

C-TACE 0.008, DEB-TACE 0.001), especially in pts with partial

response (p = 0.001) or stable/progressive disease (p = 0.007). HIF

levels significantly decreased from t0 to t1 (p = 0.029) overall and

in partial response-pts. VEGF and HIF at t0 were positively corre-

lated (p = 0.017). VEGF t0 levels, tumor size and Child-Pugh score

emerged as independent predictors of survival, with no significant

results regarding HIF. DEB-TACE and C-TACE groups didn’t differ

in terms of mRECIST response rate, side effects and survival (22

months for C-TACE C.I. 18–26 and 28 for DEB-TACE C.I. 21–35,

p = 0.665; overall 24 months C.I. 20–28).

Conclusions: VEGF was confirmed as an independent predic-

tor of survival and of response to TACE. HIF levels dropped after

treatment and did not correlate with pts’ prognosis. DEB-TACE and

C-TACE have similar effectiveness, side effects and impact on sur-

vival.



T-38

Absolute quantification of intrahepatic HBVcovalently-closed-circular DNA by dropletdigital PCR

G.P. Caviglia 1, M.L. Abate 1, A. Olivero 1, C. Rosso 1,

A. Ciancio 1, E. Bugianesi 1, G.M. Saracco 2,

A. Smedile 1

1 Department of Medical Sciences, University of

Turin, Turin, Italy2 Department of Oncology, University of Turin, Turin,

Italy

Introduction: Novel antiviral strategies for chronic hepati-

tis B virus (HBV) treatment are under development in order to

achieve not only viral suppression but covalently-closed-circular

DNA (cccDNA) elimination. Therefore, a sensitive quantification of

intrahepatic cccDNA is becoming crucial.

Aim: To develop a new assay for cccDNA absolute quantification

using droplet digital PCR (ddPCR) technology.

Materials and methods: Plasmid AM-12 containing whole HBV

genome and DNA extracts from HBsAg-positive and -negative

liver specimens were used for assay characterization. Intrahep-

atic total DNA was isolated by phenol/chloroform method. DNA

concentration and quality were assessed by NanoDrop ND1000

(NanoDrop Technologies). For cccDNA quantification, plasmid-

safe ATP-dependent DNase (Epicentre) was added to digest linear

single- and double-strand DNA. Digested samples were further

purified by phenol/chloroform. Specific primers and FAM-labeled

probe flanking HBV DNA gap region were used for cccDNA quan-

tification. Intrahepatic cccDNA values were normalized for cellular

DNA content using RPP30 probe assay (BioRad) and reported as

cccDNA copies/cell.

Results: A 10-fold dilution of AM12 plasmid was used to test

linearity (105–100 copies/ddPCR reaction, R2 = 0.9998, p < 0.0001)

and concordance correlation coefficient between expected and

observed values (rc = 0.9953, 95%CI 0.9927–0.9970). Reproducibil-

ity was assessed by intra- and inter-run tests using 2 different

cccDNA-positive DNA extracts. Average coefficient of variation

(CV) was 8.29% and 7.92% for intra- and inter-run test, respec-

tively. To test cccDNA recovery, quantification of cccDNA was

performed on digested and undigested paired samples; average

cccDNA copies/ddPCR reaction were 153 ± 23 vs. 434 ± 36, respec-

tively (recovery = 35%; p < 0.0001). Probit analysis was performed to

determine lower limit of quantification (LLoQ) and detection (LLoD)

using 10 replicates of a serially diluted cccDNA-positive sample.

LLoQ was 1.1 × 10−4 copies/cell equal to 2.4 copies/ddPCR reaction

whereas LLoD was 3.4 × 10−5 copies/cell equal to 0.8 copies/ddPCR

reaction.

Conclusions: Our ddPCR-based cccDNA quantitation system is

sensitive and could be suitable for monitoring patients with chronic

HBV infection during antiviral treatment.


T-39

Hepatocellular carcinoma and metabolic riskfactors in a main reference center in Italy

R. Ibrahim Kamal Jouness, C. Rosso, M. Marietti,

G.P. Caviglia, A. Nascè, D. Campion,

A. Cantamessa, P. Carucci, E. Bugianesi


Department of Medical Sciences, University of

Torino, Turin, Italy

Background and aims: Hepatocellular carcinoma (HCC) is

increasingly reported to be related with metabolic risk factors, par-

ticularly in patients with nonalcoholic fatty liver disease (NAFLD)

and Chronic Hepatitis C (CHC).

Methods: Following the introduction of a centralized specialist

team to manage patients with HCC, we characterized the demo-

graphics of patients referred to the GI Division at the University

Hospital of Torino and sought the relationship between the severity

of HCC and their metabolic comorbidities.

Results: In total 1039 patients with HCC were consecutively

referred since 2011. The large majority were HCV (n = 640, 61.6%),

followed by HBV (n = 126, 12.1%), NAFLD (n = 86, 8.3%) and alco-

hol (n = 157, 15.1%). Across the 5-years period (2011–2016), there

was a trend in increase of HCV- and NAFLD-HCC, while alcohol-

HCC decreased and HBV-HCC was stable. In the same time lag, the

age of patients with HCV-HCC progressively decreased (p < 0.001),

while it was unchanged in the other etiologies. Diabetes mellitus

(DM) was diagnosed in 30% of the whole HCC cohort (23% in HCV-,

28.3% in HBV-, 51% in NAFLD- and 47% in alcohol-HCC). Barcelona

Clinic Liver Cancer (BCLC) stage was inversely related with BMI

(OR 0.64, 95% CI 0.42–0.98; p = 0.0384) in the whole cohort and

in the NAFLD-HCC cohort it was directly related to the presence

of DM (OR 11.3, 95% CI 2.1–62.1; p = 0.0052). However, the asso-

ciation between DM and BCLC score was not maintained when

the analysis was restricted to Child-Pugh A. Diabetic patients were

less likely to be treated by surgery (OLT or liver resection) in the

whole HCC cohort. Accordingly, DM was associated with multiple

loco-regional treatments (p = 0.041).

Conclusions: DM is associated with HCC severity according to

BCLC score in the NAFLD-HCC cohort and it is also associated with

multiple loco-regional therapy and less likelihood of surgical treat-

ment in the whole HCC cohort.



T-40

Entecavir monotherapy improves renalfunction in patients developing renal sideeffects during long-term tenofovir treatmentwithout compromising virological response: Amulticenter real-life study in 103 patients

M. Viganò 1, G. Grossi 2, A. Loglio 2,

M. Cappelletti 1, S. Zaltron 3, F. Castelli 3,

P. Andreone 4, V. Messina 5, R. Ganga 6,

N. Coppola 7, A. Marrone 8, M. Russello 9,

A. Marzano 10, G. Taliani 11, M. Fasano 12,

S. Fagiuoli 13, E. Villa 14, F. Bronte 15,

T. Santantonio 16, G. Brancaccio 17, F. Facchetti 2,

P. Lampertico 2

1 UO Epatologia, Ospedale San Giuseppe, Università

degli Studi di Milano, Milan, Italy2 Divisione di Gastroenterologia ed Epatologia,



Italy3 Clinica Malattie infettive e tropicali, Spedali Civili

Brescia, Università degli Studi di Brescia, Brescia,

Italy4 Dipartimento di Scienze Mediche e Chirurgiche,

Università di Bologna, Bologna, Italy5 UOC Malattie Infettive, AO S. Anna e S. Sebastiano,

Caserta, Italy6 SC Medicina Interna, Ospedale S. Michele AO

Brotzu, Cagliari, Italy7 Malattie Infettive, Seconda Università di Napoli,

Dipartimento Salute Mentale e Medicina Preventiva,

Naples, Italy8 Dipartimento di Scienze Mediche, Chirurgiche,

Neurologiche, Metaboliche e dell’Invecchiamento,

Seconda Università di Napoli, Naples, Italy9 UOS Epatologia e Malattie gastroenteriche

dell’A.R.N.A.S. Garibaldi-Nesima, Catania, Italy10 UO Gastroenterologia Universitaria, Ospedale San

Giovanni Battista, Città della Salute e della Scienza di

Torino, Turin, Italy11 Unità di Malattie Infettive e tropicali,

Dipartimento di Medicina Clinica, Università La

Sapienza, Roma, Italy12 Malattie Infettive Ospedale Triggiano, Triggiano,

Italy13 Dipartimento di Gastroenterologia, Epatologia e

Trapianto di fegato, Ospedale Papa Giovanni XXIII,

Bergamo, Italy14 Divisione di Gastroenterologia, AOU Policlinico di

Modena, Università di Modena e Reggio Emilia,

Modena, Italy15 Unità di Gastroenterologia ed epatologia, DiBiMIS,

Università di Palermo, Palermo, Italy16 Dipartimento di Medicina Clinica e Sperimentale,

Università degli Studi di Foggia, Italy17 Cattedra di Malattie Infettive, Seconda Università

di Napoli, Naples, Italy

Introduction: Tenofovir disoproxil fumarate (TDF) is a recom-

mended first-line therapy for chronic hepatitis B (CHB) patients.

However, reduced estimated glomerular filtration rate (eGFR),

hypophosphatemia and Fanconi syndrome have been reported in

some TDF-treated patients. We assessed whether entecavir (ETV)

may be a safe and effective rescue strategy for such patients.

Methods: Serum creatinine, eGFR, serum P, fraction of P re-

absorption (TmPO4/GFR), ALT and HBV DNA were collected every

4 months.

Results: 103 CHB patients (mean age 63 years, 49% cirrhosis, 26%

NUCs-naïve, 41% diabetes and/or arterial hypertension, 98% unde-

tectable HBV DNA) consecutively switched from TDF to ETV due

to renal toxicity were included in this multicenter study. At base-

line (TDF stop and ETV start), patients have been treated with TDF

(41% on reduced doses) for a median time of 35 (3–112) months;

63% had eGFR <60 mL/min, 60% P <2.3 mg/dL and 43% TmPO4/GFR

<0.60 mmol/L, 2 patients had TDF-induced Fanconi syndrome. Dur-

ing 27 months (range: 4–93) of ETV treatment (dosed according

to previous LMV-R and eGFR) all renal parameters improved sig-

nificantly: serum creatinine from 1.26 to 1.11 mg/dL (p < 0.0001),

eGFR from 54 to 65 mL/min (p = 0.003), P from 2.2 to 2.6 mg/dL

(p < 0.0001), TmPO4/GFR from 0.47 to 0.62 mmol/L (p < 0.0001).

Kidney glomerular and tubular dysfunction improved in 46% and

73% of patients, respectively. Renal function fully recovered in

two patients with TDF-induced Fanconi syndrome after 16 and 24

months of ETV therapy. Four out of 48 (8%) LMV-R patients had viro-

logical failure due to ETV-R (4–48 months of treatment, HBV DNA:

112–244 IU/mL, no ALT increase). Early TDF rescue was effective in

all of these patients.

Conclusions: A TDF to ETV switch improves glomerular and

tubular function in most patients developing kidney dysfunction

while on long-term TDF treatment. However, renal function fully

recovered in 38% of the patients, only.


T-41

Copper levels contribute together with the myconcogene to liver transformation

C. Porcu 1, L. Antonucci 2, B. Barbaro 1,

C. Balsano 1,2

1 Institute of Molecular Biology and Pathology

(IBPM)-CNR, Rome, Italy2 Laboratory of Molecular Virology and Oncology,

Francesco Balsano Foundation, Rome, Italy

Introduction: Hepatocellular carcinoma (HCC) represents the

third most frequent cause of cancer death. Biometals metabolism

results significantly altered in tumors: in particular, high serum and

tissue levels of copper were found in HCC patients.

Aim: The purpose of this study was to evaluate the role of cop-

per in liver tumorigenesis, exploiting the action of a known copper

chelator, the ammonium tetrathiomolybdate (TM), alongside to the

assessment of the effect of Omomyc, a dominant negative that it

inhibits the transcriptional activity of myc.

Materials and methods: Human hepatic HepaRG cells were

treated with different concentrations (20, 35 and 50 �M) of CuSO4,

while hepatoma HepG2 and HuH7.5 cells were treated with 50

and 100 �M of TM. These cell lines were also engineered to

express Omomyc under the control of a doxicycline inducible pro-

moter. We evaluated the intracellular copper content by atomic

absorption, cell viability by MTS assay, gene expression by RT-

PCR, protein levels by western blot, the binding of myc on

Ctr1 promoter by ChIP. Cell cycle and death were analyzed by

FACs.

Results: HepaRG treated with CuSO4 showed an increase

of S and G2/M phases, associated with an elevated expres-

sion of pcna, cyclins D, E and B and any increase of cell death.

Accordingly, we highlighted a significant copper up-regulation of

myc. Copper increased the binding of myc on Ctr1 promoter, the


main transporter of copper in hepatocytes. Accordingly, HepG2 and

HuH7.5 treated with TM displayed a strong down-regulation of myc

and the activation of Omomyc, determined a significant reduction

of the intracellular copper content and a reduced expression of Ctr1.

Conclusions: Our data indicate that it exists a positive feedback

between myc and copper intake in liver cells. Thus, the high levels

of copper in liver parenchyma could contribute to the onset of a

favorable conditions for cell transformation.


T-42

Screening of oesophagogastric varices invirus-related compensated advanced chronicliver disease: Beyond the Baveno VI criteria

G. Tosetti 1, V. La Mura 2, A. Aghemo 1,

P. Lampertico 1, R. D’Ambrosio 1, M. Viganò 3,

G. Grossi 1, M. Fraquelli 1, M. Colombo 1,

M. Primignani 1


University of Milan and IRCCS Ca’ Granda Maggiore

Hospital Foundation, Milan, Italy2 Internal Medicine, Biomedical Science for Health,

IRCCS Policlinico San Donato, University of Milan,

Italy3 Division of Hepatology, Ospedale San Giuseppe,

Università di Milano, Milan, Italy

Background: According to Baveno VI consensus, patients with

virus-related compensated advanced chronic liver disease (cACLD),

liver stiffness <20 kPa and platelet count >150,000/mm3 can safely

avoid endoscopy because of a negligible risk of varices requiring

prophylaxis. Such threshold values have been retrospectively val-

idated in several series and allow sparing screening endoscopy in

10 to 32% of patients. However, the accuracy of less conservative

threshold values for TE and platelet count has not been addressed

yet.

Aim: To assess the accuracy of less conservative threshold val-

ues for TE (<25 kPa; <30 kPa) and platelet count (>125,000/mm3;

>100,000/mm3) in a cohort of HBV and HCV untreated cACLD

patients.

Methods: Virus-related cACLD patients undergoing endoscopic

screening for varices were evaluated. Exclusion criteria were:

TE unavailable/unsuccessful, current hepatocellular carcinoma or

other neoplasm, portal vein thrombosis, previous liver decompen-

sation, known OV, splenectomy, interferon exposure within one

year.

Results: 165 of 318 patients fulfilled inclusion criteria. Fourty-

three (26%) had varices; of these, 14 (8%), all identified by the

Baveno VI criteria, had varices requiring prophylaxis. Less con-

servative criteria for TE (<25 kPa or <30 kPa) and platelet count

(>125,000/mm3) maintained the highest accuracy (100% sensitiv-

ity and 100% negative predictive value) and would have spared

endoscopy in 44% and 49% of patients, respectively (p < 0.001 vs

Baveno VI criteria, McNemar test). Further lowering platelet count

threshold to 100,000/mm3 would result in additional saving of

endoscopies (up to 56% or 64% for <25 kPa or <30 kPa TE value),

but 7% or 15% patients with varices requiring prophylaxis would

have been missed, respectively.

Conclusions: Whereas Baveno VI criteria are valid and repro-

ducible in untreated viral-related cACLD to rule out varices

requiring prophylaxis, but allow sparing no more than 30% endo-

scopies, l less conservative threshold values for TE (up to <30 kPa)

and platelet count (up to >125,000/mm3) could further spare up

to 49% endoscopies without losing accuracy.


T-43

Clinical outcomes with long-term sorafenibtreatment: A multicenter, real-life study

R. Sacco 1, S. Parodi 1, T. Zolfino 2, C. Saitta 3,

L. Marzi 4, N. Simonetti 1, S. Attardo 5, M. Rossa 5,

G. Bresci 1, G. Cabibbo 5

1 U.O. Gastroenterologia e Malattie Ricambio-AOUP,

Pisa, Italy2 S.C. Gastroenterologia, AO Brotzu, Cagliari, Italy3 Divisione di Epatologia Clinica e Molecolare,

Dipartimento di Medicina Interna-Università di

Messina, Messina, Italy4 U.O. Gastroenterologia, AOU di Modena-Policlinico,

Modena, Italy5 Sezione di Gastroenterologia, Di.Bi.M.I.S.,

Universita’ di Palermo, Palermo, Italy

Background and aim: The efficacy of sorafenib in patients

with advanced HCC has been shown in multiple clinical trials and

‘field-practice’ experiences. However, only scant information is

available on the characteristics and clinical outcomes of patients

who maintain sorafenib therapy over a long term. In this multi-

center, field-practice study, we evaluated outcomes and safety of

sorafenib in HCC in a cohort of patients receiving long-term treat-

ment.

Patients and methods: HCC patients were retrospectively iden-

tified from 5 Italian referral centers. Enrolled subjects had received

sorafenib treatment for ≥12 months.

Results: 53 patients were enrolled. Mean age at HCC diagnosis

was 65 ± 12 years. Most patients were males (88.7%), had por-

tal vein hypertension (67.9%) and esophageal varices (66%). Prior

locoregional treatments were administered to 69.8% of patients,

with TACE being the most frequent. Child-Pugh (CP) A class was

the most represented (94.3%), followed by CP B (9.4%). Twenty-five

patients (47.2%) had BCLC-C disease and 25 BCLC-B. 86% of patients

had alpha fetoprotein (AFP) level ≤400 ng/l. The most common

underlying etiology was hepatitis infections from C virus (54.7%)

and B virus (20.8%), followed by alcohol use (18.9%). 21/53 (39.6%)

patients had cirrhosis.

Median duration of treatment was 22.3 (12.3–93.6) months,

and the mean daily dose of sorafenib was 537 ± 167 mg. Seven

complete responses (13.2%) were reported; 84.9% of patients expe-

rienced stable disease, with a median response duration of 16

(range, 4–72) months. Median OS was 28.1 (13.1–93.4) months.

AEs were reported in 84.9% of cases, with diarrhea (53.3%), asthe-

nia/fatigue (42.2%) and hand-foot syndrome (35.6%) being the most

frequent AEs.

Conclusions: This multicentre, ‘field-practice’ study highlights

that sorafenib treatment could result in long-term control of HCC

without any major safety issue. In particular, BCLC-B patients seem

to have a prolonged treatment duration.



T-44

DAAs treatment in HCV recurrence after livertransplantation: Clinical usefulness ofnon-invasive methods

F. Ravaioli, M.R. Tamè, G. Marasco, L. Vizioli,

M.C. Morelli, A.D. Pinna, F. Conti, P. Andreone,

A. Colecchia, D. Festi, Research Center for the

Study of Hepatitis (CRS)

Department Medical and Surgical Sciences,

University of Bologna, Bologna, Italy

Introduction: Hepatitis C virus (HCV) recurrence after liver

transplantation (LT) is highly associated with graft severe fibrosis

within 5 years. New direct-acting antiviral agents (DAA) achieve

sustained virological response (SVR) in almost 90% of patients and

it is associated with a significant improvement in clinical outcomes.

Liver (LSM) and spleen (SSM) stiffness measurement by transient

elastography (TE) [Fibroscan] are used to identify liver fibrosis also

in liver transplant recipients. Fibrosis-4 Score (FIB-4) and Aspar-

tate aminotransferase-platelet ratio index (APRI index) are further

non-invasive biomarkers validated for fibrosis evaluation.

Aims: To evaluate changes of LSM, SSM, FIB-4 and APRI Index

at the end of DAAs treatment (EOT) and at 24 weeks of follow-up

(FU24) in patients with HCV recurrence after LT and with advanced

fibrosis stage.

Materials and methods/Results: We enrolled 45 patients (73%

male, median age 63, median of 75 months from LT to DAA; 67% F4,

C-P A in 91%, 96% of the patients achieved SVR24) with HCV recur-

rence after LT, who received DAA treatments. LSM, SSM, FIB-4 and

APRI fibrosis scores and biochemical tests were performed before

DAAs treatment (BL), at EOT and FU24 after. In SVR patients, non-

invasive tests for liver fibrosis assessment significantly changed

(p-value < 0.0001).

(Median; kPa) BL EOT FU24 p-Value

LSM 14.2* 10.4◦ 8.9# <0.0001

LSM Delta% EOT-BL −24% (−9% to 31%)

LSM Delta%FU24-BL −41% (−25% to 53%)

SSM 45* 42.1◦ 35.8# <0.0001

APRI 1.13* 0.47◦ 0.43 <0.0001

FIB4 3.83* 2.68◦ 2.33 <0.0001

* p < 0.05 BL vs EOT.◦

p < 0.05 EOT vs FU24.# p < 0.05 BL vs FU24.

Conclusions: LSM, SSM reduced in SVR HCV patients with

advanced fibrosis after LT not only at EOT but also at FU24, while

serum fibrosis biomarkers only change after EOT, thus suggesting

that TE more accurately detects the long term positive effect of DAA

treatment.


T-45

Liver stiffness and serum fibrosis biomarkervariations after DAAs treatment: Predictive rolein HCC development in cirrhotic patients

F. Ravaioli 1,∗, G. Mazzella 1, P. Andreone 1,

F. Conti 1, S. Brillanti 1, F. Buonfiglioli 1, I. Serio 1,

G. Verucchi 1, M.L. Bacchi Reggiani 2, G. Marasco 1,

A. Colecchia 1, D. Festi 1, Research Center for the

Study of Hepatitis (CRS)


University of Bologna, Bologna, Italy2 Department of Experimental, Diagnostic and

Specialty Medicine, University of Bologna, Bologna,

Italy

Introduction: Direct acting antivirals (DAAs) are an effective

treatment in HCV patients since SVR is achieved in more than 90%

of the patients after 12–24 months. However, HepatoCellular Car-

cinoma (HCC) development risk does not seem to reduce in SVR

patients after DAA-treatments. Recently, it has been suggested that

liver stiffness measurement (LSM) by Fibroscan [Echosens®

] can

predict the HCC risk in liver cirrhosis patients.

Aims: Evaluate the role of LSM and clinical parameters as pre-

dictors of HCC development in patients treated with DAAs.

Materials and methods/Results: In 110 HCV-related cirrhotic

patients (F4 >12.5 kPa) before (BL) and at the end of treatment

(EOT) with DAAs, TE and laboratory tests were performed. AST

to platelet ratio test (APRI) and Fibrosis-4 score (FIB4) were also

assessed. Patients were followed- up for one years after EOT. LSM

variation was expressed as percentage (%). Uni and multivariate

logistic regression analysis was used to identify prognostic factors

for HCC development after DAA. LSM, APRI Test and FIB4 score

significantly (p < 0.001) reduced from BL to EOT. The median

percentage variation between EOT and BL (DELTA% EOT-BL) was

−24.4% (IQR −40% to 14%). Factors associated with increased HCC

development after DAAs treatment (p-value < 0.05) at univari-

ate analysis were MELD, Child-Pugh, Oesophageal varices, HCC

history, LSM EOT, LSM EOT (cut-off = 13.6 kPa) (OR = 3.906;

95% CI = 1.02–14.89), LSM DELTA%EOT-BL (OR = 12.577;

95% CI = 1.56–88.97), LSM DELTA%EOT-BL (cut-off = −24.4%)

(OR = 15.721; 95% CI = 1.69–36.76), APRI EOT (OR = 6.701; 95%

CI = 1.94–23.20), FIB4 BL and EOT.

At multivariate model only Child-Pugh Score (OR = 5.3214;

95% CI = 1.943–14.571) and DELTA%EOT-BL (OR = 24.828; 95%

CI = 2.12–291.63) were independent predictors of HCC develop-

ment (p < 0.05).

Conclusions: Our preliminary result indicates that in cirrhotic

HCV-related patients treated with DAA a reduction of less than

24.4% DELTA% (EOT-BL) LSM, together with Child-Pugh Score can

predict HCC development. Further studies are needed on a larger

population to confirm our data.



T-46

An elevated degree of genetic variabilitycharacterizes Hepatitis Delta Antigen (HDAg)and correlates with high levels of serumHDV-RNA: Implication for disease progressionand design of new pharmacological targets

L. Colagrossi 1, R. Salpini 1, R. Scutari 1, A. Battisti 1,

L. Piermatteo 1, A. Bertoli 1, C. Minichini 2,

P. Trimoulet 3, H. Fleury 3, E. Nebuloso 4,

M. De Cristofaro 4, G. Cappiello 4, A. Spanò 4,

V. Malagnino 5, T. Mari 6, A. Barlattani 6,

N. Iapadre 7, M. Lichtner 8, C.M. Mastroianni 8,

I. Lenci 9, C. Pasquazzi 10, G.M. De Sanctis 11,

A. Galeota Lanza 12, M. Stanzione 13,

G. Stornaiuolo 13, M. Marignani 10, L. Sarmati 5,

M. Andreoni 5, M. Angelico 9, C.F. Perno 1,

N. Coppola 2, V. Svicher 1


Tor Vergata University, Rome, Italy2 Department of Mental Health and Public Medicine,

Section of Infectious Diseases, Second University of

Naples, Naples, Italy3 Laboratoire de Virologie, Hôpital Pellegrin tripode,

Bordeaux, France4 Sandro Pertini Hospital, Rome, Italy5 Infectious Diseases Unit, Tor Vergata University

Hospital, Rome, Italy6 Nuovo Regina Margherita Hospital, Rome, Italy7 San Salvatore Hospital, L’Aquila, Italy8 Department of Public Health and Infectious

Diseases, Sapienza University, Rome, Italy9 Hepatology Unit, Tor Vergata University Hospital,

Rome, Italy10 Department of Gastroenterology, S. Andrea

Hospital, Rome, Italy11 Umberto I Hospital, Rome, Italy12 Gastroenterology Unit, AO Cardarelli, Naples, Italy13 Viral Unit, Second University of Naples, Naples,

Italy

Introduction: HDV-antigen (HDAg) interacts with HBV surface

protein (HBsAg). No information is available on the extent of genetic

variability in HDAg and its impact on virological parameters.

Methods: Among 78 patients (pts) with chronic HBV + HDV

infection, HDAg gen-1 sequences are obtained for 47 pts and HBsAg

gen-D sequences for 31 pts.

Shannon Entropy (SE) is used to measure the extent of amino

acid variability at each HDAg- and HBsAg-position in overall pop-

ulation and by stratifying patients according to serum HDV-RNA:

18 pts with HDV-RNA < 5logIU/ml defined as low-viremic and 29

with HDV-RNA > 5logIU/ml defined as highly-viremic. Positions

with SE = 0 are defined conserved.

Results: A lower % of conserved residues is observed in HDAg

than HBsAg (49.5% vs 69.2%, P < 0.001). In particular, HDAg-domains

with a lower % of conserved positions are multimerization-domain

(MD, aa: 31–52) and RNA-binding domains (RDBs, aa: 2–27;

97–107; 136–146), followed by nuclear-localization signal (NLS, aa:

68–88) and viral-assembly signal (VAS, aa: 195–214) (% conserved

residues: 27.3%, 31.3%, 52.4% and 70%, respectively).

Stratifying pts according to HDV-RNA, a higher degree of genetic

variability is observed in highly-viremic than in low-viremic pts

(%conserved residues: 55.6% vs 65.9%, P = 0.037). In addition, HDAg-

mutations S6R, A22S and L90S significantly occur more frequently

in highly-viremic than in low-viremic pts (S6R: 24.1%[7/29] vs

0%[0/18], P = 0.034; A22S: 72.4%[21/29] vs 33.3%[6/18], P = 0.015;

L90S: 31%[9/29] vs 0%[0/18], P = 0.008). In particular, median (IQR)

serum HDV-RNA in presence of ≥1 of these mutations is 5.7

(5.1–6.3) vs 4.4 (3.8–5.6) in their absence (P = 0.003). S6R and A22S

reside in RDB-I, while L90S is close to NLS (domains crucial for HDV

life-cycle), suggesting that these mutations can confer a replicative

advantage to HDV.

Conclusions: An extensive genetic variability in HDAg corre-

lates with elevated serum HDV-RNA, suggesting a still ongoing

evolutionary HDV adaptation to human host. This genetic vari-

ability should be taken into account for the design of novel

pharmacological targets.


T-47

Spleen stiffness measurement: A usefulprognostic tool in HCV patients treated withDAAs regimens

F. Ravaioli 1, G. Marasco 1, M.L. Bacchi Reggiani 2,

G. Mazzella 1, F. Buonfiglioli 1, A. Porro 1,

S. Brillanti 1, A. Colecchia 1, D. Festi 1, Research

Center for the Study of Hepatitis (CRS)


University of Bologna, Bologna, Italy2 Department of Experimental, Diagnostic and

Specialty Medicine, University of Bologna, Bologna,

Italy

Introduction: The new Hepatitis C Virus (HCV) treatment

with direct-acting antivirals (DAA) reaches a sustained virologic

response (SVR) in more than 90% of the patients and an improve-

ments of liver stiffness (LSM) by transient elastography (TE)

[Fibroscan] has been reported. Recently, it has been shown that

portal hypertension, evaluated with hepatic venous pressure gra-

dient, ameliorates after DAA treatment. Spleen (SSM) stiffness

measurement by TE can be used for non-invasive assessment and

monitoring of portal hypertension (PH) in CHC patients; however,

to date no evidence on the role of SSM by TE in CHC patients treated

with DAA is available.

Aims: Evaluate the role of SSM and LSM in HCV patients treated

with DAA.

Materials and methods/Results: 100 HCV patients (73% male,

median age 63, 93% CP-A, 93%, 95% SVR24) with advanced liver

fibrosis who received DAA treatments were prospectively evalu-

ated. SSM, LSM together with biochemical tests were performed

before (BL), at the End of Therapy (EOT) and 24 wk (FU24) after DAA.

In 10 SSM was not technically feasible. Table shows the results: SSM

and LSM were significantly reduced at EOT and FU24 (p < 0.0001);

however, SSM significantly decreased in F4, but not in F3 patients.

BL EOT FU24 p-Value

SSMAll (n = 90) 49.6 44 35.6 <0.0001

F3 (n = 15) 27.4 28.9 27 n.s

F4 (n = 75) 63.8 48.8 39 <0.0001

LSMAll (n = 100) 15.1 11.4 10.1 <0.0001

F3 (n = 25) 10.4 8.7 6.1 <0.0001

F4 (n = 75) 17.3 13.5 12 <0.0001

Conclusions: SSM and LSM by TE decreased in all patients

at EOT and FU24 after DAA, suggesting a possible treatment’s

effect on inflammation and fibrosis and consequently on PH. The

changes in SSM may be mainly due to a portal pressure reduction,


being present only in F4 patients. SSM and LSM represent a useful

prognostic tools in patients treated with DAA.


T-48

The role of Spleen Stiffness measurement aspredictor of HCC recurrence after curativeresection in cirrhotic patients

G. Marasco 1,∗, A. Colecchia 1, A. Colli 2,

G. Casazza 3, F. Ravaioli 1, A. Cucchetti 1,

M. Cescon 1, A.D. Pinna 1, D. Festi 1


University of Bologna, Bologna, Italy2 Department of Internal Medicine, Manzoni Hospital

Lecco, Lecco, Italy3 Department of Clinical and Biochemical Sciences,

University of Milan, Milano, Italy

Introduction: Hepatocellular carcinoma (HCC) is a frequent

complication in patients with chronic liver diseases and one of

the most common malignancies worldwide. Liver resection is the

gold standard treatment option for patients with solitary tumors;

however, tumor recurrence complicates 70% of cases of hepatic

resection at 5 years. Recently it has been demonstrated that the

degree of portal hypertension (PH) measured by HVPG is directly

correlated with the risk of developing HCC. We recently docu-

mented that spleen (SSM) and liver (LSM) stiffness measurement

are accurate non-invasive markers of portal hypertension in cirrho-

sis.

Aims: The aim of our study was to identify the role of SSM and

LSM as predictors of HCC recurrence after curative resection.

Materials and methods/Results: 157 patients with HCC who

underwent curative resection between 2008 and 2014 were

prospectively enrolled to assess early (<12 months) and late (>24

months) recurrence. The results of LSM and SSM assessed with

TE (Fibroscan®

, Echosens) together with clinical and histological

data were collected before surgery and their association with early

or late recurrence was assessed by uni and multivariate logistic

regression analysis. Forty-nine (49) patients with early and 22 with

late HCC recurrence were identified during follow-up period. At

univariate analysis, early recurrences were associated with eti-

ology, number of nodules, HCC diameter and grading, infiltrated

resection margins and satellitosis. Multivariate analysis showed

that only viral (HCV, HBV) etiology, tumor diameter and margin

infiltration were independently associated with early recurrence

with an area under the curve (AUC) of 0.73. At univariate analysis

late recurrence was associated only with SSM (p = 0.0027) with an

AUC of 0.70.

Conclusions: Early HCC recurrence is associated with HCC clin-

ical and pathological features; late recurrence was best predicted

by the assessment of SSM, thus suggesting a role of portal hyper-

tension in the development of HCC late recurrence.


T-49

Impact of adrenal dysfunction on psoas musclethickness assessed by computed tomography inpatients with liver cirrhosis

G. Privitera, L. Spadaro, D. Russo, S. Marchisello,

F. Purrello

Department of Clinical and Experimental Medicine,

University of Catania, Catania, Italy

Background and aims: Sarcopenia and adrenal insufficiency

(AI) are common features of cirrhosis and contribute to mortality.

Nausea and weight loss represent common symptoms of AI and

may participate to muscle waste. The aim of our study was to eval-

uate the role of AI on psoas muscle thickness assessed by CT in a

cohort of cirrhotics.

Methods: 74 cirrhotic patients were examined. Laboratory

parameters of malnutrition (albumin, pre-albumin, transferrin and

lymphocytes) were assessed. Axial (APMT) and Transversal psoas-

muscle-thickness (TPMT) were measured on CT at the level of the

umbilicus. Psoas-muscle-thickness was normalized to stature by

division by height (APMT/h and TPMT/h). Adrenal function was

assessed using the Standard-Dose-short-synacthen test. A peak

cortisol > 18 �g/dl was defined normal.

Results: AI was present in 23 patients. The severity of cirrho-

sis graded by Child-Pugh and MELD was increased in AI compared

to normal adrenal function (NAF) patients (p = 0.001). AI patients

exhibited lower values of pre-albumin (6 ± 3 vs 10 ± 8; p = 0.03)

and transferrin (150 ± 84 vs 220 ± 76; p = 0.003) compared to NAF

subjects. A significant reduction of TPMT values was observed in

female compared to male (23.5 ± 6 vs 31 ± 8; p = 0.002). Cirrhotics

with AI showed increased levels of both APMT (44 ± 6 vs 20 ± 5;

p = 0.02) and TPMT (32 ± 8 vs 27 ± 7; p = 0.03) compared to NAF. A

significant correlation was found between TPMT/h and peak cor-

tisol values (r = 0.38; p = 0.01). When we stratified our population

using TPMT/h < 16.8 mm/h, the number of NAF patients was signif-

icantly increased compared to AI (p = 0.01). Finally, after stratifying

our our population according to ascites presence, we observed a

significant reduction of APMT in ascites (37 ± 5 vs 43 ± 7; p = 0.02).

Conclusion: Our data suggest that adrenal dysfunction does

not contribute to sarcopenia in cirrhotic patients. Cortisol is an

important catabolic hormone, and its deficiency seems to play a

protective role on muscle waste in cirrhotic patients.



T-50

Validation of a simple scoring system to predictsorafenib effectiveness in patients withhepatocellular carcinoma

R. Tortora 1, A. Casadei Gardini 2, G. Cordone 1,

G. Marisi 3, F.G. Foschi 4, M. Scartozzi 5,

R. Granata 1, L. Faloppi 5, S. Cascinu 6,

N. Silvestris 7, O. Brunetti 7, V.O. Palmieri 8,

G. Ercoloani 9, G.G. Di Costanzo 1

1 Transplantation-Liver Unit, Cardarelli Hospital,

Naples, Italy2 Medical Oncology, Istituto Scientifico Romagnolo

per lo Studio e Cura dei Tumori, Meldola, Italy3 Biosciences Laboratory, Istituto Scientifico

Romagnolo per lo Studio e Cura dei Tumori, Meldola,

Italy4 Internal Medicine, Faenza Hospital, Faenza, Italy5 Medical Oncology, University Hospital Cagliari,

Cagliari, Italy6 Hematology and Oncology, University of Modena

and Reggio Emilia, Modena, Italy7 Medical Oncology, Cancer Institute “Giovanni Paolo

II”, Bari, Italy8 Biomedical Sciences and Human Oncology,

University of Bari, Bari, Italy9 Surgical Oncology, General Hospital

Morgagni-Pierantoni, Forlì, Italy

Background and aims: Sorafenib is the recommended treat-

ment in patients with advanced stage hepatocellular carcinoma

(HCC). Previously, we constructed a simple scoring system based

on the occurrence of main sorafenib off-target effects (OTE); that

was able to predict patient’s outcomes after four weeks of ther-

apy. The aim of the present study is to validate this score in an

independent, real-life cohort.

Methods: Clinical records of 275 outpatients treated with

sorafenib in 8 Italian centers from September 2008 to September

2015 were retrospectively analysed. Skin toxicity, diarrhoea and

arterial hypertension, occurring within the first month of therapy,

were the OTEs considered to calculate the score. At each OTE was

assigned 1 point if present; with the score ranging between 0 and 3.

Results: Median overall survival (OS) was 10.8 months; median

time-to-progression (TTP) was 5.1 months. A progressive increase

in median OS and TTP was observed from patients with score 0

to patients with score 3 (p = 0.000). The survival probability at 6,

12, and 24 months was 55.1%, 24.5%, and 7.9% in patients with

score 0; 62.8%, 40.4%, and 19.6% in patients with score 1; 85.6%,

59.0%, and 22.8% in patients with score 2; 100%, 80.9%, and 46.2% in

patients with score 3, respectively. Disease control rate in patients

with score 0, 1, 2, 3 was 34.3%, 51.6%, 80.9%, and 96.3%, respectively

(p = 0.000). Complete or partial response was absent in patients

with score 0, but it occurred in 12.1%, 23.5% and in 44.4% of patients

with score 1, 2 and 3 respectively (p = 0.000). Multivariate analysis

showed that only performance status and the simple score were

independently associated with OS.

Conclusions: We validated a scoring system useful to predict

outcomes in sorafenib treated patients with HCC. This score is sim-

ple to calculate and for its characteristics is an ideal tool to be

implemented in daily clinical practice.








Selected Posters Friday

F-01

Advanced BCLC hepatocellular carcinomaincludes a very heterogeneous patientpopulation treatable with different therapiesand with different prognosis

F. Garuti 1, E.G. Giannini 2, L. Bucci 1, M. Valente 1,

B. Lenzi 1, F. Trevisani 1, on behalf of Italian Liver

Cancer (ITA.LI.CA) group


Semeiotica Medica, Bologna, Italy2 Department of Internal Medicine, University of

Genova, Genova, Italy

Introduction: The Barcelona Clinic Liver Cancer advanced stage

(BCLC-C) of hepatocellular carcinoma (HCC) includes heteroge-

neous patients. Sorafenib is the recommended treatment.

Aim: To investigate: overall survival (OS) of BCLC-C stage

patients, subclassified by Performance Status (PS) and tumoral fea-

tures; treatment distribution; results of Sorafenib therapy.

Materials and methods: Retrospective analysis of 837 consec-

utive patients diagnosed with advanced HCC from 2008 to 2014.

Patients were divided as follows: 386 with stand-alone PS1, i.e.

without other BCLC-C characteristics (PS1); 147 with stand-alone

PS2 (PS2); 224 with macrovascular invasion (MVI), regardless of

PS; 51 with extra-hepatic spread (EHS), regardless of PS; 29 with

both MVI + EHS, regardless of PS.

Results: Patients with MVI, EHS and MVI + EHS presented with

larger, more frequently with multifocal/infiltrating/massive HCC

and higher alpha-fetoprotein levels compared to PS1 and PS2 sub-

jects. Median OS was 38.6 months in PS1 patients, 22.3 months in

PS2, 11.2 months in EHS, 8.2 months in MVI, and 3.1 in MVI + EHS

(p < 0.001). OS was longer in patients with peripheral than in those

with central MVI (11.2 vs. 7.1 months; p = 0.005). In PS1 patients

prevailed loco-regional therapies (39.6%) and in PS2 the best sup-

portive care (BSC; 42.2%). Sorafenib and BSC were the main utilized

treatments in patients with MVI, EHS and MVI + EHS. Sorafenib

achieved different OS according to the type of MVI (peripheral: 14.2

months, central: 8.2 months), EHS (11.1 months), or MVI + EHS (4.1

months). Sorafenib was significantly superior to BSC in MVI and EHS

groups but not in MVI + EHS patients. Child-Pugh class, ascites, MVI,

EHS, AFP and treatment were independent predictors of mortality.

Conclusions: (1) PS1 alone is not a sufficient criterion to allo-

cate HCC patients to the advanced BCLC stage; (2) BCLC-C patients

should be sub-classified according to PS and tumoral features; (3)

Sorafenib confirms its superiority to BSC in patients with MVI and

EHS.


F-02

A genic and epigenetic combination therapy forliver cancer

L. Rinaldi 1, G. Franci 2, V. Folliero 2, L. Palomba 2,

R. Isticato 3, C. Zannella 2, R. di Francia 4,

I. De Sio 5, G. Morelli 6, S.Lastoria 7, L. Altucci 8,

C. Pedone 6, A. Ascione 9, L.E. Adinolfi 1,

M. Galdiero 2

1 Department of Medical, Surgical, Neurological,

Metabolic and Geriatric Science, Università della

Campania Luigi Vanvitelli, Naples, Italy2 Department of Experimental Medicine, Università

della Campania Luigi Vanvitelli, Naples, Italy3 Department of Biology Federico II University,

Naples, Italy4 Department of Hematology, Foundation C. Pascale,

Naples, Italy5 Department of Clinical and Experimental Internal

Medicine, Università della Campania Luigi Vanvitelli,

Italy6 Department of Pharmacology, Federico II

University, Naples, Italy7 Department of Diagnostic, Foundation C. Pascale,

Naples, Italy8 Department of Biochemistry, Biophysics and

Pathology, Università della Campania Luigi

Vanvitelli, Naples, Italy9 Department of Internal Medicine, Buon Consiglio

Fatebenefratelli, Naples, Italy

Introduction and aim: Genetic and epigenetic mechanisms are

the baseline of cancer initiation, progression and prognosis. Liver

cancer can be the result of viral infections, metabolic disorder,

1590-8658/


genetic variation/mutation and epigenetic deregulation. Among

those phenomena evidence of oncosuppressor gene silencing like

p53 and TRAIL represent the major class of liver cancer patients.

Aim of the project is the re-activation of silenced apoptotic path-

way in liver cancer models, plasmidic gene delivery and epigenetic

treatment.

Material and methods: HepG2 ATCC were selected for all

the experiments. Lipofectamine 2000 (Invitrogen) was used for

pEGFP-TRAIL and pEGFP-p53 (Addgene plasmids) and the respec-

tive control were selected and propagated in LB broth in order to

obtain the necessary amount. Plasmid were purified with Invitro-

gen PureLink (Thermo) kit. GFP (Green Fluorescent Protein) was

acquired via FACS excalibur DB analysis. MS.275 (HDACi class I)

was acquired from selleckchem.

Results: Cell cycle analysis was achieved on HepG2 cells

transfected with TRAIL-GFP and pEGFP-p53 recombinant protein.

Results were analysed with Cell-Quest and ModIFit software. Data

shown the re-expression of selected recombinant proteins in over

than 30% cells post 24 h from transfection. The transfected cells

were treated post 24 h with MS-275 for other 8 h and the cells were

collected. The total protein extract was analysed by Western blot

and the apoptosis pathways were evaluated via caspase activation

proteins. In details we detect the relative bands for caspase 8 and

caspase 9 full lengths and activated form in transfected cells and

post MS-275 treatment.

Conclusion: Results showed the possibility to restore the

expression of pro-apoptotic gene TRAIL and p53 in a liver cancer

model HepG2. Moreover, the treatment with epigenetic modula-

tors MS-275 enhanced the pro-apoptotic effect mediated by the

re-expression of those silenced genes.


F-03

Risk factors of early emergent hospitalreadmission and 6-month mortality in patientswith cirrhosis after a recovery from bacterial orfungal infection

F. Morando, S. Piano, S. Rosi, M. Stanco, C. Pilutti,

E. Vettore, A. Romano, S. Fasolato, M. Tonon,

A. Brocca, A. Sticca, P. Angeli

Department of Medicine, University of Padova,

Padova, Italy

Introduction and aims: In patients with cirrhosis, infections

represent a frequent trigger for complications, increasing fre-

quency of hospitalizations and mortality rate. The study aims to

identify predictors of early readmissions (30-days) and to iden-

tify predictors of midterm mortality (6-months) in patients with

liver cirrhosis discharged after a hospitalization for bacterial and/or

fungal infection.

Materials and methods: All patients with cirrhosis discharged

from the University Hospital of Padova after an admission for a

bacterial and/or fungal infection from January 2010 and July 2016,

were included in the study and followed up for at least 6-months.

Results: 199 patients with liver cirrhosis were included in the

study. C-reactive protein (CRP) was found to be the only indepen-

dent predictor of early readmission due to an infection (OR = 1.76;

p = 0.004). Considering early readmissions as a whole, the CRP

value at discharge was found to be an independent predictor of

readmission (OR = 1.91; p = 0.022), as well as the diagnosis of acute-

on-chronic liver failure (ACLF) during the hospital stay (OR = 2.48;

p = 0.008) and the hospitalization in the last 30 days previous to the

admission/inclusion in the study (OR = 1.50; p = 0.042).

Moving to the second part of analysis, age (HR = 1.05;

p = 0.001), diabetes mellitus (HR = 2.14; p = 0.010), refractory

ascites (HR = 2.21; p = 0.008), MELD score at discharge (HR = 1.11;

p < 0.001), diagnosis of sepsis (HR = 2.40; p = 0.019) and CRP values

at discharge (HR = 1.73; p = 0.002) were found to be independent

predictors of 6-months mortality.

Conclusions: CRP showed to be an independent predictor of

early hospital readmission and of 6-months mortality in patients

with cirrhosis after a hospitalization for bacterial and/or fungal

infection. We identified a cut-off value of CRP, 10 mg/L, able to

stratify patients at low or high risk of readmission and mortality.

CRP values could be used, both in the stewardship of antibiotic

treatment and to identify fragile patients that deserve a strict

surveillance program.


F-04

Effectiveness of percutaneous ethanol injectionin relation to hepatocellular carcinoma size: Asingle centre experience

G.G. Di Costanzo, R. Granata,

M. Sanduzzi-Zamparelli, L. Falco, G. Cordone,

R. Tortora

Department of Transplantation – Liver Unit,

Cardarelli Hospital, Naples, Italy

Background and aims: Percutaneous ethanol injection (PEI) for

hepatocellular carcinoma (HCC) has been progressively replaced by

thermal ablation due to its predictable ablation volume and better

efficacy in nodules >20 mm. Nonetheless, PEI remains still used in

selected patients with very small or high-risk located nodules, and

data on its efficacy in relation to nodule volume are scanty. Aim

of this study was to evaluate PEI response rate in nodules with

different size.

Methods: Clinical records of 291 naïve HCC patients treated

with PEI between 1991 and 2010 at our Unit were retrospectively

analysed. Tumor response and recurrence were evaluated at CT or

MRI after four weeks, and then every six months from the proce-

dure according to mRECIST-criteria. Main outcome was complete

tumor-response (CTR), secondary outcomes were HCC recurrence

and time to progression (TTP).

Results: Median follow-up was 20 months (range: 2–189). All

patients had cirrhosis; 59.1% were Child-A; 30.2% Child-B and 10.6%

Child-C. The overall CTR rate was 58.7% (171/291), 81.3% (61/75)

in patients with lesions sized 10–20 mm (Group 1); 59% (52/88)

in patients with lesions of 21–30 mm (Group 2); 60% (36/60) for

lesions 31–40 mm (Group 3), and 29.5% (20/68) for lesions >40 mm

(Group 4). Fourty-two/171 CTR patients had more than one lesions:

11 patients in Group 1, 18 in Group 2; 8 in Group 3 and 5 in Group

4. Fifty-nine/120 of non-CRT patients had more than one lesion.

The overall and local recurrence rate was 46% (28/61) and 36% for

Group 1, 52% (27/52) and 15% for Group 2, 50% (18/36) and 28% for

Group 3, and 60% (12/20) and 30% for Group 4, respectively. Median

TTP was 21 months in Group 1; 11 months in Group 2, 12 months

for Group 3 and 9 months for Group 4. Median overall-survival 28

months (range: 2–189).

Conclusion: PEI efficacy is mainly influenced by the size of the

nodule. Although the introduction of thermal ablative treatments,

in selected cases PEI may be still employed even in nodules >20 mm.



F-05

In HBeAg-negative chronic HBV infection,HBsAg levels profoundly differ amongHBV-genotypes and can be affected by theextent of HBsAg variability: Can quantitativeHBsAg truly reflect intra-hepatic HBV reservoir?

R. Salpini 1, A. Battisti 1, O. Anastasiou 2, U. Gill 3,

L. Colagrossi 1, A. Bertoli 1, L. Fabeni 4, V. Fini 1,

L. Piermatteo 1, A. Iuvara 5, V. Malagnino 6,

C. Cerva 6, M. Lichtner 7, C. Mastroianni 7,

G. De Sanctis 8, M. Paoloni 9, M. Marignani 10,

C. Pasquazzi 10, N. Iapadre 11, T. Mari 12,

G. Parruti 13, I. Vecchiet 14, L. Sarmati 6,

M. Andreoni 6, M. Angelico 15, S. Grelli 1,5,

P. Kennedy 3, J. Verheyen 2, C.-F. Perno 1,

V. Svicher 1


Tor Vergata University, Rome, Italy2 Institute of Virology, University-Hospital,

University Duisburg-Essen, Essen, Germany3 Hepatology, Centre for Immunobiology, Blizard

Institute, Barts and The London School of Medicine &

Dentistry, QMUL, London, UK4 Antiretroviral Drug Monitoring Laboratory,

National Institute for Infectious Diseases, L.

Spallanzani, IRCCS, Rome, Italy5 Microbiology and Virology Unit, Tor Vergata

University Hospital, Rome, Italy6 Infectious Diseases Unit, Tor Vergata University

Hospital, Rome, Italy7 Department of Public Health and Infectious

Disease, “Sapienza” University, Rome, Italy8 “Umberto I” University Hospital, Rome, Italy9 Infectious Disease Unit, “S.S. Filippo e Nicola”

Hospital, Avezzano, Italy10 Department of Gastroenterology, “S.Andrea

Hospital”, Rome, Italy11 “San Salvatore Hospital”, L’Aquila, Italy12 “Nuovo Regina Margherita” Hospital, Rome, Italy13 Infectious Disease Unit, Pescara General Hospital,

Pescara, Italy14 Clinic of Infectious Diseases, Department of

Medicine and Science of Aging, University “G.

d’Annunzio” Chieti-Pescara, Chieti, Italy15 Hepatology Unit, Tor Vergata University Hospital,

Rome, Italy

Introduction: HBsAg-levels are proposed as marker of intra-

hepatic HBV-reservoir. A recent in-vitro study showed variation in

HBsAg-production in different HBV-genotypes. Limited informa-

tion is available on HBsAg-levels in patients infected with different

HBV-genotypes in HBeAg-negative chronic HBV-infection.

Methods: This study includes 301 consecutive-patients with

HBeAg-negative chronic HBV-infection, drug-naïve, and monitored

for >1 year: 126 inactive-carriers with persistent serum HBV-

DNA <2000 IU/ml and normal transaminases (group-A), and 175

with persistent serum HBV-DNA >2000 IU/ml (group-B). Degree of

HBsAg-variability is measured by mean genetic-distance.

Results: Median (IQR) HBV-DNA is 2.8 (2.3–2.9) and 4.1

(3.7–5.2) IU/ml, while median (IQR) ALT is 28 (21–38) and 34

(25–55) U/L in group-A and -B, respectively. HBV-genotypes are:

D = 72.2%, A = 15.9%, E = 11.9% in group-A, and D = 78.3%, A = 14.3%,

E = 7.4% in group-B.

In group-A, median (IQR) HBsAg is significantly lower in

genotype-D than in genotype-A and -E (730 [204–2932] vs. 5741

[3526–14,290] and 10,288 [7172–13,408] IU/ml, P < 0.001). Simi-

lar results are observed in group-B (3436 [1466–8126] vs. 7992

[5069–21,221] and 10,825 [6544–18,216] IU/ml, P < 0.01). More-

over, in group-A, HBsAg-levels <1000 IU/ml (proposed to define

genotype-D patients as inactive-carriers) are observed in 57.1% of

genotype-D, 15.0% of genotype-A and 0% of genotype-E (P < 0.001).

In group-A, the degree of HBsAg C-terminus genetic-variability

(aa: 170–226, known to modulate HBsAg-secretion) is higher

in genotype-D and progressively declines in genotype-A and -

E (0.033 + 0.023 for D, 0.029 + 0.015 for A, 0.026 + 0.012 for E).

By stratifying group-A according to HBsAg-levels in genotype-D,

the degree of HBsAg C-terminus genetic-variability is significantly

higher in patients with HBsAg < 1000 IU/ml than in patients with

HBsAg > 1000 IU/ml (0.041 + 0.024 vs. 0.022 + 0.017, P < 0.001).

Conclusions: HBsAg-levels in HBV genotype-D are significantly

lower than in genotype-A and -E in different phases of HBeAg-

negative chronic HBV-infection including inactive-carrier status. In

genotype-D infected patients, higher genetic-variability in HBsAg

C-terminus correlates with lower HBsAg-levels (presumably by

impairing proper HBsAg-secretion). In this setting, HBsAg-levels

cannot be a direct measure of intrahepatic cccDNA reservoir,

supporting HBV-genotyping to better characterize patients with

HBeAg-negative chronic HBV-infection.


F-06

Hepatocellular carcinoma recurrence rate inHCV infected patients treated with directantiviral agents. A single center experience

R. Granata, G.G. Di Costanzo,

M. Sanduzzi Zamparelli, M. Guarino, G. Cordone,

G. D’Adamo, R. Tortora

Department of Transplantation – Liver Unit,

Cardarelli Hospital, Naples, Italy

Background and aims: In the last few years many HCV patients

with previous diagnosis of hepatocellular carcinoma (HCC) have

been treated with direct antiviral agents (DAAs) for HCV infection.

However there are conflicting data on HCC-recurrence rate after

DAAs therapy. Aim of this study was to prospectively evaluate the

rate of HCC recurrence following sustained virological response

(SVR) by DAAs.

Methods: From April 2015 to September 2016 we consecutively

enrolled HCV-infected patients previously treated for HCC at our

Unit. All patients had a free-disease survival from HCC of at least

6 months before starting DAAs. The efficacy of HCC therapy was

evaluated according to mRecist criteria at CT or MRI, within 30 days

from the start of therapy. All patients underwent DAAs therapy,

selected on an individual basis according to the recommendation

issued by the AISF.

Results: A total of 71 patients were enrolled. Among them, 42

patients had available data on SVR status and were considered for

the analysis. M/F ratio was 21/15. Median age of the patients was

73 years (range: 52–85). Median follow-up was 12 months after the

beginning of treatment (range: 6–18). Genotype distribution was as

follows: 36 patients infected with genotype 1 (85.7%), 5 with geno-

type 2 and 1 patients with genotype 3. SVR was achieved in 38/42

patients (90.5%). HCC recurrence was observed in 11/38 patients

with SVR (28.9%). Median time for recurrence was 9 months from

the start of therapy with a range of 1–13 months. Two patients

showed recurrence during therapy. Among the patients who did


not achieve SVR, 1/4 showed HCC recurrence after 10 months from

end of treatment.

Conclusions: Treatment with DAAs are highly effective even in

patients with advanced liver disease. Nonetheless, in patients with

previous history of HCC, the eradication of HCV did not reduce the

risk of short and medium term recurrence.


F-07

Effects of treatment with Maraviroc a CCR5inhibitor on a human hepatic stellate cell line

N. Coppola 1, A. Perna 2, A. Lucariello 2,

S. Martini 1, M. Macera 1, M.A. Carleo 3,

G. Guerra 4, V. Esposito 5, A. De Luca 2

1 Department of Mental Health and Preventive

Medicine, Section of Infectious Diseases, Second

University of Naples, Italy2 Department of Mental Health and Preventive

Medicine, Section of Human Anatomy, Second

University of Naples, Italy3 Department of Infectious Disease and Infectious

Emergencies, Immunodepression and Systemic

Infections Unit, P.O. Cotugno – A.O. Ospedali dei

Colli, Naples, Italy4 Department of Medicine and Health Sciences,

University of Molise, Campobasso, Italy5 Department of Infectious Disease and Infectious

Emergencies, General Infectious Diseases Unit, P.O.

Cotugno – A.O. Ospedali dei Colli, Naples, Italy

Aims: We evaluated the effects of the treatment with the CCR5

inhibitor Maraviroc on LX-2, a human hepatic stellate cell line

(HSC), derived from normal human stellate cells spontaneously

immortalized.

Methods: LX-2 viability was determined using MTT [3-

(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]; the

cells, pretreated with Maraviroc and TGF-�1, have been studied by

Western blot assay to evaluate the expression of cyclin D1, p21, p53,

collagen type I, a-SMA, TGF-b1. The expression of MMP-2, MMP9,

TIMP-1 and TIMP-2 were evaluated by RT-PCRs in correlation to

GADPH expression to standardize differences in the quantity of

cDNA used in the PCR reaction.

Results: Treatment with Maraviroc resulted in a block in S phase

of LX-2 cells with increased expression levels of cyclin D1 and p21

while the expression of p53 was reduced. Treatment with Maravi-

roc was also able to block the accumulation of fibrillar collagens

and extracellular matrix proteins (ECM), as demonstrated by the

decrease of specific markers as Collagen type I, �-SMA and TGF-�1.

In addition we observed a down regulation of both metalloproteins

(MMP-2, MMP-9), used for the degradation of the extracellular

matrix and their inhibitors (TIMP-1, TIMP-2).

Conclusions: The identification of a compound that may mod-

ulate the dynamic of liver fibrosis could be crucial in all chronic

liver diseases. Maraviroc could play an important role because, in

addition to its own anti-HIV activity, it could reduce the release of

pro-inflammatory citokynes implicated in liver fibrogenesis, mak-

ing this drug particularly recommended for antiretroviral regimens

chosen to treat HIV/HCV coinfected patients.


F-08

Child-Pugh score predicts ribavirinoverexposure in cirrhotic patients treated withdirect-acting antiviral agents

V. Guardigni, L. Badia, M. Rinaldi, S. Ianniruberto,

P. Viale, G. Verucchi

Department of Medical and Surgical Sciences,

Research Centre for the Study of Hepatitis, University

of Bologna, Bologna, Italy

New direct-acting antivirals (DAAs) regimens have led to high

rate of HCV eradication even in individuals with cirrhosis. Use of

ribavirin (RBV) in the era of DAAs is still recommended for difficult-

to-treat patients. Role of RBV therapeutic drug monitoring (TDM) in

the age of 2nd generation DAAs has not been elucidated yet and data

on RBV TDM among patients with advanced cirrhosis treated with

RBV and DAAs are lacking. Aim of our retrospective study was to

determine whether RBV levels differ according to cirrhosis stage in

a cohort of subjects with advanced liver disease treated with inter-

feron (IFN)-free DAA-regimens and RBV. We included patients with

HCV and cirrhosis, Child-Pugh (CP) A or B, GFR ≥ 60 ml/min, who

started DAAs and RBV (weight-based dosage) between October

2014 and February 2016 at Outpatient Clinic of Infectious Dis-

eases at University Hospital of Bologna. RBV concentrations were

assessed by high-performance Liquid Chromatography in plasma

collected before next dose of drug (Ctrough). We focused our analysis

on the first 8 weeks. We studied 68 patients: 54 with compen-

sated and 14 with decompensated liver disease (CP score <7 and

≥7, respectively). As shown in Fig. 1, patients with decompen-

sated cirrhosis had significantly higher RBV levels at 1, 2, 4 and

8 weeks, with all p < 0.025. RBV levels were positively correlated

with loss of Hb at week 4 and 8 (with r > +0.27 and p < 0.04). In

71.4% of Child Pugh B patients (vs. 50% in CP A), a reduction of RBV

dosage was necessary during the treatment. At multivariate analy-

sis (adjusted for confounders), only per kg RBV dosage and CP score

remained significantly associated (95%CI 35.6, 286, p = 0.013; 95%CI

35, 348, p = 0.017, respectively) to RBV levels in the first 8 weeks.

Liver failure might affect RBV clearance leading to an overexpo-

sure and increased related toxicities in decompensated cirrhosis.

Our findings underscore the importance of RBV TDM and early dose

adjustments in these patients and suggest that an initial lower dose,

rather than weight-based, of RBV might be preferred in those with

advanced liver disease (CP ≥ 7) treated with new DAAs.

Fig. 1.



F-09

Serum markers for early diagnosis of HCC inHCV cirrhotic patients with SVR to DAAtreatment

A. Sangiovanni 1, R. D’Ambrosio 1, G. Lunghi 2,

M. Bruccoleri 1, E. Alimenti 1, M. Borghi 1,

R. Perbellini 1, A. Aghemo 1, M. Iavarone 1,

M. Colombo 3, P. Lampertico 1

1 Gastroenterology and Hepatology Unit, Fondazione

IRCCS Ca’ Granda Ospedale Maggiore Policlinico,

University of Milan, Milan, Italy2 Virology Unit, Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico, University of Milan,

Milan, Italy3 Center for Translational Research Humanitas,

IRCCS Hospital and University, Rozzano, Italy

Introduction: Serum markers for the diagnosis of HCC were

withdrawn from Western Scientific Societies recommendation

because of scanty performance, however there is no data on sensi-

tivity and specificity of tumor markers in HCV patients with SVR to

DAA treatment.

Aim of this study is to define the changes of serum values of AFP,

PIVKA, SCCA-IgM after DAA treatment and to define their diagnostic

performance for the diagnosis of HCC in HCV cirrhotic patients with

SVR.

Material and methods: we enrolled 22 HCC patients and 66

sex and aged matched cirrhotic patients with no history of HCC,

all of them with SVR12 after DAA treatment. AFP (Fujrebio), PIVKA

(Fujrebio), and SCCA IgM Xeptagen) were tested at HCC diagnosis in

HCC patients and at starting DAA and of SVR 12 in cirrhotic patients.

Results: After DAA treatment AFP median value significantly

falls from 16 to 7 ng/ml (p < 0.0001), while PIVKA and SCCA-

IgM remained unchanged (36 vs. 38 mAU/ml, p = 0.96 and 127

vs. 122 U/ml, p = 0.06, respectively). AFP was significantly lower

in cirrhotic patients on SVR12 than in HCC patients (7 vs.

12 ng/ml, p < 0.05), while PIVKA and SCCA-IgM were similar (38 vs.

49 mAU/ml, p 0.61 and 122 and 133 U/ml, respectively). Consider-

ing a cut-off value of 20 ng/ml for AFP, 80 mAU/ml for PIVKA and

156 U/ml for SCCA-IgM, sensitivity of AFP, PIVKA and SCCA-IgM

after DAA treatment were 37%, 41%, 45%, respectively, specificity

98%, 86%, 56%, respectively, PPV 0.86, 0.5 and 0.4, NPV 0.80, 0.81

and 0.69, diagnostic accuracy 81%, 68%, 52%, respectively.

Conclusions: AFP, but not PIVKA and SCCA-IgM value signifi-

cantly decreases after DAA treatment. Sensitivity of AFP >20 ng/ml

for HCC diagnosis in cirrhotic patients was nearly absolute after

DAA treatment.


F-10

Eradication of HCV in patients awaiting livertransplantation does not increase drop-out dueto HCC progression

S. Shalaby 1, A. Zanetto 1, A. Vitale 2, A. Ferrarese 1,

I. Bortoluzzi 1, M. Gambato 1, M. Senzolo 1,

G. Germani 1, C. Mescoli 3, A. Romano 4,

E. Gringeri 2, G. Zanus 2, P. Angeli 4, U. Cillo 2,

P. Burra 1, F.P. Russo 1



University Hospital, Padua, Italy2 Hepatobiliary Surgery and Liver Transplantation

Unit, Department of Surgery, Oncology and

Gastroenterology, Padua University Hospital, Padua,

Italy3 Surgical Pathology & Cytopathology Unit,


Padua, Italy4 Unit of Internal Medicine and Hepatology,


Padua, Italy

Introduction: The loss of intrahepatic immune surveillance, due

to viral eradication with Direct Antiviral Agents (DAAs), may be

associated with increased recurrence of HCC in HCV patients who

previously achieved complete response. Data on the impact that

this may have in terms of drop-out in HCV-HCC patients awaiting

liver transplantation (LT), are lacking.

Materials and methods: All HCV-HCC patients listed for LT

between 01/2015–05/2016, and successfully treated with DAAs

achieving SVR, were retrospectively evaluated (cases). For each

patient clinical, serological, virological data and HCC characteris-

tics were taken into account. A group of untreated patients listed

for HCV-related cirrhosis and HCC, with similar HCC-characteristics

were also enrolled (controls).

Results: Forty-nine patients were enrolled (23 cases/26 con-

trols); HCC characteristics at time of LT-listing were comparable

between the 2 groups: median HCC nodules number was 2 (range

0–4) in cases group vs. 2 (range 0–6) in controls (p = NS); median

nodules total diameter was 22 mm (range 0–65) in cases group vs.

22 mm (range 0–53) in controls (p = NS). Median follow-up was 7

months (range 4–19) in cases group vs. 5 months (range 3–19) in

controls group, during which 2/23 (8.7%) and 1/26 (3.8%) drop-out

events due to HCC-progression between cases and controls were

respectively registered (p = NS). Comparing radiologic images at

the beginning and end of FU, no significant differences in terms

of radiologic-progression were highlighted (p = NS).

8/23 (35%) patients treated with DAAs and 13/26 (50%) controls

underwent LT, and histopathological analysis of HCC performed on

explanted liver showed no differences in terms of median num-

ber of HCC nodules [5 (range 1–14) vs. 3 (range 0–14), p = NS] and

median maximum diameter [26 mm (range 10–65 mm) vs. 28 mm

(range 0–80 mm), p = NS], tumor differentiation [G3-HCC% 13% vs.

15%, p = NS] or microvascular invasion [cases% 38% vs. 23%, p = NS].

During post-LT FU 1/8 DAAs treated patient (11%) and 1/12 control

(8.3%) experienced HCC-recurrence (p = NS).

Conclusions: Viral eradication does not seem to be associated

with increased risk of drop-out due to neoplastic disease-

progression in HCV-HCC patients awaiting LT. Therefore, DAAs

treatment can be safely offered to this patient population.



F-11

FAK depletion/inhibition reduces theexpression of liver cancer stem cells markers

I. Romito 1, D. Gnani 1, S. Artuso 2, C. De Stefanis 1,

N. Panera 1, A. Crudele 1, C. Balsano 3,

E. Carcarino 4, V. Nobili 5, R. Rota 4, C. Leonetti 2,

A. Alisi 1

1 Liver Research Unit, Bambino Gesù Children’s

Hospital, IRCCS, Rome, Italy2 Experimental Preclinical Laboratory, Regina Elena

National Institute, Rome, Italy3 Institute of Molecular Biology and Pathology,

National Research Council, Rome, Italy4 Department of Oncohematology, Bambino Gesù

Children’s Hospital, IRCCS, Rome, Italy5 Hepato-Metabolic Disease Unit, Bambino Gesù

Children’s Hospital, IRCCS, Rome, Italy

Introduction: Hepatocarcinoma (HCC) is one of the most com-

mon human cancers. New insights into HCC pathogenesis have

demonstrated that there are two theories concerning the mecha-

nism of hepacarcinogenesis: (i) a stochastic model, which includes

all genetic and epigenetic changes transforming mature hepato-

cytes in tumour cells; and (ii) a hierarchical model, which is based

on cancer stem cell (CSCs) hypothesis. We recently found that the

knockdown of focal adhesion kinase (FAK), may reduce in vitro and

in vivo HCC growth.

Aim: In this study, we pointed to investigate how FAK deple-

tion/inhibition may reduce HCC growth and if these mechanisms

may involve CSCs.

Materials and methods: FAK depletion was performed by trans-

duction with shRNA lentiviral particles in HCC cells. While FAK

inhibition was obtained by a chemical drug (FAKi). PTK2 plasmid

was used to over-express FAK. Cell cycle and apoptosis were inves-

tigated by cytofluorimetry. mRNA and protein expression were

evaluated by Real-time PCR and western blotting.

Results: We found that FAK depletion/inhibition was able to

reduce in vitro HCC by inducing cell cycle arrest into G2/M, and

consequent apoptosis. The main role of FAK on these effects was

confirmed by the rescue of protein expression after transfection of

the PTK2 plasmid, which is able to revert G2/M phase arrest and

apoptosis in FAK-depleted HCC cells. Furthermore, we found that

FAK-mediated apoptosis may occur in p53 wild type HCC cells or in

a p53-mutant HCC cells, and in both cases p21 was up-regulated.

Finally, these events occur in parallel with alteration of genes

related to CSC features, such as Nanog, Oct-4 and Gankyrin that

were significantly down-regulated by FAK depletion/inhibition.

Conclusions: In summary, our results suggest that FAK deple-

tion/inhibition by pharmacological approaches might reduce

tumour mass and local tumor progression by altering the home-

ostasis of both HCC cells and liver CSCs.


F-12

In HCV infected patients with cirrhosisSquamous Cell Carcinoma Antigen (SCCA)-IgMlevels may contribute to identify the individualrisk of HCC development after antiviral therapy

G. Ricco 1, D. Cavallone 1, P. Pontisso 2,

G. Fassina 3, A. Gallotta 3, P. Colombatto 1,

F. Oliveri 1, V. Romagnoli 1, B. Coco 1, A. Salvati 1,

F. Bonino 4, M.R. Brunetto 1,5

1 Hepatology Unit and Laboratory of Molecular

Genetics and Pathology of Hepatitis Viruses,

Reference Center of the Tuscany Region for Chronic

Liver Disease and Cancer, University Hospital of Pisa,

Pisa, Italy2 Department of Medicine, University of Padua,

Padua, Italy3 Xeptagen S.p.A., VEGA Science Park, Marghera,

Venice, Italy4 UPMC Institute for Health, Chianciano Terme,

Siena, Italy5 Department of Clinical and Experimental Medicine,

University of Pisa, Pisa, Italy

Introduction: In HCV-infected patients with cirrhosis the risk of

hepatocellular carcinoma (HCC) persists even after Direct-Acting-

Antivirals-(DAAs)-induced HCV clearance. Therefore, biomarkers

of the residual HCC risk are still an unmet need. Serum levels

of squamous-cell-carcinoma antigen-immunoglobulin-M (SCCA-

IgM) were associated with higher risk of HCC development.

Aim: To retrospectively evaluate the kinetics of SCCA-IgM dur-

ing DAAs in HCV-infected patients with cirrhosis with and without

subsequent HCC development.

Methods: Among 572 HCV pts with cirrhosis DAAs-treated

according to Italian Drug Agency (AIFA) from February 2015 to

August 2016 at the Hepatology-Unit of Pisa University-Hospital we

enrolled all 20 HCC cases (de novo/recurrence), 24 pts previously

treated for HCC and 41 without HCC. SCCA-IgM serum-levels were

measured at therapy-start (BL), after 12 and 24 weeks by ELISA

(Hepa-IC, Xeptagen S.p.A., Venice, Italy). All pts completed DAAs

treatment, 2 experienced a relapse.

Results: Overall, 9 (10.6%) and 11 (13.0%) patients were diag-

nosed with recurrent or newly-developed HCC, after a median of

24.9 (4.7–65.7) weeks from the end-of-therapy. The remaining 24

(28.2%) and 41 (48.2%) patients, with and without history of HCC,

remained HCC-free during a comparable follow-up.

Fig. 1.


Median SCCA-IgM values were not significantly different

between the four groups at baseline, week-12 and 24 (p = 0.300,

p = 0.448 and p = 0.378, respectively) after therapy-start. On-

therapy median SCCA-IgM-levels decreased similarly in all groups.

None of the patients with BL-SCCA-IgM values <100 AU/mL (8/85,

9.1%) developed HCC. A Receiver-Operating-Characteristics-(ROC)

analysis showed that the diagnostic performances of SCCA-IgM

levels in discriminating pts with or without HCC development,

improved significantly in pts with lower HCV-RNA (Fig. 1) reaching

the highest diagnostic accuracy (100% Sensitivity/Specificity) for a

viremia below 500,000 UI/mL.

Conclusions: SCCA-IgM serum levels alone or in combination

with BL HCV-RNA could contribute to better define the individual

risk of HCC development in the first 18 months after DAAs-

treatment in HCV-infected patients with cirrhosis. Our findings

prompt further investigation in larger cohorts.


F-13

Validation of Liver Imaging Reporting and DataSystem (LI-RADS) Version 2014

A. Pecorelli 1, R. Nani 1, F. Sala 1, D. Pinelli 2,

M. De Giorgio 2, G. Magini 2, M. Colledan 2,

S. Fagiuoli 2, S. Sironi 1

1 Department of Radiology, Università degli studi

Milano-Bicocca, ASST Papa Giovanni XIII, Bergamo,

Italy2 ASST Papa Giovanni XXIII, Bergamo, Italy

Introduction: Liver Imaging Reporting and Data System (LI-

RADS) attempts to standardize the interpretation of liver lesions

detected at computed tomography (CT) and magnetic resonance

(MR) in cirrhotic patients on surveillance for hepatocellular carci-

noma (HCC), stratifying them on the probability of HCC (categories

LR3, LR4 and LR5 as intermediate probability, probably and defi-

nitely HCC, respectively).

Aim: This study aims to assess the diagnostic accuracy of LI-

RADS categories.

Materials and methods: We retrospectively reviewed CT and

MR images of 47 patients consecutively submitted to liver resection

or transplantation for HCC from January 2015 to June 2016. Liver

lesions were classified according to LI-RADS (LR3 = 21, LR4 = 26,

LR5 = 27). Sixteen lesions belonged to categories LRT that refers

to HCC treated with loco-regional approaches. Reference standard

was histological sample. Diagnostic accuracy was assessed with

receiver operating curve analysis and defined by area under the

curve and 95% confidence interval. Continuous values are expressed

as mean and standard deviation, categorical variables as number

and percentage.

Results: CT or MRI were performed 1.7 ± 1.2 months before sur-

gical procedure.

Ninety liver lesions (diameter 22.8 ± 19.2 mm) were detected at

imaging: 66 were histologically proven HCC and 24 were negative.

HCC was confirmed in: 11/21 (52.4) lesions classified as LR3,

21/26 (80.8) classified as LR4 and 26/27 (96.3) classified as LR5.

HCC was also confirmed in 8/16 (50.0) LRT lesions, despite no signs

of recurrence at imaging.

After removing LRT observations the overall diagnostic accu-

racy of each LI-RADS category was: LR3 = 0.274 (0.121–0.426),

LR4 = 0.525 (0.366–0.684), LR5 = 0.693 (0.564–0.822).

Sensibility, specificity, positive predictive value (PPV) and

negative predictive value (NPV) progressively increased across

categories: LR3 (17.2%, 37.5%, 52.4%, 11.3%), LR4 (36.2%, 68.7%,

80.8%, 22.9%), LR5 (44.8%, 93.7%, 96.3%, 31.9%).

Conclusions: In cirrhotic patients a liver lesion categorized as

LR5 can be confidently diagnosed as HCC. However, the low sen-

sibility implies that a relevant number of neoplastic nodules are

eventually missed. Moreover, a high proportion of HCC are still

detected among LR3 categories.

These findings highlight the need of further refinements of

imaging features emerging from LI-RADS.


F-14

Multiclass HCV resistance to interferon-freedirect acting antivirals regimens in real lifefailures advocates for tailored second-linetherapies

V.C. Di Maio 1, V. Cento 1, I. Lenci 2, M. Aragri 1,

S. Barbaliscia 1, S. Francioso 2, S. Paolucci 3,

M. Melis 4, G. Verucchi 5, C. Masetti 2,

N. Coppola 6, C.F. Magni 7, V. Micheli 8,

T. Pollicino 9, T. Ruggiero 10, S. Landonio 7,

A. Mancon 8, M. Starace 6, F. De Leonardis 2,

F. Santopaolo 2, A. Bertoli 1, F.P. Antonucci 1,

C. D’Ambrosio 11, V. Calvaruso 12, M.C. Sorbo 1,

F. Morisco 13, C. Pasquazzi 14, I. Maida 4,

A. Picciotto 15, A. Di Biagio 16, B. Bruzzone 17,

L. Sticchi 17, V. Ghisetti 10, R. Cozzolongo 18,

D. Romagnoli 19, V. Boccaccio 20, A. Grieco 21,

J. Vecchiet 22, G. D’Ettorre 23, M. Merli 24,

G.B. Gaeta 6, A. Ciancio 25, L. Marinaro 10,

E. Polilli 26, P. Cacciatore 26, P. Andreone 27,

G. Barbarini 28, R. Gulminetti 29, S. Novati 29,

V. Pace Palitti 30, P. Tarquini 31, M. Puoti 32,

V. Sangiovanni 33, G. De Stefano 33, A. Giorgini 34,

M. Paoloni 35, N. Caporaso 13, S. Babudieri 4,

G. Gubertini 7, S. Bruno 20, M. Andreoni 36,

A. Pellicelli 11, G. Parruti 26, G. Raimondo 9,

F. Baldanti 3, G. Rizzardini 7, A. Craxì 12,

M. Angelico 2, C.F. Perno 1,

F. Ceccherini-Silberstein 1, on behalf of HCV

Virology Italian Resistance Network Group

(Vironet C)


University of Rome Tor Vergata, Rome, Italy2 Hepatology Unit, University Hospital of Rome Tor

Vergata, Rome, Italy3 Virologia Molecolare, Fondazione IRCCS Policlinico

San Matteo, Pavia, Italy4 Infectious Diseases Unit, University of Sassari,

Sassari, Italy5 Policlinico S. Orsola-Malpighi, Bologna, Italy6 Infectious Diseases and Viral Hepatitis Unit, Second

University of Naples, Naples, Italy7 Division of Infectious Disease, ASST Fatebenefratelli

Sacco, Milan, Italy8 Clinical Microbiology, Virology and Bioemergencies,

ASST Fatebenefratelli Sacco, Milan, Italy9 Department of Internal Medicine, University

Hospital of Messina, Messina, Italy10 Unit of Infectious Diseases, Laboratory of

Microbiology and Virology, “Amedeo di Savoia”

Hospital, Turin, Italy


11 Hepatology Unit, San Camillo Forlanini Hospital,

Rome, Italy12 Gastroenterology, “P. Giaccone” University

Hospital, Palermo, Italy13 Department of Clinical Medicine and Surgery,

University “Federico II” of Naples, Naples, Italy14 Infectious Diseases, Sant’Andrea Hospital – “La

Sapienza” University, Rome, Italy15 Division of Hepatology, IRCCS San Martino, IST

Genova, Genoa, Italy16 Infectious Disease, IRCCS AOU San Martino – IST,

Genova, Italy17 Hygiene Unit, IRCCS AOU San Martino-IST, Genoa,

Italy18 Department of Gastroenterology, Scientific

Institute for Digestive Disease “Saverio de Bellis”

Hospital, Castellana Grotte, Bari, Italy19 Department of Biomedical, Metabolic and Neural

Sciences, University of Modena and Reggio Emilia,

Modena, Italy20 Internal Medicine, Humanitas University,

Rozzano, Milan, Italy21 Liver Transplant Unit, Catholic University of Rome,

Rome, Italy22 Infectious Disease Clinic, Hospital of Chieti, Chieti,

Italy23 Department of Public Health and Infectious

Diseases, “La Sapienza” University of Rome, Rome,

Italy24 Gastroenterology, “La Sapienza” University of

Rome, Rome, Italy25 Unit of Gastroenterology, University of Turin,

Department of Medical Sciences, Città della Salute e

della Scienza di Torino Molinette Hospital, Turin,

Italy26 Infectious Disease Unit, Pescara General Hospital,

Pescara, Italy27 Department of Medical and Surgical Sciences,

University of Bologna, Bologna, Italy28 Division of Infectious and Tropical Diseases,

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy29 Institute of Infectious Diseases, University of

Pavia, Pavia, Italy30 Hepatology Unit, Pescara General Hospital,

Pescara, Italy31 Infectious Disease, Hospital “G. Mazzini”, Teramo,

Italy32 Department of Infectious Diseases, Hospital

Niguarda Ca’ Granda, Milan, Italy33 Hospital Cotugno, Naples, Italy34 General Medicin Unit, SST Santi Paolo e Carlo,

Milan, Italy35 Infectious Disease Unit, Avezzano General

Hospital, Avezzano, Italy36 Infectious Diseases, University Hospital of Rome

Tor Vergata, Rome, Italy

Background: This study aims to characterize resistance-

associated-substitutions (RAS) in a large cohort of HCV patients

who failed an Interferon-free Direct-Acting-Antivirals (DAA)

containing-regimen.

Methods: Among 325 patients failing a DAA Interferon-free-

regimen, 261 (GT1a-1b-2c-3a/h-4a/d/n/r = 57-91-12-64-37; 79.4%

cirrhotic; 70.6% treatment-experienced, 16 with DAA), with avail-

able Sanger-sequencing test at failure were analyzed.

Results: The majority of patients experienced a relapse

(84.5%) and 59.0% failed a recommended-regimen according

to 2015 guidelines: simeprevir + sofosbuvir ± ribavirin (N = 58),

daclatasvir/ledipasvir + sofosbuvir ± ribavirin (N = 23/39), 3D/2D

(paritaprevir/ombitasvir ± dasabuvir) ± ribavirin (N = 23), sofosbu-

vir + ribavirin (GT2, N = 11). Interestingly, 4.2% of failures had

a misclassified genotype. Overall, 59.0% of patients showed

at least one RAS related to the DAA-failure; RASs prevalence

was higher in breakthrough/non responders than in relapsers

(92.3% vs. 50.9%, p < 0.001) and in patients with unfavorable

IL28 CT/TT vs. patients with IL28 CC (57.7% vs. 12.5%, p = 0.024).

RASs prevalence varied according to the DAA-class used (92.4%

NS5A-RASs [N = 105], 72.3% NS3-RASs [N = 101], 34.5% dasabuvir-

RASs [N = 29]), 20.6% sofosbuvir-RASs [N = 218]) and according

to HCV-GT. In NS5A-failing patients, Y93H was the most fre-

quent NS5A-RAS (61.9%), though with different prevalence among

genotypes (15.4% GT1a; 90.0% GT1b; 82.6% GT3a; 40.0% GT4).

Furthermore, 40.0% of patients presented ≥2 NS5A-RASs, with

complex patterns more frequently in GT1b failures (67.5%, e.g.

Y93H + L31M/I).

Failures to sofosbuvir-regimens showed frequent presence of

L159F ± C316N (14.7%), particularly in GT1b (37.3%), followed by

S282T in 3.6%. Notably, 42.9% of patients treated with ≥2 DAA

classes showed multiclass-resistance. Overall, 6.1% of patients

showed RASs in all 3 targets and 13.0% of patients showed also

extra-target-RASs, probably due to natural resistance. Finally, 11

patients, all cirrhotic, experienced at least 2 subsequent virologic-

failures to interferon-free DAA-regimens.

Conclusions: In this real life setting, RASs prevalence at failure

was remarkably high in all genes tested (with a partial exception

for NS5B). This multiclass-resistance advocates for HCV resistance-

testing at failure in all 3 genes for the best second-line therapeutic

tailoring.


F-15

Liver stiffness and portal hypertension predictfailure to DAA treatment in a real-life cohort ofHCV-infected patients treated withrecommended regimens

C. Masetti, F. De Leonardis, P. Rossi, A. Bosa,

D. Di Paolo, M. Milana, F. Santopaolo, A. Pecchioli,

S. Di Nardi, S. Francioso, I. Lenci, L. Baiocchi,

A. Brega, T. Marianelli, F. Antenucci, M. Angelico

Liver and Transplant Unit, Policlinico Tor Vergata,

Rome, Italy

Interferon-free regimens have dramatically improved HCV

treatment. Unfortunately, a few patients fail to reach a sustained

virological response even with direct-acting antiviral agents (DAA).

Little is known about risk factors associated with treatment failure.

Among 369 HCV-infected patients who started an optimal

(according to 2016 EASL guidelines) DAA treatment, we included

253 with at least a 12-week follow up after treatment completion.

The cohort included mainly males (n = 154, 60.8%), with cirrhosis

(n = 168, 66.4%), of whom 25.6% (47/183) showed clinically signif-

icant portal hypertension, as evidenced by presence of esophageal

varices. Most patients (n = 152, 60.1%) were infected with geno-

type 1, 51 (20.1%) with genotype 2, 30 (11.8%) and 20 (8%) with

genotype 3 and 4, respectively. Patients underwent treatment with

sofosbuvir (n = 50, 20.1%), sofosbuvir/simeprevir (n = 34, 13.3%),

sofosbuvir/daclatasvir (n = 26, 10.3%), sofosbuvir/ledipasvir (n = 80,

31.5%), ombitasvir/paritaprevir/ritonavir with (n = 56, 22.1%) or


without (n = 7, 2.7%) dasabuvir. Data were processed by intention-

to-treat (ITT) with univariate and multivariate analyses.

The population included 229 patients who achieved SVR-12

(90.5%) and 24 (9.5%) who failed for any reason: virological relapse

(n = 9), death (n = 10) or drop-out (n = 5). At univariate analysis, cir-

rhosis (p = 0.005), presence of medium/large esophageal varices

(p = 0.0001), a higher liver stiffness (p = 0.00007), previous HCC

(p = 0.002), diabetes (p = 0.006), viral genotype 2 (p = 0.02), low

platelet count (p = 0.02), low total cholesterol level (p = 0.001), INR

prolongation (p = 0.02) and a higher MELD score (p = 0.000001)

were all significantly associated with treatment failure. Failure

was unrelated to HCV viral load (p = 0.16) and treatment sched-

ule (p = 0.25). At stepwise multivariable logistic regression, only

liver stiffness and the presence of medium or large esophageal

varices were associated with treatment failure (p = 0.02, p = 0.02 and

p = 0.01 respectively), with an area under ROC curve of 0.93.

In a real-life setting, around 10% of HCV-infected patients fails

after DAA treatment. Failure is strongly associated with high liver

stiffness and clinically significant portal hypertension.


F-16

Laparoscopic ablation for HCC: proposal of a6-months mortality score for patient selectionbased on more than 1000 procedures

A. Bertacco 1, A. Marchini 1, A. Vitale 1, C. Ungaro 1,

F. D’Amico 1, E. Gringeri 1, D. Neri 1, D. Bassi 1,

G. Zanus 1, R. Carandina 2, C. Aliberti 2, U. Cillo 1


Gastroenterology, Hepatobiliary Surgery and Liver

Transplantation, Padua University, Padua, Italy2 Oncology Radiodiagnostics, Oncology Institute of

Veneto, Institute for the Research and Treatment of

Cancer (IRCCS), Padua University, Padua, Italy

Background: Trans-arterial-chemoembolization is the only

therapeutic option for patients unsuitable for liver resection or

percutaneous ablation according to international guidelines. The

aim of our study was to evaluate safety and efficacy of video-

laparoscopic (VLS) ablation as a therapeutic option for these HCC

patients and to define an early mortality predictor score to help

clinicians in patient selection.

Methods: We collected patients with HCC who were unsuitable

for liver resection and/or percutaneous ablation and who under-

went VLS ablation (microwave, or radiofrequency) in the period

2004–2015. Early mortality (6-months) was the primary endpoint;

perioperative morbidity and long term survival were secondary

endpoints.

Results: 1091 procedures in 903 patients (median age, 64 years)

were performed following a liberal selection policy (child B-C

35%; BCLC B-C-D 38%). We had not perioperative mortality but

6-months mortality was 10.5%. The overall morbidity was 33.6%

with a median length of hospital stay of 2 days. Independent pre-

dictors of 6-months mortality resulted both variables related to

liver function (Child Pugh, Portal Hypertension, ascites, sodium,

performance status) and to tumor aggressiveness (Milan criteria,

alpha-fetoprotein). A simple user-friendly score based on these 7

variables (score from 0 to 7) performed as an accurate predictor

of 6-months mortality (area under ROC curve = 0.78). A cut-off of 4

proved to be a good tool for patient selection (6 months mortality

<10%) and for identifying patients with optimal long-term survival

(median survival 53 vs. 14 months, p < .0001)

Conclusions: VLS ablation seems to be a safe and effective

treatment in patients who are ineligible for liver resection and/or

percutaneous ablation. We proposed a simple score to help clini-

cians in selecting patients for this procedure to obtain a curative

long term survival profile.


F-17

Treatment with direct-acting antiviral agents isassociated with improvement of renal functionin a cohort of HCV-infected patients withchronic kidney disease

C. Masetti, F. De Leonardis, P. Rossi, A. Bosa,

D. Di Paolo, M. Milana, F. Santopaolo, A. Pecchioli,

S. Di Nardi, S. Francioso, I. Lenci, L. Baiocchi,

A. Brega, F. Antenucci, T. Marianelli, M. Angelico


Rome, Italy

HCV is recognized as an independent risk factor for chronic kid-

ney injury. DAAs use has been approved in HCV-infected patients

with renal impairment, but little is known about their effect on

renal function.

Study includes 42 HCV-infected patients with eGFR (MDRD-4)

levels below 60 ml/min (38 in stage III, 2 in stage IV and 2 in stage

V according to KDIGO guidelines) treated with DAAs. Population

includes mainly males (24, 57.1%) cirrhotics (32, 76.2%). Twelve

(28.5%) patients had clinical portal hypertension, 10 (23.8%) had

diabetes and 11 (26.1%) had detectable cryoglobulines. Genotype

1 infection was present in 27 (64.3%), genotype 2 and 3 in 13

(31%) and 2 (4.7%) patients respectively. Thirty-six patients (85.7%)

received a sofosbuvir-containing regimen (in 18 as monother-

apy and in 18 in combination), while the other 6 patients had

ombitasvir/paritaprevir/ritonavir plus dasabuvir.

Paired T-test analysis was used to detect any modification in

eGFR and creatinine levels at baseline and at the end-of-treatment

(EOT).

HCV RNA was undetectable at EOT in all patients. No adverse

events were observed. The majority (74.3%) of patients showed

improvement of both creatinine and eGFR. Mean creatinine level

decreased from 1.4 ± 1.3 mg/dl at baseline to 1.31 ± 1.1 mg/dl at

EOT (p = 0.017) with an increase in eGFR from 50.1 ± 10.7 to

57.1 ± 16.4 ml/min (p = 0.0002). This improvement was significant

even including only cirrhotic patients with an increase in eGFR

from 52.1 ± 7.2 to 60.2 ± 14.9 ml/min (p = 0.00088). Seven patients

(16.6%) experienced a worsening in renal function with a decrease

in eGFR from 51.1 to 45.2 ml/min. All patients had CKD stage III, 5

were cirrhotic (1 in CPT-B) and 6 had sof-based regimens.

DAAs treatment in a HCV-infected population with impaired

renal function is associated with improved eGFR and creatinine.

Treatment is safe also in patients receiving sof-based regimens,

though a slight decrease in eGFR is observed in some.



F-18

Natural HCV resistance is common in Italy anddifferently associated to genotypes

M.C. Sorbo 1, V. Cento 1, A. Bertoli 1, I. Lenci 2,

E. Polilli 3, C. Masetti 2, L. Gianserra 4, E. Teti 5,

E. Biliotti 6, C.F. Magni 26, M. Aragri 1, V. Micheli 7,

M. Melis 8, L.A. Nicolini 11, S. Marenco 10,

V. Calvaruso 12, S. Paolucci 13, F. Baldanti 13,

F. Morisco 14, M. Siciliano 15, V. Pace Palitti 16,

P. Andreone 17, B. Bruzzone 18, N. Coppola 19,

T. Ruggiero 27, M. Lichtner 20, B. Menzaghi 21,

D. Romagnoli 22, N. Iapadre 23, V.C. Di Maio 1,

F. De Leonardis 2, M. Milana 2, P. Cacciatore 3,

A. Pieri 3, L. Sarmati 5, S. Landonio 26,

A. Gasbarrini 15, M. Puoti 24, A. Craxì 12, V. Vullo 25,

A. Pellicelli 9, S. Babudieri 8, G. Rizzardini 26,

G. Taliani 6, M. Andreoni 5, C. Pasquazzi 4,

G. Parruti 3, M. Angelico 2, C.F. Perno 1,

F. Ceccherini-Silberstein 1

1 Experimental Medicine and Surgery, University of

Rome “Tor Vergata”, Rome, Italy2 Hepatology Unit, University Hospital of Rome “Tor

Vergata”, Rome, Italy3 Infectious Diseases Unit, Pescara General Hospital,

Pescara, Italy4 Infectious Diseases Unit, Sant’Andrea Hospital –

“Sapienza” University, Rome, Italy5 Infectious Diseases Unit, University Hospital of

Rome “Tor Vergata”, Rome, Italy6 Tropical Diseases, Umberto I Hospital – “Sapienza”

University, Rome, Italy7 Clinical Microbiology, Virology and Bioemergencies,

ASST Fatebenefratelli Sacco, Milan, Italy8 Clinical and Experimental Medicine, University of

Sassari, Sassari, Italy9 Hepatology Unit, San Camillo Forlanini Hospital,

Rome, Italy10 Division of Hepatology, IRCCSAOU San

Martino-IST, Genoa, Italy11 Infectious Diseases Unit, IRCCSAOU San

Martino-IST, Genoa, Italy12 Gastroenterology,“P.Giaccone” University

Hospital, Palermo, Italy13 Molecular Virology, Fondazione IRCCS Policlinico

San Matteo, Pavia, Italy14 Gastroenterology, “Federico II” University, Naples,

Italy15 Gastroenterology, Catholic University of Rome,

Rome, Italy16 Hepatology Unit, Pescara General Hospital,

Pescara, Italy17 Medicine and Surgery, University of Bologna,

Bologna, Italy18 Hygiene Unit, IRCCSAOU San Martino-IST, Genoa,

Italy19 Infectious Diseases Unit, Second University of

Naples, Naples, Italy20 Infectious Diseases Unit, “Sapienza” University,

Latina, Italy21 Infectious Diseases Unit, Ospedale di circolo di

Busto Arsizio, Varese, Italy22 Department of Biomedical, Metabolic and Neural

Sciences, NOCSAE Baggiovara, Baggiovara, Italy

23 Infectious Diseases Unit, S. Salvatore Hospital,

L’Aquila, Italy24 Hospital Niguarda Ca’ Granda, Milan, Italy25 Infectious Diseases Unit, Umberto I Hospital –

“Sapienza” University, Rome, Italy26 1st Division of Infectious Diseases, ASST

Fatebenefratelli Sacco, Milan, Italy27 Unit of Infectious Diseases, Laboratory of


Hospital, Turin, Italy

Introduction: Natural resistance associated substitutions

(RASs) are highly variable prevalent across different HCV genotypes

(GTs) and countries. We investigated natural RASs frequency, and

NS5A-RASs impact on treatment efficacy, in a large Italian real-life

database including the 4 main HCV-GTs.

Methods: RASs in NS3/NS5A/NS5B (N = 1032/833/496) were

analysed in 1193 HCV-infected DAA-naïve patients (pts; 68%

treatment-experienced; 55% cirrhotic; 5% HIV co-infected). Sanger-

sequencing was performed by home-made protocols on 714 GT1a,

989 GT1b, 135 GT2c, 333 GT3a, 190 GT4a/d samples. RASs with

fold-change >100 were defined as major.

Results: Overall, 415/1193 (35%) pts showed natural RASs, inde-

pendently by cirrhosis, with important GT/subtypes differences.

GT1a/1b/4a frequently showed NS3-RASs (52-20-36%, respec-

tively), with major-RAS 80K (17%) in GT1a and 168A/E/T/V in

GT2c/4d (3–4%). Also in NS5A, GT1a/1b/4a showed the high-

est RASs prevalence (10-31-38%, respectively), higher in IFN/RBV

experienced-patients (35%) vs. IFN-naive (22%, p = 0.02) only in

GT1b. Major NS5A-RASs were detected in 10% GT1a (28V-30H/R-

31M-93C/H), 9% GT1b (30R-93H), 5% GT2c (31M-93H), 4% GT3a

(93H) and 2% GT4d (30S). In NS5B, the 159F and 316N sofosbu-

vir putative-RASs were exclusively detected in GT1b (13% and 19%)

often associated (phy-correlation = 0.67, p < 0.001). Among 372 pts

with NS3/NS5A/NS5B resistance-test, 10% showed multiple RASs,

mainly NS3 + NS5A RASs (mainly in GT1-4); 2 GT1b pts showed

RASs on 3 drug-targets.

Lastly, natural RASs impact was evaluated in 138 pts treated

with NS5A-inhibitors. 4/26 non-cirrhotic pts with minor-baseline

NS5A-RASs (GT1b: 30Q, 31M, 58S, 92T) reached a sustained viral

response (SVR). 4/112 cirrhotic pts, showed major-baseline NS5A-

RASs: 2 pts (GT1b: 93H; GT4d: 30S) treated with not-recommended

regimens, experienced virologic failure; 2 (GT1b: 93H; GT1a: 30R)

received a recommended-regimen with RBV, reached SVR.

Conclusions: Natural RASs are common across all HCV-GTs in

Italy. Up to 10% of pts show multi-class RASs, though only the major

mutations seem clinical relevant. Therefore, qualitative identifica-

tion of only major-RASs is required to properly guide DAA-based

therapy.



F-19

HCV resistance test guided retreatments afterprotease inhibitors failures can induce maximalefficacy rate in real-life

V. Cento 1, S. Barbaliscia 1, I. Lenci 2, T. Ruggiero 3,

C. Masetti 2, C.F. Magni 4, V. Micheli 5,

S. Paolucci 6, Y. Troshina 7, E. Biliotti 8, M. Milana 2,

M. Melis 9, E. Teti 10, L. Lambiase 11,

B. Menzaghi 12, L.A. Nicolini 13, S. Marenco 14,

V.C. Di Maio 1, M. Aragri 1, A. Pecchioli 2,

A. Bertoli 1, F.P. Antonucci 1, L. Sarmati 10,

C. Sarrecchia 10, M. Macera 15, N. Coppola 15,

E. Danieli 16, D. Romagnoli 17, A. Pellicelli 18,

S. Bonora 3, S. Babudieri 9, A. Di Biagio 13,

A. Picciotto 14, S. Novati 6, M. Siciliano 19,

V. Messina 20, E. Claar 21, F. Baldanti 6,

C. Pasquazzi 11, A. Ciancio 7, M. Puoti 16,

V. Ghisetti 3, M. Andreoni 10, G. Taliani 8,

G. Rizzardini 4, M. Angelico 2, C.F. Perno 1,

F. Ceccherini-Silberstein 1



Vergata, Rome, Italy3 Infectious Diseases, “Amedeo di Savoia” Hospital,

Turin, Italy4 1st Division of Infectious Diseases, ASST

Fatebenefratelli Sacco, Milan Italy5 Clinical Microbiology, Virology and Bioemergencies,

ASST Fatebenefratelli Sacco, Milan Italy6 Molecular Virology, Policlinic Foundation San

Matteo, Pavia, Italy7 Gastroenterology, Department of Medical Sciences,

City of Health and Science of Turin, University of

Turin, Turin, Italy8 Tropical Diseases, Umberto I Hospital – “Sapienza”

University, Rome, Italy9 Infectious Diseases Unit, Department of Clinical and

Experimental Medicine, University of Sassari, Italy10 Infectious Diseases, University Hospital of Rome

Tor Vergata, Rome, Italy11 Infectious Diseases, Sant’Andrea Hospital –

“Sapienza” University, Rome, Italy12 Infectious Diseases, Ospedale di Circolo di Busto

Arsizio, ASST Valleolona, Varese, Italy13 Infectious Diseases, Department of Health Sciences

(DISSAL), University of Genoa-AOU IRCCS San

Martino-IST, Genova, Italy14 Division of Hepatology, University of Genoa-AOU

IRCCS San Martino-IST, Genova, Italy15 Infectious Diseases, Department of Mental and

Physical Health and Preventive Medicine, Second

University of Naples, Naples, Italy16 Infectious Diseases, Hospital Niguarda Ca’ Granda,

Milan, Italy17 Department of Biomedical, Metabolic and Neural

Sciences, NOCSAE Baggiovara, Modena, Italy18 Gastroenterology, San Camillo Hospital, Rome,

Italy19 Gastroenterology, “Cattolica” University of Rome,

Rome, Italy20 Infectious Diseases Unit, AO Caserta, Italy

21 Hepatology, Ospedale Evangelico Villa Betania,

Naples, Italy

Background and aims: We analyzed the efficacy of retreatment

after protease inhibitors (PI) plus pegylated-interferon (pegIFN)

and ribavirin (RBV)-failure with various IFN-free regimens, and the

role of genotypic-resistance-testing (GRT) in real-life settings.

Methods: This is a multi-center observational real-

life study including 121 patients retreated after PI

(telaprevir–boceprevir–simeprevir) plus pegIFN and RBV fail-

ure. Sustained-virological-response (SVR) was evaluated at week

12 of follow-up. GRT was performed by Sanger-based home-made

protocols.

Results: In this setting, 121 patients (cirrhotic = 86.8%) were

retreated after PI-failure following 3 different strategies: (A)

with “GRT-guided” regimens (N = 18); (B) with “AASLD/EASL rec-

ommended, not GRT-guided” regimens (N = 72); (C) with “Not

recommended, not GRT-guided” regimens (N = 31). Overall SVR

rate was 91%, with differences according to strategy choice: all 18

patients treated with “GRT-guided” regimens reached SVR (100%),

despite heterogeneity in treatment-duration, PI-inclusion and RBV

use; 68/72 patients (94.4%) receiving a second-line regimen accord-

ing to guidelines achieved SVR; SVR was strongly reduced (77.4%)

among the 31 patients who received a “not recommended, not

GRT-guided regimen” (p-trend < 0.01).

Overall, 37/121 patients were retreated with a PI (simeprevir,

paritaprevir) and 33/37 (89.2%) achieved SVR. The 4 failing GT-1a

cirrhotic patients (all in option C) used a simeprevir-containing

regimen; 3/4 showed historical R155K NS3-RAS. All 7 patients

treated with a paritaprevir-containing plus RBV regimen reached

SVR, regardless treatment-duration and performance of a baseline-

GRT.

Conclusion: Retreatment after first-generation PI-failure can

induce a maximal SVR rate if guided by GRT in real-life, greater than

SOF + NS5A inhibitors plus RBV for 12/24 weeks, as recommended

by guidelines. PIs can be fruitfully reconsidered if appropriately

chosen after a punctual GRT-based RASs evaluation.

Keywords: HCV-resistance; NS5A-inhibitors; Protease-

inhibitors; HCV-failure



F-20

Impact of Acute-on-Chronic Liver Failure (ACLF)on response to treatment with terlipressin andalbumin in patients with type 1 hepatorenalsyndrome

S. Piano 1, H. Schmidt 2, X. Ariza 3, A. Amoros 4,

A. Romano 1, E. Solà 3, A. Gerbes 5, M. Bernardi 6,

C. Alessandria 7, J. Trebicka 8, T. Gustot 9,

F. Nevens 10, V. Arroyo 4, P. Gines 3, P. Angeli 1

1 Unit of Internal Medicine and Hepatology,

University of Padova, Padua, Italy2 Klinik für Transplantationsmedizin,

Universitätsklinikum Münster, Germany3 Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD,

Barcelona, Spain4 EF-CLIF and EASL-CLIF Consortium, Barcelona,

Spain5 Department of Medicine II, University Hospital

LMU Munich, Liver Center Munich, Munich, Germany6 Department of Medical and Surgical Sciences,

University of Bologna, Bologna, Italy7 Division of Gastroenterology and Hepatology, San

Giovanni Battista Hospital, Turin, Italy8 Department of Internal Medicine I, University of

Bonn, Bonn, Germany9 Erasme Hospital, Université Libre de Bruxelles,

Brussels, Belgium10 University Hospital Gasthuisberg, KU Leuven,

Leuven, Belgium

Introduction and aims: Type 1 hepatorenal syndrome (HRS)

is the most life threatening type of renal failure in cirrhosis. Ter-

lipressin and albumin is effective in treating HRS. According to

the EASL-CLIF consortium definition, patients with type-1 HRS

meet ACLF criteria, however, the impact of ACLF grade on the

response to treatment has never been assessed. The aims of our

study were: (a) to evaluate predictors of response to treatment with

terlipressin and albumin in patients with type-1 HRS(reduction

in serum creatinine[sCr] < 1.5 mg/dl); (b) to evaluate predictors of

90-day mortality.

Methods: In this multicenter European study patients with

type-1 HRS treated with terlipressin and albumin were included.

Demographic, clinical and laboratory data were collected before

the initiation of treatment. Patients were followed up until death,

liver transplantation or 90 days.

Results: 298 patients were included. Patients were treated for

a median of 8 days and response was found in 53% of them.

Responders were more likely to have a precipitating event of

HRS (76 vs. 65%; p = 0.037), had lower bilirubin (3.3 vs. 4.8 mg/dl;

p = 0.003), lower INR (1.6 vs. 1.8; p = 0.004) and lower sCr (2.7

vs. 3.2 mg/dl; p < 0.001) than non-responders. Response rate had

a stepwise decrease moving from grade-1 to grade-3 ACLF (60,

48 and 29% for grade 1, grade 2 and grade 3, respectively;

p < 0.001). In multivariate analysis the presence of precipitating

events (OR = 2.08; p = 0.008), baseline sCr (OR = 0.21; p = 0.001) and

ACLF grade (OR = 0.62; p = 0.005) were found to be independent pre-

dictors of response to treatment. During the 90-day follow-up 40%

of patients died. Responders to treatment had a lower transplant-

free mortality rate than non responders (33 vs. 68%; p < 0.001). In

multivariate analysis, age (HR = 1.05; p < 0.001), white blood cell

count (HR = 1.03; p = 0.015), ACLF grade (HR = 2.09; p < 0.001) and

response to treatment (HR = 0.42; p < 0.001) were found to be inde-

pendent predictors of 90-day mortality.

Conclusions: ACLF grade is a main determinant of response to

terlipressin and albumin in patients with type-1 HRS. ACLF grade

affects survival independently from the response to treatment. New

therapeutic strategies should be developed for patients with type-1

HRS and extrarenal organ failures.


F-21

Low viremic HBeAg negative HBsAg carriers:Clinical outcome and non invasive diagnosticaccuracy for chronic hepatitis B or inactiveinfection by combinations of HBV markers

F. Oliveri 1, L. Surace 1, D. Cavallone 1,

P. Colombatto 1, G. Ricco 1, N. Salvati 2, B. Coco 1,

V. Romagnoli 1, R. Gattai 1, A. Salvati 1,

F. Moriconi 1, Q. Yuan 3, F. Bonino 4,

M.R. Brunetto 1,5



Reference Centre of the Tuscany Region for Chronic


Pisa, Italy2 Department of Economics and Management,

University of Pisa, Pisa, Italy3 National Institute of Diagnostics and Vaccine

Development in Infectious Diseases, School of Public

Health and School of Life Science, Xiamen University,

Xiamen, China4 University of Pittsburgh Medical Center Institute

for Health, Chianciano Terme, Italy5 Adjunct Professor of Internal Medicine, University

of Pisa, Pisa, Italy

Background and aims: HBeAg negative chronic HBV infection

is associated with a wide spectrum of clinical conditions ranging

from inactive infection (IC) to chronic hepatitis B (CHB), that some-

time mimics IC. A higher diagnostic accuracy in diagnosing the

different phases of HBeAg negative infection would improve the

management of this subset of HBsAg carriers.

Patients and methods: We performed a long-term prospec-

tive single center cohort study in 153 carriers with baseline serum

HBV-DNA ≤20,000 IU/mL and normal transaminases. HBV-DNA,

HBsAg, HBV “core-related” antigen (HBcrAg) and total-anti-HBc

were quantified at baseline (bl) and yearly (HBV-DNA and HBsAg).

Results: After 1-year 3-monthly monitoring, 87 (56.9%) sub-

jects were classified as Inactive-Carriers (IC, ≤2000-IU/mL), 46

(36%) as Low-Viremic-Active-Carriers (LV-AC, ≤20,000-IU/mL) and

20 (13.1%) as chronic-hepatitis-B patients (CHB, >20,000-IU/mL).

IC and LV-AC were followed-up for additional 57.2 (8.5–158.3)

months. CHB was independently associated with higher base-

line HBV-DNA (P = 0.030), total-anti-HBc (P < 0.001) and ALT

(P = 0.001). HBV-reactivation did not occurred in any carrier with bl-

HBsAg ≤ 1000-IU/HBV-DNA ≤ 2000-IU/mL (NPV-100%). Thereafter

none IC reactivated, 19 (21.8%) cleared HBsAg [independently asso-

ciated with older-age (P = 0.004), lower bl-HBsAg (P < 0.001), higher

HBsAg yearly-decline (P < 0.001)]. One LV-AC (2.2%) developed

CHB, 25 (54.3%) remained stable and 20 (43.5%) became IC [inde-

pendently associated with lower bl-HBsAg (P = 0.008)]. The best

single-point CHB diagnostic-accuracy was 84.2% by total-anti-HBc

(98.2%-NPV). The HBV-DNA/total-anti-HBc/HBcrAg combination

identified IC with 89.5% diagnostic-accuracy, 93% sensitivity, 84.8%

specificity (Table 1).


Table 1Diagnostic performance in identification of carriers with inactive infection.

Single markers Combining 2 markers Combining 3 markers Combining 4

markers

HBV-DNA

≤2000 IU/mL

HBsAg

≤1000 IU/mL

HBcrAg

≤3 Log

Anti-HBc

≤16,937 IU/mL

HBV-DNA

≤2000 IU/mL

and HBsAg

≤1000 IU/mL

HBV-DNA

≤2000 IU/mL

and HBcrAg ≤3

Log

HBV-DNA

≤2000 IU/mL

and Anti-HBc

≤16,937 IU/mL

HBV-DNA

≤2000 IU/mL

and HBsAg

≤1000 IU/mL

and HBcrAg ≤3

Log

HBV-DNA

≤2000 IU/mL

and HBsAg

≤1000 IU/mL

and Anti-HBc

≤16,937 IU/mL

HBV-DNA

≤2000 IU/mL

and HBcrAg ≤3

Log

and Anti-HBc

≤16,937 IU/mL

HBV-DNA

≤2000 IU/mL

and HBsAg

≤1000 IU/mL

and HBcrAg ≤3

Log and Anti-HBc

≤16,937 IU/mL

Sensitivity 100.0% 69.0% 96.5% 95.3% 69.0% 96.5% 95.4% 66.3% 67.8% 93.0% 65.1%

Specificity 60.6% 60.6% 22.7% 54.5% 83.3% 74.2% 74.2% 84.8% 89.4% 84.8% 90.9%

PPV 77.0% 69.8% 61.9% 73.2% 84.5% 83.0% 83.0% 85.1% 89.4% 88.9% 90.3%

NPV 100.0% 59.7% 83.3% 90.0% 67.1% 94.2% 92.5% 65.9% 67.8% 90.3% 66.7%

DA 83.0% 65.4% 64.5% 77.6% 75.2% 86.8% 86.3% 74.3% 77.1% 89.5% 76.3%

Conclusions: HBeAg-negative carriers with viremia persistently

≤20,000 IU/mL show a benign clinical outcome with transition to

IC in almost half of LV-AC and to Occult-HBV-Infection in 20% of

IC within 5 years; however 13.1% of individuals with low viremia

at presentation are CHB patients: 1-year HBV-DNA monitoring

resulted the most accurate diagnostic approach. The single point

HBV-DNA/HBsAg measurement can halve the carriers requiring

12 month monitoring. The best IC diagnostic-accuracy combining

HBV-DNA/total-anti-HBc/HBcrAg needs to be confirmed in further

studies.


F-22

Thromboelastographic evaluation ofhemostatic balance in cirrhotic patients withinfection

E. Nadal 1, P. Simioni 2, L. Spiezia 2, P. Angeli 3,

S. Fasolato 3, A. Zanetto 1, A. Ferrarese 1,

S. Shalaby 1, G. Germani 1, F.P. Russo 1, P. Burra 1,

M. Senzolo 1


Surgery, Oncology and Gastroenterology, University

of Padua, Padua, Italy2 Thrombotic and Hemorrhagic Diseases Unit,

Department of Medicine, University of Padua, Padua,

Italy3 Internal Medicine and Hepatology, Department of

Medicine (DIMED), University of Padua, Padua, Italy

Introduction: Bacterial infection is a complication in decom-

pensated cirrhosis representing a precipitating factor for “Acute on

Chronic Liver Failure” and its effect on the hemostatic balance is

poorly understood.

Aim: To assess hemostatic balance during infection.

Materials and methods: 39 cirrhotic patients were analyzed

prospectively, including 23 infected and 16 noninfected patients.

For comparison 23 infected without cirrhosis were included. Each

patient was assessed using haemocoagulative thrombelastome-

try ROTEM test. In addition, 10 cirrhotic patients were studied

before and after the infection passed using impedance aggregom-

etry (Multiplate®

).

Results: When compared cirrhotics, patients with infection

reported a more hypocoagulable state and hyperfibrinolysis than

those without (CT EXTEM media ± SD: 78 ± 33 s vs. 57 ± 27,

p = 0.002; ML EXTEM media ± SD: 2.26 ± 1.6% vs. 1.00 ± 0.2%,

p = 0.031). These coagulation abnormalities were maintained also

when compared with patients without cirrhosis. Our findings

suggested a reduction of the intrinsic and extrinsic pathway

(AUC INTEM and EXTEM media ± SD: 6890 ± 1215 vs. 4460 ± 1474,

p = 0.0001 and 6854 ± 1232 vs. 4050 ± 1439, p = 0.0001 respec-

tively) as well as of fibrinogen levels (AUC in FIBTEM media ± DS:

3521 ± 1656 vs. 1257 ± 1053, p = 0.0001). After resolution of infec-

tion, recovery of coagulation changes depended on the rebalance

of secondary heamostasis (before and after infection MCF INTEM

media ± SD: 48 ± 9.7 mm vs. 50.50 ± 14 mm, p = 0.001. MCF EXTEM

media ± SD: 45.9 ± 13 mm vs. 49 ± 13.5 mm, p = 0.026. ML INTEM

media ± SD: 4.78 ± 2.9% vs. 2.44 ± 1.5%, p = 0.012) together with

platelet reactivity (ADP media ± SD: 32 ± 21 vs. 35 ± 21, p = 0.029;

TRAP media ± SD: 53 ± 43 vs. 72 ± 37, p = 0.125; COL media ± SD:

29 ± 24 vs. 36 ± 21, p = 0.001).

Conclusions: In cirrhotic patients, infection is associated with

a hypocoagulable and hyperfibronolytic state which could be

improved after resolution of infection. Furthermore independent

factors such as platelet aggregation could contribute to the clot

strength.


F-23

Ultrasound-guided Percutaneous IrreversibleElectroporation (IRE) of HepatocellularCarcinoma (HCC) not suitable for surgery orthermal ablation: Initial report on safety andefficacy from a western center

A. Giorgio 1, P. Gatti 1, C. Coppola 1, A. Calvanese 1,

F. Amendola 1, B. Santoro 1, M.G. Merola 1,

F. Merola 1, P. Matteucci 2, V. Giorgio 3

1 Tortorella Clinical Institute, Interventional

Ultrasound Unit, Salerno, Italy2 Radiation Oncology Department, Campus

Biomedico University of Rome, Rome, Italy3 Internal Medicine and Gastroenterology Area,

Fondazione Policlinico Universitario A. Gemelli,

Catholic University of Rome, Rome, Italy

Introduction and aim: IRE is a new non-thermal ablation

technique for ablation of liver tumors that uses electrical pulses

inducing necrosis of tumoral cells without damage of vascular or

biliary structures. We report our western experience on the first

seven patients treated with IRE.

Materials and methods: Seven patients (5 males; age range

49–67 ys, mean 56 y) with HCC not suitable for surgery or ther-

mal ablation consecutively seen in our Institution were included.

Diagnosis of HCC was based on histological diagnosis in all patients.

Only one patient had liver cirrhosis. HCC diameter ranged from 2 to

6 cm (mean 2.6 cm). All nodules were located at liver hylum and in

all cases dilatation of biliary tree was present. Only one patient had

a non-metallical biliary stent. The only controindication for IRE was

the presence of a cardiac disease. The follow-up ranged from 6 to


24 months (mean 13 months). IRE was performed percutaneously

under ultrasound guidance using Nanoknife®

system and insertion

of 2 needles (19G) at a distance of 2 mm. Efficacy of procedure was

evaluated with CEUS and enhanced CT one month after IRE.

Results: On imaging, complete necrosis was achieved in all

patients. Only in one patient 2 sessions of IRE were needed to obtain

complete necrosis. Six patients are still alive, while one patient died

6 months after IRE for stroke. No deaths occurred after procedure.

Only one patient presented with a small, symptomless hematoma

found on US seven days after IRE.

No other complications (either major or minor) occurred: in

particular no injury to biliary tree was observed.

Conclusions: IRe of HCC not suitable for resection or ablation

seems safe and effective in treatment of HCC closed to vascular

and/or biliary structures. A larger number of cases will confirm such

promising tool.


F-24

Transjugular intrahepatic portosystemic shuntis a safe and effective approach in cirrhoticpatients with splanchnic vein thrombosis

A. Airoldi 1, S. De Nicola 1, G. Perricone 1,

M. Vangeli 1, R. Viganò 1, R. Vercelli 2,

C. Migliorisi 2, M. Solcia 2, F. Barbosa 2, F. Musca 3,

A. De Gasperi 4, L.S. Belli 1, A.G. Rampoldi 2

1 Epatologia e Gastroenterologia, ASST Grande

Ospedale Metropolitano Niguarda, Milan, Italy2 Radiologia Interventistica, ASST Grande Ospedale

Metropolitano Niguarda, Milan, Italy3 Cardiologia 4, ASST Grande Ospedale

Metropolitano Niguarda, Milan, Italy4 Anestesia e Rianimazione 2, ASST Grande Ospedale

Metropolitano Niguarda, Milan, Italy

Introduction: TIPS is a well-known treatment strategy in por-

tal hypertension complications but its role, applicability and safety

in cirrhotic patients with splanchnic vein thrombosis are not com-

pletely established.

Aim: To compare clinical outcomes between patients with or

without splanchnic thrombosis at the time of TIPS placement.

Methods and results: From February 2014 to July 2016, 50

consecutive patients (40 males) underwent TIPS placement at

Niguarda Hospital and were analyzed for various clinical outcomes

including mortality, early complications (≤72 h) and success rate.

Median follow up was 16 months (4–32). Forty-seven patients

(94%)were cirrhotics (Child Pugh score A24%, B68% and C8%).

Median age was 56 years (range 29–78), the main etiologies of

liver disease were alcohol (15 cases, 30%) and viral disease (18

cases, 36%). Indication for TIPS placement was refractory ascites

in 19 patients (38%), variceal bleeding in 10 (20%) and splanchnic

thrombosis in 18 (36%). Splanchnic thrombosis had been com-

plicated by ascites in 6 patients (33%) and by digestive bleeding

in 10 (20%); only 2 patients (11%) had a single vessel involved

(portal vein), 11 (61%) had thrombosis of 2 vessels and 5 (28%) of

3 vessels (portal, mesenteric and splenic trunk). Overall the death

rate after the first 6 weeks from TIPS placement was 6%. Patients

with and without splanchnic thrombosis at baseline (18 vs. 29)

did not behave differently in terms of sepsis (33% vs. 24%, p = 0.52),

bleeding related complications (11% vs. 3%, p = 0.54), days of hos-

pitalization (13 vs. 16 days, p = 0.5), need for TIPS revision (11% vs.

17%, p = 1) and occurrence of hepatic encephalopathy (50% vs. 27%,

p = 0.21). All patients with thrombosis received anticoagulation

therapy, thirteen patients with thrombosis (72%) had a complete

or partial recanalization within 3 months from intervention.

Conclusions: TIPS is a realistic therapeutic option for patients

with splanchnic thrombosis as it is associated with a favorable clin-

ical outcome and the risk profile is in line with that observed for

other indications.


F-25

Decreased alpha-fetoprotein levels in HCVcirrhotic patients after direct-acting antiviralagents therapy. Does this indicate a reducedrisk of hepatocellular carcinoma?

F. De Leonardis, C. Masetti, P. Rossi, D. Di Paolo,

A. Bosa, M. Milana, F. Santopaolo, S. Cucchiarelli,

A. Pecchioli, S. Francioso, I. Lenci, A. Brega,

T. Marianelli, F. Antenucci, S. Di Nardi, L. Baiocchi,

M. Angelico


Rome, Italy

The risk of hepatocellular carcinoma (HCC) in HCV+ cirrhotic

patients attaining sustained virological response (SVR) is debated.

Although alpha-fetoprotein (AFP) has a limited usefulness in HCC

surveillance due to poor sensitivity, recent data showed that high

levels predict HCC development in patients achieving SVR after

peginterferon/ribavirin therapy. We thus investigated serum AFP

changes in a cohort of cirrhotics treated with direct-acting antiviral

agents (DAAs).

The study comprised 143 consecutive HCV cirrhotics (76M/67F;

mean age 64.4 ± 11.2) receiving an optimal DAA treatment

(2016 EASL guidelines), including 7 (5.4%) in Child-Pugh B/C

stage and 10 (7.0%) with previous HCC. Genotype-1 infection

was present in 88 (61.5%). DAAs schedules included: sofosbuvir

(n = 28, 19.6%), sofosbuvir/simeprevir (n = 24, 16.8%), sofosbu-

vir/daclatasvir (n = 13, 9.0%), sofosbuvir/ledipasvir (n = 48, 33.6%)

and ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 30, 21.0%).

AFP values were assayed at baseline and after treatment. Predic-

tors of >50% AFP reduction (AFP-Response) were investigated by

univariate and multivariate analyses.

SVR-12 was achieved in 137 patients (95.8%). Mean

AFP decreased significantly (p < 0.000001) from baseline

(15.9 ± 23.8 ng/ml) to the end of follow-up (4.9 ± 3.7 ng/ml).

While a decrease of AFP was observed in the vast majority,

40.5% patients showed AFP-Response. Patients with AFP <6 ng/ml

increased from 39.2% to 73.1% (p = 0.0001). During the follow-up, 2

patients developed HCC (2/2 without AFP-Response). At univariate

analysis, no previous HCC, DAAs schedule, elevated ALT and high

AFP at baseline appeared significant predictors of AFP-Response.

MELD and SVR had no significant impact on AFP-Response. At

multivariable logistic regression (n = 116), AFP-Response was

associated with high baseline AFP levels (p = 0.0009) and sofos-

buvir/simeprevir therapy (p = 0.02), with an area under the ROC

curve of 0.89.

In HCV cirrhotic patients, DAA therapy significantly reduces AFP

levels, particularly in those with high baseline values. Whether this

favorable AFP trend underscores a diminished residual risk of HCC

in the long-term requires more extended studies.



F-26

Bacterial infection is an uncommon occurrencein cirrhotic patients undergoing endoscopicvariceal ligation

S. Maimone 1, G. Caccamo 1, R. Filomia 1,2,3,

S. Sabatini 2, M.S. Franzè 2, C. Saitta 1, K. Sitajolo 2,

M.A. Aragona 2, F. Saffioti 3, C. Pitrone 2,

I. Cacciola 1, G. Squadrito 1,2,3,4, G. Raimondo 1,2,3

1 Division of Clinical and Molecular Hepatology,

University Hospital of Messina, Messina, Italy2 Department of Internal Medicine, University

Hospital of Messina, Messina, Italy3 Department of Clinical and Experimental Medicine,

University Hospital of Messina, Messina, Italy4 Department of Human Pathology of the Adult and

Evolutive Age, University Hospital of Messina,

Messina, Italy

Introduction and aim: Patients with cirrhosis are at high risk

of developing bacterial infections (BIs), in particular in occasion of

invasive procedures. Aim of this prospective study was to investi-

gate the incidence of BIs in cirrhotic patients undergoing elective

endoscopic variceal ligation (EVL).

Patients and methods: We enrolled 60 cirrhotic patients (51

males; mean age 66.2 ± 11.07 years) consecutively hospitalized

from March 2015 to June 2016, for a total of 112 EVL proce-

dures. EVL was performed by multiple-band ligator, applying 3–7

bands at each session until variceal eradication. Full blood cells

count, C-Reactive Protein (c-RP), Procalcitonine (PCT) and blood

cultures (aerobic and anaerobic mediums) were performed before

EVL and within 24 h after the procedure and were then compared

by Wilcoxon test.

Results: Twenty (33.3%) had virus-related, 12 (20%) alcoholic

and 28 (46.7%) metabolic/cryptogenic liver disease. Child-Pugh

class A/B/C distribution was 29/26/5, respectively; mean MELD

score was 10.6 ± 3. Fifteen patients (25%) had hepatocellular car-

cinoma. Blood cultures were negative in all samples before EVL,

whereas 3/112 (2.67%) cultures tested positive after procedures.

The bacteria isolated were Staphylococcus epidermidis and Strep-

tococcus mitis in 2 and 1 cases, respectively. Of note, none of

these three patients showed any evidence of clinically relevant

infection or change of c-RP, PCT and WBC values suggesting

that the positivity of cultures was expression of a transient bac-

teremia. There was no statistically significant difference before and

after endoscopic procedures in median white blood cells (WBC)

[4200 (1600–14,500) cells/mmc vs. 4550 (1700–14,000) cells/mmc;

p = 0.4]; PCR [0.4 (0.1–8.7) mg/dL vs. 0.47 (0.1–9.8) mg/dL, p = 0.2];

PCT [0.06 (0.03–2.09) ng/mL vs. 0.1 (0.01–2.56) ng/mL, p = 0.6].

Conclusions: EVL is not a risk factor for BIs in patients with

cirrhosis.


F-27

Frailty index is a strong predictor of in-hospitaloutcomes and mortality after discharge incirrhotic patients

G. Caccamo 1, G. Basile 2, S. Maimone 1,

D. Vadalà 1, T. Crea 1, M.S. Franzè 1, A. Sitibondo 1,

R. Filomia 1, C. Saitta 1, I. Cacciola 1,

G. Squadrito 1,3, G. Raimondo 1,4


University Hospital of Messina, Messina, Italy2 Unit of Geriatrics, Department of Clinical and

Experimental Medicine, University Hospital of

Messina, Messina, Italy3 Department of Human Pathology of the Adult and


Messina, Italy4 Department of Clinical and Experimental Medicine,

University Hospital of Messina, Messina, Italy

Background: Frailty is a multiply determined vulnerability state

causing a higher risk of adverse outcomes including death.

Aim: To evaluate the impact of the frailty measured by Rock-

wood frailty index (FI) on in-hospital outcomes and mortality after

discharge in a cohort of hospitalized cirrhotic patients.

Methods: We applied the FI to 101 cirrhotic patients (72% male;

65.6 years ± 12.2 SD) consecutively hospitalized from January to

May 2015. Using medical, nursing and laboratory records we esti-

mated FI taking into account 45 potential combinable deficits. The

ratio between the number of deficits presented by each patient and

the 45 considered deficits corresponds to FI: a value >0.25 identifies

a frail patient.

Results: Cirrhosis was cryptogenic in 40% of cases; viral in 39%,

alcoholic in 21%. CPT class distribution was 51A/30B/20C, median

MELD score was 11.0 (6.0–29.0). Thirty-five/101 (34.6%) and 29/101

(28.7%) patients were frail at admission (FI-a) and discharge (FI-d),

respectively. No difference was found in FIa between CPT-B and C

[16/30 (53.3%) vs. 15/20 (75%), p = 0.1]. Frail patients had a longer

in-hospital stay (17 ± 14.8 vs. 10.8 ± 14.3 days; p = 0.04); a higher

probability of re-hospitalisation within 3 months [23/35 (65.7%)

vs. 40/66 (60.6%), p = 0.005]; a higher in-hospital mortality [5/35

(14.3%) vs. 2/66 (3%), p = 0.03]; a higher mortality either at 3 months

[14/29 (48.3%) vs. 8/72 (11.1%), p < .001], 6 months [18/29 (62.1%)

vs. 10/72 (13.8%), p < .001], and 12 months [18/29 (62.1%) vs. 16/72

(22.2%), p < .001]. Patients with a FI-d > 0.25 had a risk of mortality

higher than that predicted by CPT and MELD.

Mortality risk

3 months 6 months 12 months

HR 95% CI p HR 95% CI p HR 95% CI p

FI-d > 0.25

30.8 6.1–155.9 <0.0001 39.0 9.9–156.2 <0.0001 27.9 7.3–106.3 <0.0001

CPT 1.6 1.3–1.9 <0.0001 1.5 1.3–1.8 <0.0001 1.4 1.2–1.6 <0.0001

MELD 1.16 1. 1–1.2 <0.0001 1.15 1.1–1.2 <0.0001 1.11 1.05–1.17 <0.0001

Conclusion: FI strongly predicts in-hospital outcomes and mor-

tality after discharge in hospitalized cirrhotic patients.



F-28

Efficacy of early empiric antibiotic treatmentand its impact on short-term mortality incirrhotic patients with subsequentidentification of the infecting bacteria

G. Caccamo 1, M.S. Franzè 2, R. Filomia 1,

P. Mondello 3, I.A. Paolucci 3, K. Sitajolo 2,

M.A. Aragona 2, T. Lembo 2, C. Saitta 1, I. Cacciola 1,

G. Squadrito 1,2,3,4, G. Raimondo 1,2,3,4,5,

S. Maimone 1


University Hospital of Messina, Messina, Italy2 Department of Internal Medicine, University

Hospital of Messina, Messina, Italy3 Department of Infectious Disease, University

Hospital of Messina, Messina, Italy4 Department of Human Pathology of the Adult and


Messina, Italy5 Department of Clinical and Experimental Medicine,

University Hospital of Messina, Messina, Italy

Introduction: Empiric antibiotic treatment (EAT) is mandatory

in cirrhotic patients with bacterial infections (BIs).

Aim: To analyze antibiotic sensitivity of bacteria isolates from

microbiological culture and to assess the efficacy of EAT in terms of

clinical outcomes and short-term mortality in patients with micro-

biological cultures proven bacterial infections.

Patients and methods: We retrospectively evaluated 157

BIs in 146 cirrhotics [55.5% male; age 65.8 ± 12.5 years; Child-

Pugh A/B/C: 25/87/34, MELD: 14.4 ± 7.6] consecutively hospitalized

from January 2009 to March 2015. Bacteria isolates were clas-

sified in sensitive (SI), multi-drug-resistant (MDR), extensively

drug-resistant (XDR) and pandrug-resistant (PDR). Clinical and lab-

oratory features associated to EAT failure, mortality at 1-month

(M-1) and 3-months (M-3) were evaluated.

Results: Cultures tested positive in 81/157 (51.6%) of BIs

episodes. Thirty-five of 81 (43.2%) isolates were SI, 39 (48.1%)

MDR, 6 (7.4%) XDR, and 1 (1.8%) PDR. EAT was changed accord-

ing to antibiogram in 26/81 (32%) of the cases. MDR were more

frequently isolated in patients who changed EAT than in those who

did not (5/26 vs. 30/55, respectively, p = 0.003). BIs with EAT failure

had longer duration of antibiotic therapy (13.1 ± 6.1 vs. 6.1 ± 2.8

days, p < 0.001), longer in-hospital-stay (19.6 ± 11.6 vs. 11.4 ± 6.1,

p = 0.002), higher MELD (15.35 ± 7.40 vs. 12.06 ± 4.12, p = 0.012)

and MELD-Na scores (18.12 ± 7.45 vs. 14.24 ± 5.51, p = 0.01), higher

bilirubin (3.9 ± 6.8 vs. 1.8 ± 3.4, p = 0.025), C-reactive protein (c-

RP) (2.41 ± 1.44 vs. 1.74 ± 0.73, p = 0.007), higher white blood cells

count (WBC) (9196 ± 7737 vs. 4651 ± 2239, p = 0.007) and lower

albumin (2.99 ± 0.53 vs. 3.32 ± 0.55, p = 0.014). M-1 and M-3 was of

13.6% and 25.9%, respectively and it was not statistically different

in patients who changed EAT and those who did not.

Conclusions: EAT was not confirmed in about one third of cases

of positive cultures mainly due to selection of MDR isolates. The

change of EAT was associated to a longer antibiotic-therapy, longer

in-hospital-stay, higher MELD, c-RP, WBC count, but did not affect

short term mortality.


F-29

Liver Stiffness Based Model (LSPS) predictsportal hypertension (PH), esofageal varices (EV)and HCC in Caucasian patients with HBV-relatedcirrhisis responsive to antiviral therapy

A. Tucci, W. Debernardi Venon, C. Chialà,

M. Fadda, G.M. Saracco, A. Marzano

Department of Gastroenterology and Hepatology,

San Giovanni Battista Hospital, Città della Salute e

della Scienza, University of Torino, Turin, Italy

Introduction and aims: Antiviral therapy reduces but does not

eliminate the risk of HCC in HBV-related cirrhosis. Endoscopic mon-

itoring of EV remains controversial in responsive patients. LSPS has

been correlated with PH, EV and risk of HCC [1].

Methods: A longitudinal study was performed in 121 cirrhotics

(median age 54, median fu 8 years, M/F 100/21, HBeAg/antiHBe

5/116, no HCV, HIV or HDV) responsive to antiviral therapy

who underwent HVPG and LS measurement. Sixty-one (50.4%)

had clinical PH (cPH) (US, EV, ascites and/or LS > 11 KPa and/or

plts < 100,000) at baseline.

Results: LSPS ≤0.62 and <1.4 identified all patients without

measured PH (HVPG <6 mmHg, NPV 100%) and EV (PPV 63.3%,

NPV 93.7%), respectively. After antiviral therapy LSPS ≤0.62 was

detected in 51.3% of the patients (16.4% and 76.6% with and with-

out cPH at baseline, p < 0.0001). Overall median LS decreased from

16.1 to 9.5 KPa (p < 0.0001). HCC developed in 26 patients (21.5%,

2.6% year) with a higher incidence in patients with LSPS > 0.62 after

antiviral therapy (36% vs. 7%, 7.1% vs. 0.75% year, p < 0.001), without

difference in lamivudine-exposed patients. On univariate and mul-

tivariate analysis patients with HCC had a higher LSPS after therapy

and cPH baseline (p < 0.001). Quantitative HBsAg was not different.

Conclusions: LSPS is useful to identify patients with PH and EV,

avoiding endoscopy. LSPS ≤0.62 baseline or inducted by antiviral

therapy (regression of cirrhosis) is associated with a lower risk of

HCC. This goal is obtainable in 75% and 20% of patients without and

with cPH baseline. These results support early antiviral treatment

of CHB in order to maintain or to induce LSPS ≤0.62 and the use

of the score to define the HCC risk and the individual endoscopic

surveillance in treated patients.

Reference

[1] Abreldes JG. Hepatology 2016.



F-30

HBV reactivation in pOBI is influenced bydetectable viremia at baseline rather thanduration of prophylaxis with lamivudine

F. Cavallo 1, P. Ghione 1, M. Battaglini 1, B. Botto 2,

D. Caracciolo 1, S. Ferrero 1, R. Passera 3,

U. Vitolo 2, M. Boccadoro 1, A. Marzano 4

1 Department of Molecular Biotechnologies and

Health Sciences, Division of Hematology, University

of Torino, Torino, Italy2 Citta’ della Salute e della Scienza, Division of

Hematology, Torino, Italy3 Citta’ della Salute e della Scienza, Division of

Nuclear Medicine, Torino, Italy4 Division of Gastro-Hepatology, San Giovanni

Battista Hospital, University of Torino, Torino, Italy

Introduction: Non Hodgkin Lymphoma (NHL) patients under-

going chemo-immunotherapy are at risk of HBV reactivation (HR)

and clinical events which can be life-threatening and compro-

mise treatment. HR can develop in both overt (HBsAg-positive) and

Occult B Infected (OBI; HBsAg-negative) carriers. AntiHBc positive

patients are defined as potential OBI (pOBI). Antiviral prophylaxis

in pOBI is effective in preventing HR, but its use and timing remain

controversial.

Materials and methods: All the patients with NHL treated with

Rituximab (R) in the period 2007–2016 at our institution were ana-

lyzed (inclusion criteria: 18 years or older, positive for anti-HBc

or HBsAg; exclusion criteria: HIV, chronic lymphocytic leukemia,

Lymphoblastic and T cell lymphoma). HR was defined by the reap-

pearance of HBsAg (Sieroreversion, SR), and clinical reactivation

(ALT > 1.5ULV).

Results: Among 2063 patients screened, 154 pOBI were ana-

lyzed (excluded: 550 R−; 26 HIV+; 1333 HBV−, 18 HBsAg+). POBI

characteristics: 90% Caucasian; median age 68 y (39–85), M/F ratio

1.17; HBV-DNA positive baseline 5/97 (3%); Lymphoma: DLBCL 76

(49%), FL 35 (23%), MCL 12 (8%), other 31 (20%). Patients received

one (109, 71%) or more lines of R (44, 29%), 9 (5, 9%) autologous

transplantation (ASCT). 139 (90%) patients received Lamivudine

(LAM) prophylaxis, and the drug was stopped in 45%. After R, pro-

phylaxis was maintained for <6, 6–12, 12–24 and >24 months in 7%,

17%, 43% and 32% of cases. HR developed in 5 (3.6%) cases (3/139

LAM+, 2.2%; 2/15 LAM−, 13.3%; p = 0.07). In LAM+ HR occurred 2 and

5 months after the discontinuation and in one case (with HBV-DNA

baseline >1500 IU) during prophylaxis. The number of chemother-

apy lines (p = 0.024) and detectable HBV-DNA baseline (p = 0.006)

were associated with HR.

Conclusions: (1) Antiviral prophylaxis is effective in preventing

>95% reactivation of HBV in NHL treated with R; (2) HR is more fre-

quent after LAM discontinuation than during antiviral treatment;

(3) detectable HBV-DNA baseline in pOBI and number of therapy

lines received were correlated with HR; (4) lymphoma subtype,

ASCT and duration of prophylaxis did not influence HR.


F-31

Risk of hepatocellular carcinoma (HCC)recurrence in HCV cirrhotic patients treatedwith Direct Acting Antivirals (DAAs)

G. Cabibbo, I. Cacciola, M.R. Cannavò, S. Madonia,

V. Calvaruso, S. Petta, M. Distefano, L. Larocca,

T. Prestileo, F. Tinè, A. Digiacomo, G. Bertino,

L. Giannitrapani, F. Benanti, A. Davì, R. Volpes,

I. Scalisi, C. Iacobello, G. Mazzola, F. Cartabellotta,

L. Guarneri, V. Portelli, A. Averna, M. Russello,

G. Scifo, G. Squadrito, G. Raimondo, A. Craxì,

V. Di Marco, C. Cammà, on behalf of RESIST-HCV

(Rete Sicilia Selezione Terapia – HCV)

Rete Sicilia Selezione Terapia – HCV (RESIST-HCV),

Italy

Background and aims: Conflicting data exists regarding the

impact of Direct Acting Antivirals (DAAs) on early recurrence in

successfully treated HCV-related HCC. With this aims, we analysed

the on-going dataset of RESIST-HCV.

Methods: We evaluated 185 cirrhotic patients with complete

radiological response after curative treatment of HCC (mean age

70 ± 9 years, 63.8% males, 41% naïve to antiviral therapy, 156

(84.3%) Child-Pugh A and 29 (1.7%) Child-Pugh B) who completed

the treatment between March 2015 and October 2016 in 22 centers

of RESIST-HCV. Each physician established DAA regimens and use

of Ribavirin. Seventy-nine patients received 12 weeks of therapy,

while 106 received a DAA regime of 24 weeks. All patients received

HCC surveillance according to the clinical practice policy. The pri-

mary endpoint of the analysis was the rate and the time of HCC

recurrence from the start of DAAs.

Results: At the end of October 2106, 145 patients (78.4%) com-

pleted the DAA regime and 40 were still on treatment. During the

follow-up (mean 24 weeks, range 8–60) 24 patients had a recur-

rence of HCC with a crude rate of 13%.

Pattern of HCC recurrence was nodular in 83% patients (20/24)

and infiltrative in 17% (4/24).

The 6- and 12-mo HCC recurrence rates by Kaplan–Meier

method were 7.9% and 16.3%, respectively. One patient died during

follow-up.

Conclusions: In patients with HCV-related successfully treated

HCC DAAs does not increase the risk of HCC recurrence. More-

over, potential benefit of DAA on preservation of liver function,

resulting in a lower cirrhosis-related mortality and a greater

change of receiving curative treatments, should improve survival of

patients with HCV-related HCC who achieved complete radiological

response after curative treatment.



F-32

Early occurrence of hepatocellular carcinoma(HCC) in patients with HCV cirrhosis treatedwith direct-acting antivirals (DAAs)

V. Calvaruso, G. Cabibbo, I. Cacciola, S. Petta,

S. Madonia, A. Bellia, F. Tinè, M. Distefano,

L. Giannitrapani, T. Prestileo, G. Mazzola, A. Davì,

L. Larocca, A. Ardiri, A. Digiacomo, M. Gussio,

L. Guarneri, A. Magro, A. Averna, C. Iacobello,

I. Scalisi, F. Cartabellotta, F. Savalli, M. Russello,

G. Scifo, G. Squadrito, C. Cammà, G. Raimondo,

A. Craxì, V. Di Marco, on behalf, RESIST-HCV (Rete

Sicilia Selezione Terapia – HCV)

Rete Sicilia Selezione Terapia – HCV (RESIST-HCV),

Italy

Background and aims: The risk of HCC occurrence during and

after DAA based treatment is still debated. The aims of this analysis

were to evaluate the early HCC occurrence and to analyse the HCC

pattern in a large cohort of treated cirrhotic patients.

Methods: We evaluated 2684 cirrhotic patients (mean age

65.3 ± 10.8 years, 58.4% males, 45.8% naïve to antiviral therapy,

2,364 (88%) Child-Pugh A and 320 (12%) Child-Pugh B) who com-

pleted the treatment between March 2015 and October 2016 in

22 centers of RESIST-HCV. Ribavirin was associated to DAAs in

1354 patients (50.4%), 1537 patients (57.3%) received DAAs for

12–14 weeks and 1147 (42.7%) for 24 weeks. Patients received HCC

surveillance as indicate by guidelines.

Results: During the observation (mean 34.2 weeks, range 4–72)

55 patients (2.0%) developed HCC. The rate was 1.73% in Child-

Pugh A and 4.37% in Child-Pugh B cirrhosis (p = 0.004). HCC met

Milan criteria in 29 patients (52.7%) while 26 (47.3%) were Milan-

out. Seven of 29 patients with Milan-in criteria developed HCC on

therapy and 22 out therapy, while 3 of 26 patients with Milan-

out criteria developed HCC on therapy and 23 out therapy (p = 0.3).

The evaluation of SVR was available in 1628 patients. By intention

to treat analysis, 1435 patients (88.1%) achieved a SVR and 193

(11.9%) no obtained SVR. The HCC occurrence was 1.88% (27/1435)

in patients whit SVR and 5.2% (10/193) in patients without SVR

(p = 0.008).

Conclusions: The occurrence of “de novo” HCC during the first

year of observation in our cohort of cirrhotic patients treated with

DAAs remained similar to that reported in historical cohorts of

untreated patients. The risk of HCC was higher in patients with

Child-Pugh B cirrhosis and in patients without SVR. The presenta-

tion pattern of HCC was no different on- and out therapy.


F-33

HLA-G is highly expressed by plasma cellsinfiltrating hepatic tissue of patients affected byautoimmune hepatitis

S. Onali 1, F. Figorilli 1, E. Sanna 1, C. Balestrieri 2,

G. Serra 2, M. Conti 2, F. Alba 3, M. Trucas 4,

D. Fanni 5, G. Senes 5, A. Mereu 5, G. Faa 5,

C. Carcassi 3, R. Littera 4, L. Chessa 1,2

1 Department of Medical Sciences and Public Health,



Cagliari, Italy3 Medical Genetics, Department of Medical Sciences,

University of Cagliari, Cagliari, Italy4 Bone Marrow Transplantation Centre, Binaghi

Hospital, Cagliari, Italy5 Division of Pathology, Department of Surgical

Sciences, University of Cagliari, Italy

Introduction: Human leukocyte antigen G (HLA-G) is an HLA

class Ib molecule with immunomodulatory, immunosuppressive

and tolerance-inducing functions. Altered HLA-G expression has

been observed in various autoimmune diseases but no data exist in

autoimmune hepatitis.

Aims: To analyse the frequency of HLA-G 14-bp inser-

tion/deletion polymorphism, known to have a functional effect on

HLA-G mRNA stability, and HLA-G hepatic expression in a cohort

of patients affected by autoimmune hepatitis type 1.

Methods: The frequencies of HLA-G 14-bp insertion/deletion

(rs371194629) polymorphism were determined by polymerase

chain reaction amplification in each patient and compared to those

of healthy individuals extracted from the Sardinian bone marrow

donor registry. Hepatic HLA-G expression was analysed on liver

biopsy samples using an immunohistochemistry staining with a

murine anti-human monoclonal antibody. HLA-G expression was

graded according to the proportion of cells displaying anti-HLA-G

positivity.

Results: Liver biopsy samples were available for immunohis-

tochemistry staining in 13 patients (female 85%, mean age 50 y).

Homozygosis for HLA-G 14-bp insertion/insertion (ins/ins) poly-

morphism was observed in 19% of patients while heterozygosis

(ins/del) was found in 47% and no significant difference was

observed between AIH and healthy group. On evaluation of hepatic

HLA-G expression, we found that 7 (54%) patients showed a marked

positivity (from 50% to 100%) for HLA-G both in the cytoplasm

and on the surface of plasma cells. Interestingly, only the plasma

cells were labelled, while hepatocytes and other cells, such as

macrophages, did not display any positivity. Three (23%) patients

were negative and showed only a mild inflammatory response at

histological examination.

Conclusions: Our study showed a strong HLA-G expression by

plasma cells infiltrating the liver of patients affected by AIH type-1.

Absence of HLA-G expression was observed only in 3 patients who

had a mild inflammatory damage, suggesting a possible correlation

between HLA-G and severity of liver inflammation.



F-34

Survival and recurrences after curativetreatments of HCV-related early hepatocellularcarcinoma. A meta-analysis of single armstudies

G. Cabibbo 1, S. Petta 1, M. Barbàra 1, G. Missale 2,

R. Virdone 3, E. Caturelli 4, F. Piscaglia 5,

F. Morisco 6, A. Colecchia 7, F. Farinati 8,

E. Giannini 9, F. Trevisani 10, A. Craxì 1,

M. Colombo 11, C. Cammà 1, on behalf of the

ITA.LI.CA study group

1 Section of Gastroenterology, Biomedical

Department of Internal and Specialized Medicine,

University of Palermo, Italy2 Unit of Infectious Diseases and Hepatology,

Teaching Hospital-University of Parma, Italy3 Division of Internal Medicine 2, Ospedali Riuniti

Villa Sofia-Cervello, Palermo, Italy4 Division of Gastroenterology, Belcolle Hospital,

Viterbo, Italy5 Division of Internal Medicine, Department of

Medical and Surgical Sciences, Alma Mater

Studiorum, University of Bologna, Italy6 Division of Gastroenterology, Department of

Medicine and Surgery, University of Naples Federico

II, Italy7 Department of Medical and Surgical Sciences,

University of Bologna, Italy8 Department of Surgery, Oncology and

Gastroenterology, University of Padua, Italy9 Gastroenterology Unit, Department of Internal

Medicine, IRCCS Azienda Ospedaliera Universitaria

San Martino IST, University of Genoa, Italy10 Division of Semeiotics, Department of Medical and

Surgical Sciences, Alma Mater Studiorum, University

of Bologna, Italy11 A.M.&A. Migliavacca Center for Liver Disease, 1st

Division of Gastroenterology, Fondazione IRCCS Ca’

Granda Maggiore Hospital, University of Milan, Italy

Background and aims: Knowing risk for recurrence and

survival after curative resection or ablation in patients with HCV-

related hepatocellular carcinoma (HCC) is important for stratifying

patients according to expected outcomes in future studies of adju-

vant therapy in the era of direct acting antivirals (DAA). The aims of

this meta-analysis were to estimate recurrence and survival prob-

ability of HCV-related early HCC who achieved complete response

after curative treatments and to identify predictors of recurrence

and survival.

Methods: Studies reporting time-dependent outcomes (HCC

recurrence or death) after curative treatment of HCV-related early

HCC were identified on MEDLINE through May 2016. Data on the

patient populations and outcomes were extracted from each study

by three independent observers and combined by a distribution-

free summary survival curve. Primary outcomes were actuarial

probability of recurrence and survival.

Results: Eleven studies met the inclusion criteria. The pooled

estimates of actuarial recurrence rates were 7.4% at 6 months and

47.0% at 2 years. The pooled estimates of actuarial survival rates

were 79.8% at 3 years and 58.6% at 5 years. Heterogeneity among

studies was highly significant for all outcomes. By univariate meta-

regression analyses, lower serum albumin, study design and follow-

up were independently associated with higher risk of recurrence,

while tumor size and alpha-fetoprotein with higher mortality.

Conclusions: This meta-analysis showed that recurrence risk

and survival are extremely variable in patients with successfully

treated HCV-related HCC, providing a useful benchmark for indirect

comparisons of the benefit of DAA and for a correct design of RCT

in the adjuvant setting.


F-35

Are detectable sofosbuvir troughconcentrations predictive of virological failureduring anti-HCV treatment? Preliminaryevidences from the KINETI-C study

A. De Nicolò, L. Boglione, C. Carcieri, J. Cusato,

S. Mornese Pinna, F. Favata, A. Ariaudo,

G. Di Perri, A. D’Avolio

Unit of Infectious Diseases, Department of Medical

Sciences, University of Turin, Turin, Italy

Introduction: In the current standard of care for HCV infection,

sofosbuvir (SOF) represents the backbone of several therapeutic

regimens. Up to now, pharmacokinetic/pharmacodynamic prop-

erties of SOF, as well as other DAAs, have been poorly studied in

“real-life” settings. SOF is a prodrug, which is firstly converted in

its active metabolite and is then measurable in plasma as its main

metabolite GS-331007. In fact, the fast conversion of SOF makes

GS-331007 the best marker of SOF exposure.

Aim: The aim of this study was to investigate pharmacokinetic

data in a real-life clinical context to identify possible predictors of

virological failure.

Materials and methods: HCV infected patients in treatment

with SOF-based regimens were enrolled in “Kineti-C” clinical study.

SOF, GS-331007 and concomitant drug concentrations were mea-

sured at 1, 3, 7, 30 and 60 days of treatment, through validated

methods in UHPLC–MS/MS. Statistical analysis was performed

through SPSS 22.0 statistical software. P values lower than 0.05

were considered as statistically significant.

Results: 95 patients who received SOF in their anti-HCV ther-

apy were enrolled: 37.9% (36) with SOF/DCV; 27.4% (26) with

SOF/SMV; 23.2% (22) with SOF/LPV; 9.5% (9) with SOF/RBV; 2.1%

(2) with SOF/RBV/PEG-IFN.SOF Ctrough was detectable at least at

one timing for 6 patients. Detectable SOF concentrations resulted

significantly associated to the onset of breakthrough (2 cases out of

3; P-value = 0.000013). GS-331007 and other drugs concentrations

resulted not significantly correlated with treatment response.

Conclusions: A residual Ctrough of SOF might underlie an incom-

plete conversion of SOF to its active metabolites: this could lead to

a lower activity than expected. Further studies are needed to clarify

the reasons behind the SOF detectable determinations and conse-

quent clinical implications. Anyway, this tool could be useful to the

clinicians for the early identification of the residual rare cases of

virological failure.



F-36

Prevalence and characteristics of resistanceassociated substitutions in DAA-naive andDAA-failed HCV-3 patients in Italy

V.C. Di Maio 1, S. Barbaliscia 1, I. Lenci 2, E. Teti 3,

F.P. Antonucci 1, V. Cento 1, M. Aragri 1,

S. Paolucci 4, B. Bruzzone 5, N. Coppola 6,

T. Ruggiero 7, T. Pollicino 8, E. Polilli 9,

C. Pasquazzi 10, V. Pace Palitti 11, C.F. Magni 12,

V. Micheli 13, A. Di Biagio 14, L. Sticchi 5,

M. Melis 15, S. Francioso 2, C. Masetti 2,

L. Foroghi 3, C. Sarrecchia 3, L. Baiocchi 2,

S. Landonio 12, A. Bertoli 1, V. Calvaruso 16,

F. Morisco 17, I. Maida 15, S. Marenco 18, A. Leo 19,

V. Ghisetti 7, A. Ciancio 20, P. Sacchi 21, S. Novati 22,

G. Brancaccio 6, A. Pieri 9, M. Puoti 23,

P. Toniutto 24, V. Vullo 25, A. Aghemo 26,

G. Di Perri 27, S. Babudieri 15, G. Rizzardini 12,

S. Bruno 19, A. Pellicelli 28, G. Taliani 29,

G. Raimondo 8, F. Baldanti 4, G.B. Gaeta 6,

A. Craxì 16, G. Parruti 9, M. Andreoni 3,

M. Angelico 2, C.F. Perno 1,

F. Ceccherini-Silberstein 1, on behalf of HCV

Virology Italian Resistance Network Group

(Vironet C)



Vergata, Rome, Italy3 Infectious Diseases, University Hospital of Rome Tor

Vergata, Rome, Italy4 Virologia Molecolare, Fondazione IRCCS Policlinico

San Matteo, Pavia, Italy5 Hygiene Unit, IRCCS AOU San Martino-IST, Genoa,

Italy6 Infectious Diseases and Viral Hepatitis Unit, Second

University of Naples, Naples, Italy7 Unit of Infectious Diseases, Laboratory of


Hospital, Turin, Italy8 Department of Internal Medicine, University

Hospital of Messina, Messina, Italy9 Infectious Disease Unit, Pescara General Hospital,

Pescara, Italy10 Infectious Diseases, Sant’Andrea Hospital–“La

Sapienza” University, Rome, Italy11 Hepatology Unit, Pescara General Hospital,

Pescara, Italy12 Division of Infectious Disease, ASST

Fatebenefratelli Sacco, Milan, Italy13 Clinical Microbiology, Virology and

Bioemergencies, ASST Fatebenefratelli Sacco, Milan

Italy14 Infectious Disease, IRCCS AOU San Martino - IST,

Genova, Italy15 Infectious Diseases Unit, University of Sassari,

Sassari, Italy16 Gastroenterology, “P. Giaccone” University

Hospital, Palermo, Italy17 Department of Clinical Medicine and Surgery,

University “Federico II” of Naples, Naples, Italy18 Division of Hepatology, IRCCS San Martino, IST

Genova, Genoa, Italy

19 Department of Internal Medicine, Humanitas

University, Rozzano, Milan, Italy20 Unit of Gastroenterology, University of Turin,

Department of Medical Sciences, Città della Salute e

della Scienza di Torino Molinette Hospital, Turin,

Italy21 Division of Infectious and Tropical Diseases,

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy22 Institute of Infectious Diseases, University of

Pavia, Pavia, Italy23 Department of Infectious Diseases, Hospital

Niguarda Ca’Granda, Milan, Italy24 Department of Medical Sciences Experimental and

Clinical, Medical Liver Transplant Section, Udine,

Italy25 Department of Public Health and Infectious

Diseases, Sapienza University of Rome, Rome, Italy26 UO Gastroenterologia ed Epatologia, Fondazione

IRCCS Ca’ Granda Ospedale Maggiore Policlinico di

Milano, Milan, Italy27 Unit of Infectious Diseases, Department of Medical

Sciences, Amedeo di Savoia Hospital, University of

Turin, Turin, Italy28 Hepatology Unit, San Camillo Forlanini Hospital,

Rome, Italy29 Infectious and Tropical Diseases Unit, Department

of Clinical Medicine, Sapienza University of Rome,

Rome, Italy

Introduction and aim: Aim of this study was to investigate

the prevalence and characteristics of resistance-associated-

substitutions (RASs) in HCV-3 infected patients, naïve to direct-

acting antivirals (DAA) and/or failing an interferon-free regimen in

Italy.

Materials and methods: Sanger-sequencing of NS5A +

NS5B + NS3-protease was performed in 204 HCV-3 infected

patients (150 DAA-naïve and 75 DAA-failures, of them, 21 at both

baseline and DAA-failure).

Results: The majority of patients were male (86.3%) and

cirrhotic (60.3%). 18 patients (8.8%) were HIV-coinfected. Further-

more, 89.5% of patients with known risk-factor of HCV-infection,

were injection-drug-users. HCV-sequencing identified two spe-

cific subtypes (HCV-3a, 99.5% and HCV-3 h, 0.5%), though 15/204

(7.3%) patients were previously misclassified as infected with

indeterminate-genotype (N = 4), non-3 genotype (N = 10), or mixed

(N = 1).

Overall, 75 patients experienced a virologic-failure to an

interferon-free-regimen: 61.3% to sofosbuvir + ribavirin and 30.7%

to daclatasvir + sofosbuvir ± ribavirin. Notably, 8.0% were treated

with 3D ± ribavirin (paritaprevir/r + ombitasvir + dasabuvir), due to

a wrong-genotype 1 assignment. A different distribution of RASs

was observed between DAA-naïve and DAA-failing patients. The

NS3-Q80K was mainly detected in the 3D-failures (33% vs. 0.7%

DAA-naïve, p = 0.004). In NS5A-experienced patients, the Y93H

was the most prevalent RASs: 5/6 (83.3%) 3D-failures, 17/23

(78.2%) daclatasvir + sofosbuvir-failures, vs. 5/130 (3.8%) DAA-naïve

patients (p < 0.0001). 2/5 DAA-naïve patients with natural Y93H

were treated with daclatasvir + sofosbuvir + ribavirin for 24 weeks

and 1/2 (50%) reached SVR. Interestingly, also 3/46 (6.5%) sofosbu-

vir + ribavirin failing-patients showed natural NS5A-RASs (2 = Y93H

and 1 = A30K + L31F). In NS5B, sofosbuvir RASs L159F and S282T

were both detected only at virologic-failures of a sofosbuvir-

containing regimen (5.8% and 2.9%, respectively).

Conclusions: HCV-sequencing at failure is useful for identi-

fying RASs and revealing previously misinterpreted genotypes

in order to select the best DAA-regimen for retreatment option.


NS5A-failing HCV-3 patients (including the 3D-failures) showed

a high frequency of Y93H, in some cases in association with

NS3 and/or NS5B-RAS. The clinical relevance of baseline Y93H in

genotype 3 deserves further investigation.


F-37

Evaluation of mild cognitive dysfunction byMontreal Cognitive Assessment test in patientswith chronic HCV infection treated with directantiviral agents

S. Onali 1, D.G. Pacini 1, C. Balestrieri 2, F. Figorilli 1,

G. Serra 2, L. Chessa 1,2

1 Department of Medical Sciences and Public Health,



Cagliari, Italy

Introduction: Cognitive impairment is frequently observed in

HCV patients, leading to impaired daily activities, adherence to

therapy and quality of life.

Aim: To investigate changes in neurocognitive status of HCV

patients undergoing antiviral treatment using the Montreal Cogni-

tive Assessment (MoCA) test.

Methods: Our single-centre prospective study included con-

secutive HCV patients treated with direct antiviral agents (DAAs)

between 2015–2016. The MoCA test was performed at baseline and

6 months after end of treatment. Various cognitive functions such

as attention, memory, language, orientation, executive and visual-

spatial skills, were evaluated. The result of MoCA was the sum of

the scores in each area for a maximum of 30 points. A score ≥26/30

was considered normal.

Results: Out of 118 patients evaluated at baseline, 31 repeated

the MoCA after therapy. All of them achieved a sustained virological

response (SVR). Male 15 (48%), mean age 58 (±11) years, geno-

type 1 23 (74%), naïve to previous treatment 14 (45%). 17 patients

(55%) had a compensated cirrhosis. Post-treatment MoCA score

improved in 26 patients (p < 0.001) with 61% of patients achiev-

ing the normal threshold vs. 26% (p = 0.003) at baseline. Execution

and memory areas, which were the most affected at baseline, sig-

nificantly improved after SVR: 81% of patients achieved a score of

at least 3/4 in execution vs. 48% at baseline (p = 0.013) while 35% of

patients had a score of at least 3/5 in memory vs. 19% at baseline

(p = 0.003). Good performances were reported in the area of orien-

tation and language with no difference before and after treatment.

Conclusions: MoCA was a simple and easy test to administer.

Although limited by the small number of cases, our results suggest

that successful treatment with DAAs could improve neurocognitive

functions, such as execution and memory, in patients affected by

HCV infection and advanced liver fibrosis.


F-38

Comparative antiviral efficacy with higher ALTnormalization of tenofovir alafenamide (TAF)versus tenofovir disoproxil fumarate (TDF) inHBeAg-negative, genotype D chronic hepatitis B

G. Ricco 1, M. Buti 2, M. Omata 3, Y.J. Kim 4,

B. Coco 1, D. Samuel 5, J.F. Flaherty 6, L. Lin 6,

A. Gaggar 6, E. Ceausu 7, U.S. Akarca 8, M.J. Tong 9,

H.L. Chan 10, M.R. Brunetto 1,11



Reference Center of the Tuscany Region for Chronic


Pisa, Italy2 Vall d’Hebron Hospital, Barcelona, Spain3 Yamanashi Prefectural Central Hospital, Kofu-shi,

Japan4 Seoul National University Hospital, Seoul, Republic

of Korea5 Hôpital Paul-Brousse, Villejuif, France6 Gilead Sciences, Inc., Foster City, CA, United States7 Spitalul Clinic de Boli Infectioase si Tropicale Dr.

Victor Babes, Bucuresti, Romania8 Ege University Medical Faculty Hospital, Izmir,

Turkey9 Huntington Medical Research Institutes, Pasadena,

CA, United States10 Prince of Wales Hospital, Hong Kong11 Department of Clinical and Experimental

Medicine, University of Pisa, Pisa, Italy

Background: TAF, a TDF prodrug, has been shown in chronic

hepatitis B (CHB) patients to have noninferior week (W) 48 efficacy

to TDF. We evaluated TAF efficacy compared to TDF in HBeAg-

negative CHB patients according to genotype (GT) D or non-D

infection.

Methods: 425 patients were randomized to receive TAF 25 mg

QD (n = 285) or TDF 300 mg QD (n = 140) for 144W; thereafter

patients receive open label TAF through 8 years. The endpoints for

this subanalysis were virologic (HBV-DNA <29 IU/mL, log10 IU/mL

changes in HBV-DNA and HBsAg levels), and biochemical (ALT nor-

malization) W48 responses.

Results: At baseline 90/285 (32%) TAF and 42/140 (30%) TDF

patients were GT-D. Within GT-D vs. non-GT-D patients baseline

characteristics were similar between the TAF and TDF arms, GT-

D patients being more likely to be male (68 vs. 58%), White (71 vs.

4%), without cirrhosis (8 vs. 13%) and have higher baseline BMI (25.8

vs. 24.2). In addition, GT-D patients had higher HBV DNA, HBsAg,

and serum ALT levels compared with non-GT-D patients. At W48,

the proportion of subjects with HBV-DNA <29 IU/mL was similar

between TAF and TDF arms for GT-D (92% vs. 95%) and non-GT-

D (95% vs. 92%) patients. Over 48 weeks declines in HBsAg were

minimal (mean change at W48 was −0.09 vs. −0.06 log10 IU/mL for

the TAF and TDF; p = 0.59) independently of GT-D or non-GT-D. ALT

normalization rates were higher in TAF vs. TDF arms when assessed

by both central laboratory (83 vs. 75%, p = 0.076) and AASLD (50 vs.

32%, p < 0.001) criteria independently of genotype.

Conclusions: In HBeAg-negative patients high rates of W48

HBV-DNA suppression were seen in TAF- and TDF-treated patients

independently of the genotype; whereas W48 HBsAg declines were

minimal in both treatment arms. Rates of ALT normalization were

higher in TAF versus TDF without any impact of HBV genotype.



F-39

Daclatasvir/sofosbuvir and ribavirin 800 mg flatdose is highly efficacy and safe in genotype 3compensated and decompensated cirrhoticpatients: The CLEO experience

A. Pellicelli 1, V. Messina 2, P. Tarquini 3,

V. Pace Palitti 4, F. Ceccherini Silberstein 5,

M. Pompili 6, R. Gulminetti 7, G. Cerasari 1,

C. D’Ambrosio 1, R. Villani 1, L. Fondacaro 1,

S. Dell’isola 8, S. Babudieri 9, V. Iovinella 10,

F. Di Candilo 11, F. Chiesara 12, V.C. Di Maio 5,

F.R. Ponziani 6, R. Sacco 13, A. Izzi 14, A. Moretti 12,

V. Giannelli 1, C.F. Perno 5, G. Barbarini 7, for the

CLEO Group

1 Liver and Transplant Unit, Azienda Ospedaliera San

Camillo Forlanini, Rome, Italy2 Infectious Disease, San’Anna and San Sebastiano

Hospital, Caserta, Italy3 Infectious Disease, G Mazzini Hospital, Teramo,

Italy4 Liver Unit, Department of Medicine, Pescara, Italy5 Virology Chair, Department of Experimental

Medicine and Surgery, “Tor Vergata” University of

Rome, Rome, Italy6 Internal Medicine, Catholic University, Rome, Italy7 Infectious Disease, IRCCS San Matteo, Pavia, Italy8 Infectious Disease, Belcolle Hospital, Viterbo, Italy9 Infectious Disease, University of Sassari, Sassari,

Italy10 Internal Medicine, San Paolo Hospital, Naples, Italy11 Infectious Disease, Azienda Ospedaliera, Perugia,

Italy12 Gastroenterology, San Filippo Neri Hospital, Rome,

Italy13 Liver Unit, Azienda Ospedaliero Universitaria

Pisana, Pisa, Italy14 Infectious Disease, Cotugno Hospital, Naples, Italy

Introduction: Genotype 3 cirrhotic patients are a difficult pop-

ulation to treat, with lower virological response rate than other

HCV genotypes (G). We aimed to explore the efficacy and safety

of SOF-DCV plus 800 mg flat dose RBV regimen in G3 naive and

experienced cirrhotic patients respect to pts treated with SOF-DCV-

weight-based RBV and SOF-DCV without RBV for 24 w.

Material and methods: We analysed the data of 140 G3 cir-

rhotic pts. 20.7% (29 pts), 46.4% (65) and 32.9% (46) received

respectively SOF-DCV, SOF-DCV-800 mgRBV, SOF-DCV-weight-

based RBV. Treatment duration was 24 weeks in all the pts.

Results: 87.9% (123 pts) were in class A Child-Pugh (CP) while

11.4% (16 pts) were in class CP-B and 0.7% (1 pts) in class CP-C.

52.1% (73 pts) were naive and 47.9% (67 pts) were experienced.

Overall SVR 12 was reached in 133 pts (95%). SVR 12 rate was

86.2% (25 pts) in pts treated with SOF-DCV, 98.5% (64 pts) in pts

treated with SOF-DCV-800 mg flat dose RBV and 95.7% (44 pts) in

pts treated with SOF-DCV-weight-based dose RBV. No significant

difference in SVR12 was found between patients treated with a flat

dose RBV respect to weight-based RBV dose, while a statistically

significant difference was disclosed in patients treated with reg-

imen containing RBV (97.2%) respect to pts treated without RBV

(86.2%) (p < 0.03). Grade II anemia was disclosed more frequently

in patients treated with weight-based dose RBV (39.1%) respect to

patients treated with a flat dose RBV (23.1%) (p < 0.05) and without

RBV (7.1%) (p < 0.003).

Conclusions: SOF-DCV plus 800 mg flat dose RBV is safe and

highly efficacy in term of SVR 12. This regimen presents less grade

2 anemia respect to other regimens. SOF-DCV without RBV regimen

presents a low SVR12 and should be prescribed only in cirrhotic pts

with a clear contraindications to the use of RBV.


F-40

Emerging players in liver fibrosis regression in achronic murine model of hepatic injury

M. Crescenzi 1, C. Frasson 2, D. Gabbia 3,

S. De Martin 3, M.T. Conconi 3, G. Basso 2,

P. Burra 1, F.P. Russo 1

1 Gastroenterology Section, Department of Surgery,

Oncology and Gastroenterology, University Hospital

Padova, Italy2 Department of Woman and Child Health,

University of Padova, Institute of Pediatric Research

Città della Speranza – IRP, Padova, Italy3 Department of Pharmaceutical and

Pharmacological Sciences, University of Padova,

Padova, Italy

Aim: To verify if gender-dependent mechanisms are responsible

for liver fibrosis establishment and regression.

Materials and methods: Balb/cJ mice were intra-peritoneally

treated with CCl4 and sacrificed at week (wk) 2, 6, 12 and after

8 weeks from the cessation of the damage. We used different

techniques to analyse the mechanisms involved: H&E, immunohis-

tochemistry, Sirius Red staining, Western Blot, and flow cytometry.

Results: A significant difference in fibrotic areas at wk2

between treated mice (mean ± ds females vs. males: 5.52 ± 1.01 vs.

8.4 ± 2.02, p = 0.021) was observed. In the recovery group fibrosis

was higher in females with respect to males (mean ± ds females

vs. males: 4.48 ± 1.39 vs. 2.46 ± 0.53, p = 0.032). Alpha-SMA+ areas

significantly differed between female and male mice at wk2

(mean ± ds females vs. males: 8.52 ± 0.7 vs. 5.47 ± 0.88, p = 0.009),

with an overall decrease over time (mean ± ds females at wk2 vs.

wk12 and males wk2 vs. wk12: 8.52 ± 0.7 vs. 2.72 ± 0.24, p < 0.001

and 5.47 ± 0.88 vs. 1.58 ± 0.68, p = 0.004, respectively). Collagens I,

III and IV were found lower in females than in males at wk2, and

a reversal of the trend in the recovery group was observed. IL-6

and IL-10 were found lower in females at wk2. Interestingly, male

mice showed a significant increase of IL-6 along with a significant

decrease of IL-10 during the recovery period. Androgen Receptor+

macrophages, were found higher in females than in males both at

wk2 and in the recovery group, while GAT6+ macrophages were

present in both control mice and were found higher in females at

wk2 and showed a reversion in their abundance in the recovery

group.

Conclusions: The higher amount of fibrosis found in females

after the recovery period suggests that a molecular mechanism, not

CYP2E1-mediated, is defective in females. Female mice inflamma-

tory status preliminary analysis could explain, in part, their defects

in fibrosis regression, in respect to male mice.



F-41

Portosystemic shunts in cirrhosis are associatedto more complications and deteriorated qualityof life. An international cohort study

M. Simón-Talero 1, D. Roccarina 2, A. Majumdar 2,

E.A. Tsochatzis 2, J. Martínez 3, C. Picón 4,

A. Albillos 3, K. Lampichler 5, D. Toth 5,

T. Reiberger 5, A. Baiges 6, A. Darnell 7,

V. Hernandez-Gea 6, G. Low 8, J.G. Abraldes 9,

P. Tandon 9, E. Llop 10, M. Lopez 10, J.L. Calleja 10,

M. Praktiknjo 11, G. Kukuk 12, J. Trebicka 11,

M. Maurer 13, A. Berzigotti 14, A. Zipprich 15,

C. Ripoll 15, M. Triolo 16, V. La Mura 16,

G. Vangrinsven 17, W. Laleman 17,

R. Garcia-Martinez 18, R. Banares 18, A. Dam 19,

A. Krag 19, S. Augustin 1, J. Genescà 1, the Baveno

VI-SPSS group

1 Liver Unit, Department of Internal Medicine,

Hospital Universitari Vall d’Hebron, VHIR,

Universitat Autònoma de Barcelona, CIBERehd,

Barcelona, Spain2 Sheila Sherlock Liver Unit and UCL Institute for

Liver and Digestive Health, Royal Free Hospital and

UCL, London, United Kingdom3 Department of Gastroenterology and Hepatology,

Hospital Universitario Ramón y Cajal, IRICYS,

Universidad de Alcalá, CIBERehd, Spain4 Department of Radiology, Hospital Universitario

Ramón y Cajal, IRICYS, Universidad de Alcalá,

Madrid, Spain5 Division of Gastroenterology and Hepatology,

Vienna Hepatic Hemodynamic Lab, Medical

University of Vienna, Vienna, Austria6 Hepatic Hemodynamic Laboratory, Liver Unit,

Hospital Clinic, IDIBAPS, Universitat de Barcelona,

CIBERehd, Spain7 Department of Radiology, Hospital Clinic, IDIBAPS,

Universitat de Barcelona, Barcelona, Spain8 Department of Radiology, University of Alberta,

Edmonton, Canada9 Cirrhosis Care Clinic, University of Alberta,

Edmonton, Canada10 Liver Unit, Hospital U. Puerta de Hierro,

Universidad Autónoma de Madrid, CIBERehd,

Madrid, Spain11 Department of Internal Medicine I, University of

Bonn, Germany12 Department of Radiology, University of Bonn,

Bonn, Germany13 Department of Radiology, Inselspital, University of

Berne, Switzerland14 Hepatology, Inselspital, University of Berne, Berne,

Switzerland15 First Department of Internal Medicine, Martin

Luther University Halle-Wittenberg, Halle (Saale),

Germany16 First Division of Internal Medicine, IRCCS

Policlinico San Donato, University of Milan, Milan,

Italy17 Department of Gastroenterology and Hepatology,

University Hospitals Leuven, Leuven, Belgium18 Liver Unit, Hospital General Universitario Gregorio

Maranón, Universidad Complutense, CIBERehd,

Madrid, Spain

19 Department of Gastroenterology and Hepatology,

Odense University Hospital, Odense, Denmark

Introduction: Spontaneous porto-systemic shunts (SPSS) have

been reported in hepatic-encephalopathy (HE). However, their

prevalence in cirrhosis and association with any decompensation

are not known.

Aim: determining the prevalence of SPSS in cirrhosis and the

impact on clinical outcome.

Methods: Retrospective, multicenter, international study of

consecutive cirrhotic patients submitted to abdominal-imaging

(angioCT/angioMR) (years: 2010–2015). Advanced hepatocellular

carcinoma, psychiatric or terminal illness were exclusion criteria.

Patients were classified into large SPSS (L-SPSS ≥ 8 mm), small SPSS

(S-SPSS < 8 mm), without SPSS (W-SPSS).

Results: 1785 of 2978 patients were included, median follow-

up: 19.4 months (IR 7.9–34.9), Child-Pugh A/B/C distribution:

42/38/20%. Prevalence of shunts: 26% L-SPSS, 30% S-SPSS, 44%

W-SPSS. L-SPSS/S-SPSS/W-SPSS distribution by Child: Child A

24/30/46%; B 35/33/32%; C 41/38/21% (p < 0.001). Patients with L-

SPSS had the highest prevalence of HE (prior abdominal-imaging, at

time of abdominal-imaging and during the follow-up): L-SPSS 58%,

S-SPSS 42%, W-SPSS 27% (p < 0.001) and recurrent/persistent HE:

L-SPSS 50%, S-SPSS 40%, W-SPSS 13% (p < 0.001) with differences in

quality of life (QoL, autonomy according to mRS): L-SPSS 76%, S-

SPSS 81%, W-SPSS 91% (p < 0.001). L-SPPS significantly influenced

the presence of HE in Child A and B (p < 0.001) and the presence of

recurrent/persistent HE in each Child class. Child A patients with

SPSS had more ascites and bleeding (p = 0.03). However, transplant-

free survival was no different according to the presence of SPSS in

the 3 Child classes.

Conclusions: SPSS are common in cirrhosis and their prevalence

increases with liver function deterioration. SPSS are associated

with frequent and severe HE-episodes, poorer QoL and more

ascites/bleeding in Child A. No association with mortality was

observed.


F-42

High rate of misclassification of fibrosis stageusing transient elastography thresholds toprioritize HCV patients for antiviral treatment

V. Calvaruso 1, F. Bronte 1, B. Magro 1, E. Conte 1,

S. Petta 1, D. Cabibi 2, A. Craxì 1, C. Cammà 1,

V. Di Marco 1

1 Sezione di Gastroenterologia e Epatologia,

Dipartimento Biomedico di Medicina Interna e

Specialistica (Di.Bi.M.I.S.), University of Palermo,

Palermo, Italy2 Istituto di Anatomia Patologica, Scienze per la

Promozione della Salute e Materno Infantile “G.

D’Alessandro”, University of Palermo, Palermo, Italy

Background: Transient elastography (TE) is largely used to stage

fibrosis in patients with Hepatitis C Virus (HCV) infection and

recently the threshold of 10 kPa, as marker of severe fibrosis, has

been considered as a criteria to prioritize HCV patients to therapy

with Direct Antiviral Agents (DAAs).

Aims: To assess diagnostic reliability of TE in identifying severe

fibrosis or cirrhosis and in ruling out patients with mild-moderate

fibrosis in a large cohort of patients with histological diagnosis of

HCV chronic hepatitis.


Methods: We included in this analysis 716 consecutive HCV

patients who underwent liver biopsy (METAVIR score) within 1

months of TE.

Results: TE was not reliable in 20 patients (2.8%) due to obesity.

TE < 10 kPa was found in 461 patients (66.2%), 49 of them had a

METAVIR stage ≥3 (F ≥ 3) with a false negative rate (FNR) of 10.6%

(sensitivity 82.2%, NPV 89.4%) and 89 patients had a F ≤ 2 (false

positive rate-FPR: 37.9%, specificity 74.9, PPV 62.1%) with a misclas-

sification rate of 48.5%. Reducing the TE cut off to 8 kPa the rate of

patients with F ≥ 3 and TE < 8kPa (FNR) was 7.4% (28/379 patients)

with a FPR (patients with F0-2 and TE ≥ 8 kPa) of 47.3% (150/317

patients) increasing the misclassification rate to 54.7%.

When the threshold of 8 kPa was used to identify patients with

METAVIR stage = 2 (F2), the rate of patients with F2 and TE < 8 kPa

(FNR) was 25.1% (95/379 patients), NPV: 74.9%; and the FPR was

17.4% (55/317 patients), NPV 82.6% and a misclassification rate of

42.5%.

Conclusions: In HCV patients, the use of TE threshold of 10 kPa

is related to a misclassification rate of the patients to prioritize

to DAAs in almost of 50% of cases with a significant risk to defer

antiviral therapy in patients with severe fibrosis. Moreover, the

low performance of TE for significant fibrosis do not allow to find

a reliable TE threshold which correctly select patients with Stage 2

fibrosis for DAAs.


F-43

The prevalence of liver diseases due Hepatitis CVirus (HCV) in Sicily: A population-based survey

F. Cartabellotta 1, V. Calvaruso 1, C. Paci 2,

F. Magliozzo 2, V. Milazzo 2, C. Crisafulli 2,

C. Lo Curcio 2, M. Russello 1, A. Digiacomo 1,

L. Galvano 2, L. Spicola 2, V. Di Marco 1

1 RESIST-HCV (Rete Sicilia Selezione Terapia-HCV),

Italy2 Società Italiana di Medicina Generale (SIMG)

Sicilia, Italy

Background and aims: HCV therapies have transformed the

treatment landscape, but data on the prevalence of HCV infection

and related liver disease in Italy are out-dated. This survey assessed

the prevalence of HCV liver disease in a large number of Sicilian

citizens.

Methods: The first step of survey was carried-out in a country

with 10,449 inhabitants (Campobello di Licata) where 7 general

practitioners evaluating patients with chronic HCV disease regis-

tered in their database.

The second step evaluated the clinical database of 84,480 per-

sons managed by 70 general practitioners of several countries of

Sicily.

Results: In Campobello di Licata the prevalence of HCV chronic

disease was 1% (101 patients/10,447 inhabitants) with differ-

ence between women (0.77% of 5548) and men (1.18% of 4899)

(p = 0.042). The rate of HCV disease decreased from 3.29% in per-

sons over 70 years to 2.0% in persons with 60–70 years and fell to

0.67% between 50–60 years. The prevalence was highest between

40–50 years (1.13%) with a significant difference between women

(4/784, 0.51%) and men (13/713, 1.81%; p = 0.025) probably due to

the risk of past drug addiction. Only 4 men of 1309 people (0.3%)

aged 30–40 years and no persons under 30 years had HCV hepatitis.

In the second survey the prevalence of HCV chronic diseases was

0.96% with a range between 0.48% and 1.53% in different geographic

area. Among 800 persons with HCV chronic disease, 230 (28.7%)

had over 75 years, 317 (39.6%) 60–75 years and 210 (26.2%) 40–60

years. Only 47 persons (5.8%) were under 40 years.

Conclusion: Our survey shows that 1% of Sicilian citizens have

a known chronic liver disease due to HCV infection. These per-

sons need to be evaluated for antiviral therapy. In the coming

years, healthcare organizations must determine the need for a

population-based screening to identify all people with chronic HCV

infection.


F-44

HCC onset and features among chronic hepatitisB patients treated with nucleos(t)ide analogues

M. Schranz 1, M. De Giorgio 1, G. Conte 2,

L. Pasulo 1, G. Magini 1, S. Fagiuoli 1

1 Department of Hepatology and Transplantology,

ASST Papa Giovanni XXIII, Bergamo, Italy2 Department of Surgery, Transplant Division, ASST

Papa Giovanni XXIII, Bergamo, Italy

Introduction: The impact of HBV antiviral treatment on HCC

occurrence is still debated.

Patients and methods: This study included 345 HBsAg positive

patients who were consecutively evaluated for the occurrence of

HCC at our centre since 2000. Patients with comorbidities like viral

co-infection, elevated alcohol consumption or metabolic syndrome

were excluded (n = 287). After removal of possible confounders,

remaining patients were divided into a study group (n = 25), includ-

ing patients who received nucleos(t)ide analogue (NA) treatment

for at least one year, and a treatment naïve (or NA experienced for

less than 1 year) control group (n = 33). The differences in features of

HCC between the two groups and the distribution of HCC according

to the duration of antiviral treatment were evaluated.

Results: Within the study group 11 (44%) patients were ini-

tially treated with lamivudine, 10 (40%) with entecavir and 3 (12%)

with tenofovir, while 1 (4%) patient received both lamivudine and

adefovir. In 12 patients treatment was subsequently modified.

No significant difference between the two groups was

found concerning number of cirrhotic patients, number of HCC

lesions, cumulative diameter, angioinvasion and histological grade

(p > 0.05).

Patients treated with NAs more frequently exceeded 400 ng/ml

alpha fetoprotein (AFP) serum concentration (24% vs. 6%, p = 0.05)

and had significantly more often tumour lesions without typical

hypervascular appearance in imaging (16% vs. 0%, p = 0.017).

Among NA treated patients the mean annual HCC occurrence

was 3 times higher during the first 7 years of therapy and decreased

subsequently to just 1 case per year.

Conclusions: In our study group (76% cirrhotic patients) the

effect of NAs on the reduction of HCC incidence becomes evident

after several years and correlates well with the expected effect on

the regression of cirrhosis. Moreover, HCC in NA treated patient

seems to show more aggressive tumour features.



F-45

Effect of interferon free antiviral therapy onglomerular and tubular kidney involvement inHCV child-A cirrhosis

D. Palazzo 1, E. Biliotti 1, F. Tinti 1, A. Bachetoni 2,

L. Volpicelli 1, A. Cappoli 1, M.D. D’Alessandro 2,

R. Labriola 2, P. Perinelli 1, S. Grieco 1, M. Subic 3,

I. Umbro 1, P. Rucci 4, A.P. Mitterhofer 1,

G. Taliani 1

1 Department of Clinical Medicine, Sapienza

University of Rome, Rome, Italy2 Department of General Surgery Paride Stefanini,

Sapienza University of Rome, Rome, Italy3 Department of Internal Medicine, Sapienza

University of Rome, Rome, Italy4 Department of Biomedical and Neuromotor

Sciences, University of Bologna, Bologna, Italy

Background: Hepatitis C virus (HCV) infection is associated with

an increased risk of renal disease. The correlation between HCV

and glomerular damage is well recognized, but limited data are

available on HCV-mediated tubular damage. Recently, several novel

direct antiviral agents (DAAs) have been approved for HCV treat-

ment, but the effects of HCV clearance on renal involvement (RI)

has not been fully characterized.

Aim: The aim of this study was to evaluate the effect of viral

eradication, by means of DAAs, on renal glomerular (GI) and tubular

involvement (TI) in pts with HCV-related cirrhosis.

Materials and methods: 94 CPA cirrhotic pts treated with

DAAs were consecutively enrolled. Estimated glomerular filtration

rate (e-GFR) assessed by CKD-EPI equation, urinary albumin-

to-creatinine ratio (ACR), urinary �1-microglobulin-to-creatinine

ratio (�1MCR) and sodium fractional excretion (FeNa) were eval-

uated before starting therapy (T0) and six months after treatment

withdrawal (FU6). GI was defined as ACR > 30 mg/g, TI was defined

as �1MCR > 14 mg/g and/or FeNa > 1%.

Results: RI (glomerular and/or tubular) occurred in 39 pts

(41.5%). GI was found in 19 pts (20.2%), 6 of them (31.6%) had dia-

betes. TI was detected in 30 pts (31.9%). Pts with RI showed lower

e-GFR values than pts without RI (95.2 ± 15.2 mL/min/1.73 m2

vs. 85.1 ± 5.8 mL/min/1.73 m2, p = 0.07). In diabetic pts with GI,

ACR did not change after treatment (316.2 ± 406.7 mg/g vs.

321.3 ± 416.2 mg/g, p = 0.92), while a significant reduction of ACR

(73.5 ± 138.5 mg/g vs. 19.9 ± 12.3 mg/g, p = 0.019) occurred in non-

diabetic HCV cirrhotic pts and GI resolved in 11/13 (84.6%) pts

without diabetes. The proportion of pts with TI decreased sig-

nificantly after DAAs treatment, since in 14/25 (56%) patients TI

recovered.

Conclusions: Our study confirms a strong relationship between

HCV and GI and underlines significant occurrence of TI. In HCV

cirrhotic pts with diabetes the GI seems to be mainly driven by

the metabolic disorder rather than by HCV infection itself. This is

the first report demonstrating a significant improvement of either

non-diabetic glomerular, either tubular HCV-induced damage after

HCV clearance by DAAs therapy, emphasizing the importance of

antiviral treatment.


F-46

The old patient in DAA era: Real life reports on5925 patients from the Lombardy HCV Network

L. Pasulo 1, A. Aghemo 2, S. Fargion 2, A. Spinetti 3,

G. Cologni 4, F. Maggiolo 4, G. Rizzardini 5,

M. Puoti 6, R. Bruno 7, L. Minoli 8, M. Zuin 9,

C. Uberti Foppa 10, T. Quirino 11,

A. D’Arminio Monforte 12, A. Colli 13, M.G. Rumi 14,

C. Iegri 1, S. Fagiuoli 1, M. Colombo 2

1 Gastroenterology, ASST Papa Giovanni XXIII,

Bergamo, Italy2 Gastroenterology, IRCSS Policlinico Milano, Milan,

Italy3 Infectious Disease, Spedali Civili, Brescia, Italy4 Infectious Disease, ASST PAPA GIOVANNI XXIII,

Bergamo, Italy5 Infectious Disease, Sacco Hospital, Italy6 Infectious Disease, Ca’ Granda Niguarda Hospital,

Milan, Italy7 Infectious Disease, Policlinico Pavia, Italy8 Infectious Disease, Policlinico Pavia, Pavia, Italy9 Gastroenterology, San Paolo Hospital, Italy10 Immunology and Infectious Disease, San Raffaele

Hospital, Milan, Italy11 Infectious Disease, Busto Arsizio Hospital, Varese,

Italy12 Infectious Disease, San Paolo Hospital, Milan, Italy13 Internal Medicine, Lecco Hospital, Lecco, Italy14 Hepatology, San Giuseppe Hospital, Milan, Italy

Background and aims: Since May 2015, 34 Prescribing Centers

from the Lombardia Region HCV Network (Northern Italy) col-

lected Real life data from DAA IFN-free treatments of older patients

(>70 yrs old) with chronic Hepatitis C (HCV).

Methods: We retrospectively/prospectively analyzed the data

of 5925 patients affected by HCV infection treated with DAA accord-

ing to the EASL and AISF guidelines. The data were stratified for

age.

Results: At the time of the analysis, 3067 patients had com-

pleted the treatment, and 2987 could be evaluated for SVR 12;

of these, 2396 (78.12%) were younger than 70 yrs (group 1) and

582 (21.87%) were older than 70 yrs (group 2). Baseline character-

istics: in group 1, higher rates of both male and HIV co-infections

were reported; the distribution of genotypes was significantly dif-

ferent among the two groups: Genotype 1b 68.6% vs. 38.5% and

Genotype 2 28.4% vs. 9% respectively in Group 2 and 1. Only 2 pts

Fig. 1.


Fig. 2.

with Genotype 3 were present in group 2. By ITT analysis, over-

all SVR12 was 95% (2834/2978) (the results are shown in Fig. 1).

Among the cirrhotic patients SVR12 was 94% and a MELD score

improvement was observed (44,6% in group 1 vs. 32.4% in group 2:

p < 0.002); no differences in MELD variation emerged when pts ≥70

y.o. were stratified by 5-year blocks. SAEs were observed in 1.8% (n.

56) during treatment or follow-up.

Conclusions: In our cohort, overall SVR12 was 95%. No sig-

nificant differences in SVR were observed between patients with

age greater or lower than 70 yrs (Figs. 1 and 2). Among cirrhotic

patients, a MELD score improvement was observed in 44.6% of

younger patients vs. 33.5% of elder patients. Comorbidities, age-

related metabolic events and/or longer disease duration might play

a role in preventing liver function restoration after HCVRNA eradi-

cation in elder patients.


F-47

Genotype 3 infection in DAA era: Reports of areal life Northern Italy Network for viralhepatitis after 2 years by the start

L. Pasulo 1, A. Aghemo 2, T. Quirino 3, P. Viganò 4,

P. Bonfanti 5, E. Buscarini 6, M. Strazzabosco 7,

M. Puoti 8, M. Vinci 8, P. Perini 9, M. Colpani 1,

M. Colombo 2, S. Fagiuoli 1


Bergamo, Italy2 Gastroenterology, IRCSS Policlinico Milano, Italy3 Infectious Disease, Busto Arsizio Hospital, Italy4 Infectious Disease, Legnano Hospital, Italy5 Internal Medicine, Lecco Hospital, Italy6 Gastroenterology Department, Crema Hospital,

Italy7 Gastroenterology Department, San Gerardo

Hospital, Monza, Italy8 Infectious Disease, Ca Grande Niguarda Hospital,

Milan, Italy9 Internal Medicine, Ponte San Pietro San Marco

Hospital, Italy

Background and aims: In this new era, HCV genotype 3 has

emerged as a difficult-to-treat viral strain, achieving response rates

lower than other genotypes. The Lombardy Region Network col-

lected data on HCV Gen3 treatments since May 2015.

Aim: To explore the real life outcome of g3infected patients

treated with DAAs.

Fig. 1.

Methods: 806 g3 infected pts were prospec-

tively/retrospectively. 30%, 66% and 4% of pts received respectively:

SOF + RBV, SOF + DAC ± RBV, PEG + SOF + RBV. Treatment duration

was 24 weeks in 85%.

Results: 85.8% of patients were cirrhotic of whom 82% were

well compensated and the remaining were waitlisted for LT. Pts

treated with DAC + SOF + RIBA were older, with a higher rate of

cirrhosis. Overall, 21 SAEs (3.28%), unrelated to therapy, were

observed during treatment or follow-up. 1 pt died for heart attack

and Another one for end stage liver disease. At the time of the

analysis, 639 pts had completed the treatment and 433 could be

evaluated for SVR 12. The overall SVR12 was 88.4%. No differences

were observed in SVR rate by stratifying the patients according

to: presence/absence of cirrhosis, HIV coinfection and treatment

duration. SVR rates in pts treated with SOF + RBV (81%) were sig-

nificantly lower (p < 0.005) than in pts treated with SOF + DAC

(89%), SOF + DAC + RBV (97%) and PEG + SOF + RBV (90%). In cir-

rhotic patients SVR12 was 87.54%: a significant MELD improvement

was observed (median EOT MELD: 6 vs. median baseline MELD:

9: p < 0.005); the patients which presented a MELD improvement

were statistically younger (median age 51 yrs vs. 54 yrs) (p < 0.005)

(Fig. 1).

Conclusions: In our cohort the highest SVR rates were achieved

with SOF + DAC + RIBA. No significant differences were observed in

SVR rate by stratifying Genotype 3 patients according to the pres-

ence or absence of cirrhosis (94% in F4 patients vs. 100% in F3) for

DAC + SOF + RIBA. Among cirrhotic patients, a MELD score improve-

ment was observed in 49.3% of patients.



F-48

Pre-emptive post-liver transplant (LT) HCVtreatment with DAAs: Proof of concept from apilot study

L. Pasulo 1, C. Mazzarelli 2, C. Iegri 1, L. De Carlis 3,

R. Viganò 2, F. Donato 4, G. Rossi 5, A. Zanetto 6,

S. Shalaby 6, S. Fagiuoli 1, L. Belli 2


Bergamo, Italy2 Gastroenterology, Ca Granda Niguarda, Italy3 Surgery, Ca Granda Niguarda, Italy4 Gastroenterology, IRCSS Policlinico Milano, Milan,

Italy5 Surgery Department, IRCSS Policlinico Milano,

Milan, Italy6 Multivisceral Transplant Unit, University Hospital

of Padua, Padova, Italy

Background and aims: The adoption of a “true” pre-emptive

treatment with DAA has never been explored so far. In our pilot

study, SOF + RIBA were administered starting on the day of trans-

plant surgery.

Aim: To evaluate feasibility, safety and efficacy of a Sofosbuvir

plus ribavirin post-LT preemptive regimen.

Methods: 45 consecutive HCV positive patients undergoing LT

were prospectively enrolled for a 24 weeks SOF + RBV treatment.

The first dose of SOF + RIBA was administered at graft implant,

through N-G tube; HCV-RNA was tested at 1st, 2nd, 4th wk and

then every 4 weeks until 24th weeks post-treatment.

Results: The baseline features of recipients/donors are shown in

Table 1. At the time of the analysis, 24/45 reached SVR 12. At week

1, in 9% HCV-RNA was undetectable (NR), in 75% the viral load was

<3 log. All patients achieved EOT response. At univariate analysis,

advanced donor age showed a statistically significant correlation

with viral load decay (slope: −0.02; correlation: −0.34; r-squared:

−0.12; p = 0.04). By ITT analysis, SVR12 was 92% (2 relapses, both

due to RBV withdrawal during treatment: 1 voluntary and 1 due

to anemia). Five patients died for complications unrelated to DAA

treatment during the post-operative period and 1 patient died

for fibrosing cholestatic hepatitis after relapse. Acute rejection

occurred in 12.1%. The peak of incidence of anemia (Hb < 9 g/dl)

occurred at week 2 in 23% of patients); Blood transfusions (BT) were

the first supportive care option followed by erythropoietin; from

treatment week 12 no more transfusion were needed.

Table 1Baseline features of recipients.

Age 52 [50–57]

Male sex (N%) 88%

BMI (kg/m2) 24.5 [22.7–27]

Indication for LT

ESLD 55%

HCC 45%

Median MELD at the time of LT 17 (14–22)

Median HCV-RNA at the time of LT 4.8 (4–5.1)

Genotype

1a 16%

1b 23%

3 26%

4 35%

Experienced (%) 52%

Donors features

Median age [95% UCL-LCL] 57 (52–71)

Anti-Hbc+ (N%) 16%

Median cold ischemia time 467 (360–506 min)

Immunosuppression regimen

FK 45%

Cyclosporine 55%

Median ribavirin dose at the start 1000 mg/day

Conclusions: Our pilot study shows that a preemptive treat-

ment strategy is a feasible strategy: adopting a “sub-optimal” RBV

containing regimen, SVR 12 was obtained in 92% (failures due to

RBV-related anaemia). Based upon this data, a RBV-free regimen

could warrant excellent result. By the time of the EASL meeting,

more patients will have reached the end-point for SVR.


F-49

Early changes in non invasive assessment ofliver fibrosis in hepatitis C virus-infectedpatients treated with DAAs: Preliminary reports

C. Iegri, L. Pasulo, M. Colpani, L. Sangiovanni,

G. Rizzatti, M. Schranz, G. Magini, M. De Giorgio,

M.G. Lucà, G. Gaffuri, S. Fagiuoli

Gastroenterology Department, ASST PAPA GIOVANNI

XXIII, Bergamo, Italy

Background and aims: Early identification of potential cirrhosis

reverser is a key-point for a personalized risk stratification of liver

related complications.

Aim: To evaluate early changes of fibrosis by liver stiffness mea-

surement and early identification of potential “cirrhosis reverser”

in patients treated with DAAs.

Methods: 88 HCV pts were treated prospectively with DAAs. LS

was measured at baseline and 24 weeks after EOT. LSM was not

reliable in 8 patients (excluded from the final analysis).

Results: Well compensated cirrhosis was present in 85%;

median MELD score was 8 [7–9]. Median baseline LS values in over-

all population (OP) were 20.4 kPa [17.3–21.5]; median LSM was

21.4 kPa in cirrhotics [18.8–22.8] vs. 10.1 kPa in non cirrhotics (95%

CI: 7.3–10.5) (p = 0.0001). SVR 24 rate was 97.5%. The median LS

value 24 wks after EOT was 13.7 kPa [10.5–16.2] in OP, significantly

lower compared to baseline (p = 0.002). The decrease was statisti-

cally significant among cirrhotics (LS24 wks: 15.6 kPa [12.6–16.9];

p < 0.05) but not in non-cirrhotics (LS24 wks: 8.2 kPa [4.7–10.4];

p = 0.17). Cirrhotic patients with ALT < 2 ULN who showed a non-

invasive “downstaging” of at least one corresponding Metavir stage

were defined “early reverser”: 14 pts reversed to a precirrhotic

stage (6 pts-F3; 6 pts-F2 and 2 pts-F1). At univariate analysis: lower

PLT count, higher MELD score, higher APRI and Liver Stiffness val-

ues were significantly associated to failure of reversing cirrhosis

(p = 0.009; p = 0.01; p = 0.04 and p = 0.001, respectively). The pres-

ence of metabolic disorders (MD) and/or clinically significant portal

hypertension was significantly higher in non-reverser (MD: 46%

and CSPH: 74%) compared to reverser (MD: 7%; p < 0.001; CSPH:

20%; p < 0.0001). At multivariate analysis, none of these variables

emerged as independent predictors of failure to reverse cirrhosis.

Conclusions: A significant decrease in LSM was observed in SVR

patients. Among cirrhotic patients, 17.5% were identified as early

reverser according with serial LSM. These initial results need to be

confirmed after longer follow-up.



F-50

Treatment of chronic hepatitis C in Lombardia:An analysis on the safety and efficacy of DAAtherapy in 5457 patients

A. Aghemo 1, L. Pasulo 2, M. Puoti 3, S. Zaltron 4,

F. Maggiolo 5, G. Rizzardini 6, S. Fargion 7,

R. Bruno 8, M. Zuin 9, T. Quirino 10, M.G. Rumi 11,

A. Pan 12, P. Grossi 13, A. Rossini 14, A. Corbellini 15,

S. Fagiuoli 2

1 Gastroenterology and Hepatology, IRCSS Policlinico

Milano, Milan, Italy2 Gastroenterology, ASST Papa Giovanni XXIII, Italy3 Infectious Disease Ca’ Granda Niguarda Hospital,

Milan, Italy4 Infectious Disease, Spedali Civili, Brescia Bergamo,

Italy5 Infectious Disease, ASST PAPA GIOVANNI XXIII,

Bergamo, Italy6 Infectious Disease, Sacco Hospital, Italy7 Internal Medicine, IRCSS Policlinico Milano, Milan,

Italy8 Infectious Disease, Policlinico Pavia, Italy9 Gastroenterology, San Paolo Hospital, Milan, Italy10 Infectious Disease, Busto Arsizio Hospital, Varese,

Italy11 Hepatology, San Giuseppe Hospital, Milan, Italy12 Infectious Disease Cremona Hospital, Italy13 Infectious Disease Varese Hospital, Italy14 Hepatology, Spedali Civili, Brescia Bergamo, Italy15 Infectious Disease Vizzolo Pradabissi Hospital,

Italy

Background: Directly acting antivirals have allowed safe and

effective treatment in patients with chronic hepatitis C infection.

Real life data in Italian patients with advanced fibrosis and older

age are still few.

Methods: The Lombardia Hepatitis Networks created in 2015

included 19 liver centers and 2 macro-area networks.

Results: From December 2014 till November 2016, 5457

patients have received treatment with DAAs and have been

included in the analysis. The mean age was 59.3 years, 23% of

patients were older than 70 years of age, 64% were male. The most

prevalent genotypes were HCV-1 (61.2%) and HCV-3 (15.1%). 908

(17.5%) patients were HIV coinfected. Advanced fibrosis/Cirrhosis

(F3–F4) was present in 74.3%, the mean Child-Pugh was 5.4 ± 0.9,

the mean MELD was 8.5 ± 3.1. The most prescribed regimens

were SOF/LED ± RBV (30%), 3D ± RBV (18.6%), SOF + RBV (16%),

SOF + DAC ± RBV (15.6%) and SOF + SIM ± RBV (15.5%). Only 1% of

patients received a PEG-IFN containing regimen. At the time of the

analysis 3067 patients have completed treatment and 12 weeks

of follow-up and could be assessed for SVR. Overall the SVR rate

was 95%, being 97.3% in HCV-1a, 96.8% in HCV-1b, 94.7% in HCV-2,

88.4% in HCV-3 and 93.6 in HCV-4 (p = 0.0001). The disappointing

SVR rates in HCV-3 were the consequence of suboptimal efficacy

of SOF + RBV (SVR 82%). In HCV-3 patients the combination of

SOF + DAC ± RBV achieved SVR rates of 94%. Serious adverse events

(SAE) were observed in 115 patients (2.1%), and were deemed to be

probably or certainly related to DAA therapy in 40.3% of cases. The

incidence of SAEs was not associated with gender or patients age,

in patients over 70 years old the SAE incidence was 2.9%.

Conclusions: In a large cohort of Italian patients with advanced

fibrosis and older age, DAAs were safe and effective in all genotypes.


Digestive and Liver Disease 49 (2017) e71


1590-8658/

A.I.S.F. 2017: Abstracts Evaluation Procedure



journal homepage: www.elsevier .com/locate/dld

Thanks to experts evaluating all the abstracts according to predetermined Clinical and Experimental categories.

The experts for the 2017 Annual Meeting are listed below:

Category A. “EXPERIMENTAL VIRAL HEPATITIS” B. Coco, Pisa - C. Ferrari, Parma – P. Pontisso,

Padua - F.P. Russo, Padua - A.L. Zignego, Florence

Category B. “HEPATITIS B & DELTA CLINICAL” B. Coco, Pisa - V. Di Marco, Palermo - C. Ferrari,

Parma - A. Marzano, Turin – M. Masarone, Salerno - F.P. Russo, Padua - G. Taliani, Rome

Category C. “HEPATITIS C CLINICAL” A. Aghemo, Milan - P. Andreone, Bologna - D. Bitetto,

Gemona del Friuli (UD) - S. Bruno, Rozzano (MI) - V. Di Marco, Palermo - A. Mangia, S.G. Rotondo (FG) - F. Morisco, Naples - G. Taliani, Rome - A.L. Zignego, Florence

Category D. “NAFLD & ALD EXPERIMENTAL” A. Alisi, Rome - P. Dongiovanni, Milan - C. Loguercio,

Naples - S. Petta, Palermo

Category E. “NAFLD & ALD CLINICAL” A. Fracanzani, Milan - C. Loguercio, Naples - S. Petta,

Palermo - C. Puoti, Grottaferrata (RM) - E. Vanni, Turin

Category F. “AUTOIMMUNE HEPATITIS & BILIARY DISEASE” V. Cardinale, Rome - A. Floreani, Padua - L. Muratori,

Bologna - C. Rigamonti, Novara - F. Rosina, Turin - C. Spirli, New Haven, CT (USA)

Category H. “EXPERIMENTAL LIVER DAMAGE, FIBROSIS, CIRRHOSIS & PORTAL HYPERTENSION”

M. Fraquelli, Milan - F. Marra, Florence – M. Parola, Turin - G. Svegliati-Baroni, Ancona

Category I. “FIBROSIS, CIRRHOSIS & PORTAL HYPERTENSION CLINICAL”

A. Berzigotti, Bern (Switzerland) - F. Campagna, Padua - P. Caraceni, Bologna - A. Dell’Era, Milan - V. La Mura, Milan - F. Schepis, Modena

Category L. “HEPATOCELLULAR CARCINOMA EXPERIMENTAL” F. Farinati, Padua - L. Gramantieri, Bologna - G. Missale,

Parma - E. Villa, Modena

Category M. “HEPATOCELLULAR CARCINOMA CLINICAL” A. Cucchetti, Bologna - F. Farinati, Padua - M. Iavarone,

Milan - G. Missale, Parma - F. Piscaglia, Bologna - G.L. Rapaccini, Rome - E. Villa, Modena

Category N. “LIVER FAILURE, HEPATOBILIARY SURGERY & TRANSPLANTATION”

M. Angelico, Rome - L. Baiocchi, Rome - P. Burra, Padua - M.F. Donato, Milan - S. Fagiuoli, Bergamo - E. Gringeri, Padua - M. Strazzabosco, Milan, New Haven, CT (USA)

Category O. “MISCELLANEOUS: GENETIC, PEDIATRIC, NUTRACEU-TICALS, DILI, OTHER”

A. Cappon, Padua - S. Fargion, Milan - A. Gasbarrini, Rome – G. Germani, Padua – F. Giannone, Bologna - A. Lleo, Rozzano (MI) - G. Svegliati Baroni, Ancona

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