Giulia Pieri

Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma

BACKGROUND & AIMS Recurrence of hepatocellular carcinoma (HCC) is a major complication after liver transplantation (LT). The initial immunosuppression protocol may influence HCC recurrence, but the optimal regimen is still unknown. METHODS 219 HCC consecutive patients under Milan criteria, who received an LT at 2 European centres between 2000 and 2010, were included. Median follow-up was 51 months (IQR 26-93). Demographic characteristics, HCC features, and immunosuppression protocol within the first month after LT were evaluated against HCC recurrence by using Cox regression. RESULTS In the explanted liver, 110 patients (50%) had multinodular HCC, and largest nodule diameter was 3±2.1cm. Macrovascular invasion was incidentally detected in 11 patients (5%), and microvascular invasion was present in 41 patients (18.7%). HCC recurrence rates were 13.3% at 3 years and 17.6% at 5 years. HCC recurrence was not influenced by the use/non-use of steroids and antimetabolites (p=0.69 and p=0.70 respectively), and was similar with tacrolimus or cyclosporine (p=0.25). Higher exposure to calcineurin inhibitors within the first month after LT (mean tacrolimus trough concentrations >10ng/ml or cyclosporine trough concentrations >300ng/ml), but not thereafter, was associated with increased risk of HCC recurrence (27.7% vs. 14.7% at 5 years; p=0.007). The independent predictors of HCC recurrence by multivariate analysis were: high exposure to calcineurin inhibitors defined as above (RR=2.82; p=0.005), diameter of the largest nodule (RR=1.31; p<0.001), microvascular invasion (RR=2.98; p=0.003) and macrovascular invasion (RR=4.57; p=0.003). CONCLUSIONS Immunosuppression protocols with early CNI minimization should be preferred in LT patients with HCC in order to minimize tumour recurrence.

The Royal Free Hospital Score: A Calibrated Prognostic Model for Patients With Cirrhosis Admitted to Intensive Care Unit. Comparison With Current Models and CLIF-SOFA Score

OBJECTIVES:Prognosis for patients with cirrhosis admitted to intensive care unit (ICU) is poor. ICU prognostic models are more accurate than liver-specific models. We identified predictors of mortality, developed a novel prognostic score (Royal Free Hospital (RFH) score), and tested it against established prognostic models and the yet unvalidated Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) model.METHODS:Predictors of mortality were defined by logistic regression in a cohort of 635 consecutive patients with cirrhosis admitted to ICU (1989–2012). The RFH score was derived using a 75% training and 25% validation set. Predictive accuracy and calibration were evaluated using area under the receiver operating characteristic (AUROC) and goodness-of-fit χ2 for the RFH score, as well as for SOFA, Model for End-Stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE II), and Child-Pugh. CLIF-SOFA was applied to a recent subset (2005–2012) of patients.RESULTS:In-hospital mortality was 52.3%. Mortality improved over time but with a corresponding reduction in acuity of illness on admission. Predictors of mortality in training set, which constituted the RFH score, were the following: bilirubin, international normalized ratio, lactate, alveolar arterial partial pressure oxygen gradient, urea, while variceal bleeding as indication for admission conferred lesser risk. Classification accuracy was 73.4% in training and 76.7% in validation sample and did not change significantly across different eras of admission. The AUROC for the derived model was 0.83 and the goodness-of-fit χ2 was 3.74 (P=0.88). AUROC for SOFA was 0.81, MELD was 0.79, APACHE II was 0.78, and Child-Pugh was 0.67. In 2005–2012 cohort, AUROC was: SOFA: 0.74, CLIF-SOFA: 0.75, and RFH: 0.78. Goodness-of-fit χ2 was: SOFA: 6.21 (P=0.63), CLIF-SOFA: 9.18 (P=0.33), and RFH: 2.91 (P=0.94).CONCLUSIONS:RFH score demonstrated good discriminative ability and calibration. Internal validation supports its generalizability. CLIF-SOFA did not perform better than RFH and the original SOFA. External validation of our model should be undertaken to confirm its clinical utility.

Nine scoring models for short‐term mortality in alcoholic hepatitis: cross‐validation in a biopsy‐proven cohort

Several prognostic models have emerged in alcoholic hepatitis (AH), but lack of external validation precludes their universal use.

Inflammation‐based scores do not predict post‐transplant recurrence of hepatocellular carcinoma in patients within milan criteria

Increased preoperative inflammation scores, such as neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR) and inflammation‐based index (IBI) have been related to post‐transplant HCC recurrence. We evaluated the association between inflammation‐based scores (NLR, PLR, IBI) and post‐LT HCC recurrence as well as tumor necrosis after transarterial embolization. 150 consecutive patients who underwent transplantation for HCC within the Milan criteria between 1996 and 2010 were included; data regarding inflammatory markers, patient and tumor characteristics were analyzed. NLR, PLR, and IBI were not significantly associated with post‐LT HCC recurrence or worse overall survival. Increased NLR and PLR were associated with complete tumor necrosis in the subset of patients who received preoperative transarterial embolization (P < 0.05). Cox regression analysis revealed that absence of neoadjuvant transarterial therapy (OR = 4.33, 95% CI = 1.28‐14.64; P = 0.02) and no fulfillment of the Milan criteria in the explanted liver (OR = 3.34, 95% CI = 1.08‐10.35; P = 0.04) were independently associated with post‐LT HCC recurrence inflammation‐based scores did not predict HCC recurrence post‐LT in our group of patients. NLR and PLR were associated with better response to TAE, as this was recorded histologically in the explanted liver. Histological fulfillment of the Milan criteria and absence of neoadjuvant transarterial treatment were significantly associated with post‐LT HCC recurrence. Liver Transpl 20:1327‐1335, 2014.

Mechanism of cell death in acute-on-chronic liver failure: a clinico-pathologic-biomarker study

Mortality of patients who develop acute‐on‐chronic liver failure (ACLF) is unacceptably high but the predominant mode of cell death is unknown. The aim of this study was to evaluate whether plasma levels of caspase‐cleaved cytokeratin M30 (marker of apoptosis) and uncleaved cytokeratin M65 (marker of total cell death) are altered in ACLF patients and relate this to liver histology.

Biochemical criteria at 1 year are not robust indicators of response to ursodeoxycholic acid in early primary biliary cirrhosis: results from a 29-year cohort study

In primary biliary cirrhosis (PBC), biochemical criteria at 1 year are considered surrogates of response to ursodeoxycholic acid (UDCA). However, due to the slow natural history of PBC, evaluation at 1 year may be suboptimal to assess the therapeutic response, particularly in early disease.

Prevention of hepatitis C recurrence by bridging sofosbuvir/ribavirin from pre to post liver transplant: a real life strategy

Hepatitis C virus (HCV) re‐infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF‐regimen from pre‐ to post‐transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV‐RNA undetectability at the time of transplant.

OC-030 Effective Stratification Of Hepatocellular Carcinoma Risk In Primary Biliary Cirrhosis: Results Of A Multi-centre International Study

Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10–9), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.

941 ALKALINE PHOSPHATASE VALUES ARE A SURROGATE MARKER IN PREDICTION OF TRANSPLANT FREE SURVIVAL IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS – AN INTERNATIONAL, COLLABORATIVE ANALYSIS

941 ALKALINE PHOSPHATASE VALUES ARE A SURROGATE MARKER IN PREDICTION OF TRANSPLANT FREE SURVIVAL IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS – AN INTERNATIONAL, COLLABORATIVE ANALYSIS W.J. Lammers, H.R. van Buuren, G.M. Hirschfield, A. Pares, T. Kumagi, L. Caballeria, P. Invernizzi, A. Lleo, P.M. Battezzati, C. Corpechot, A. Floreani, N. Cazzagon, M.J. Mayo, J.A. Talwalkar, M. Imam, A.K. Burroughs, G. Pieri, F. Nevens, A.L. Mason, R. Poupon, H.L.A. Janssen, K.D. Lindor, B.E. Hansen, Global PBC Study Group. Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Liver Centre, Toronto Western Hospital, Toronto, ON, Canada; Centre for Liver Research and NIHR Institute of Biomedical Research, University of Birmingham, Birmingham, UK; Liver Unit, Hospital Cĺinic, CIBERehd, IDIBAPS, Barcelona, Spain; Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy; Dept of Medicine, Surgery and Dentistry, Universita degli Studi di Milano, Milan, Italy; Service d’Hepatologie, Hopital Saint-Antoine, APHP, UPMC, Paris, France; Department of Surgical, Oncological and Gastroenterological, University of Padova, Padova, Italy; Digestive and Liver disease, UT Southwestern Medical Centre, Dallas, TX, Gastroenterology and Hepatology, Mayo Clinic, Rochester, MA, USA; The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, UK; Hepatology, University Hospitals Leuven, UKLeuven, Leuven, Belgium; Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada; Health Solutions, Arizona State University, Phoenix, AZ, USA E-mail: w.lammers@erasmusmc.nl

178 IMMUNOSUPPRESSION AND HEPATOCELLULAR CARCINOMA RECURRENCE AFTER LIVER TRANSPLANTATION

176 PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT STUDY EVALUATING EFFICACY AND SAFETY OF INTRAVENOUS SILIBININ IN PATIENTS WITH HCV RECURRENCE ON THE GRAFT AFTER LIVER TRANSPLANTATION M. Rendina, M. D’Amato, A. Castellaneta, N.M. Castellaneta, N. Brambilla, G. Giacovelli, L. Rovati, S.F. Rizzi, M. Zappimbulso, R. Bringiotti, A. Di Leo. Gastroenterology, University of Bari, Bari, Clinical Research, Rottapharm SpA, Milan, Italy E-mail: mariarendina@virgilio.it