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Nesrine Mouhoubi,1 Jessica Bamba-Funck,1,2 Angela Sutton,1,2 Lorraine Blaise,3 Olivier Seror,4 Nathalie Ganne-Carrié,3,5 Marianne Ziol,6,7 Gisèle N’Kontchou,3 Nathalie Charnaux,1,2 Pierre Nahon,3,5 Jean-Charles Nault,3,5,* Erwan Guyot1,2,* 1Université Sorbonne Paris Nord, Laboratory for VascularTranslational Science, LVTS, INSERM, UMR 1148, Bobigny, F- 93000, France; 2Service de biochimie, Hôpital Avicenne, hôpitaux universitaires Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris, Bobigny, F-93000, France; 3Service d’hépatologie, Hôpital Avicenne, AP-HP, hôpitaux universitaires Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris, Bondy, F-93143, France; 4Service de radiologie, Hôpital Avicenne, hôpitaux universitaires Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris, Bobigny, F-93000, France; 5Inserm, UMR 1162, Génomique fonctionnelle des tumeUrs solides, Paris, F-75010, France; 6Centre de Ressources Biologiques BB-0033-00027, Hôpital Avicenne, hôpitaux universitaires Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris, Bobigny, F-93000, France; 7Service d’anatomie et cytologie pathologique, Hôpital Avicenne, hôpitaux universitaires Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris, Bobigny, F-93000, France*These authors contributed equally to this workCorrespondence: Erwan Guyot, Hôpitaux Universitaires Paris Seine-Saint-Denis, Laboratoire Biochimie-Pharmacologie et Biologie Moléculaire, 125 Rue de Stalingrad, Bobigny, 93000, France, Tel +33 1 48 95 56 29, Fax +33 1 48 95 56 27, Email erwan.guyot@aphp.frPurpose: Sulfatase 2 (SULF2) is an enzyme related to heparan sulfate modifications. Its expression, as for some heparan sulfate proteoglycans expression, has been linked to hepatocellular carcinoma (HCC) at mRNA level and immunohistochemistry staining on biopsy samples. This study aims to evaluate the prognostic value of serum levels of SULF2 in patients with alcoholic cirrhosis with or without HCC.Patients and Methods: Two hundred and eighty-seven patients with alcoholic cirrhosis were enrolled in this study: 164 without HCC, 57 with early HCC, and 66 with advanced HCC at inclusion. We analyzed the association between SULF2 serum levels and prognosis using Kaplan–Meier method and univariate and multivariate analysis using a Cox model.Results: Child-Pugh C Patients have higher serum levels of SULF2 than Child-Pugh A patients. Serum levels of SULF2 were also higher in patients with advanced HCC compared with the other groups. In patients with advanced HCC, high serum levels of SULF2 were associated with less favorable overall survival. Combination of SULF2 with Glypican 3 (GPC3) and Syndecan 1 (SDC1) serum levels enhanced the ability to discriminate worst prognostic in advanced HCC.Conclusion: SULF2 along with GPC3 and SDC1 serum levels have been shown to be associated with a prognostic value in advanced HCC.Keywords: sulfatase 2, proteoglycans, prognosis, hepatocellular carcinoma, cirrhosis

Abstract Background The sole effective option for patients with advanced HCC is sorafenib and there is an urgent need to develop new therapeutic approaches. Immunotherapy is a promising option that deserves major investigation. In this open label, single arm clinical trial, we analyzed the effect of a low dose cyclophosphamide treatment in combination with a telomerase peptide (GV1001) vaccination in patients with advanced HCC. Methods 40 patients with advanced HCC were treated with 300 mg/m2 cyclophosphamide on day -3 followed by GM-CSF + GV1001 vaccinations on days 1, 3, 5, 8, 15, 22, 36 followed by 4-weekly injections. Primary endpoint of this phase II trial was tumor response; secondary endpoints evaluated were TTP, TTSP, PFS, OS, safety and immune responses. Results None of the patients had a complete or partial response to treatment, 17 patients (45.9%) demonstrated a stable disease six months after initiation of treatment. The median TTP was 57.0 days; the median TTSP was estimated to be 358.0 days. Cyclophosphamide, GV1001 and GM-CSF treatment were well tolerated and most adverse events, which were of grade 1 or 2, were generally related to the injection procedure and injection site reactions. GV1001 treatment resulted in a decrease in CD4+CD25+Foxp3+ regulatory T cells; however, no GV1001 specific immune responses were detected after vaccination. Conclusions Low dose cyclophosphamide treatment followed by GV1001 vaccinations did not show antitumor efficacy as per tumor response and time to progression. Further studies are needed to analyze the effect of a combined chemo-immunotherapy to treat patients with HCC. Trial registration NCT00444782

Objectives: This study aimed to evaluate the incidence and clinical implications of bile duct changes following multibipolar radiofrequency ablation (mbpRFA) for hepatocellular carcinoma (HCC)., Materials and Methods: Radiological, clinical, and biological data from consecutive cirrhotic patients who underwent first-line mbpRFA between 2007 and 2014 for uninodular HCC ≤ 5 cm were retrospectively collected. Follow-up imaging was reviewed to identify bile duct changes and factors associated with biliary changes were assessed using multivariable analysis. Baseline and 6-month liver function tests were compared in patients with and without bile duct changes. Complications, cirrhosis decompensation, and survival rates were compared in both groups., Results: A total of 231 patients (mean age 68 years [39-85], 187 men) underwent 266 mbpRFA sessions for uninodular HCC (mean size 26 mm). Of these, 76 (33%) developed bile duct changes (upstream bile duct dilatations and/or bilomas) with a mean onset time of 3 months. Identified risk factors for these changes were the infiltrative aspect of the tumor (p = 0.035) and its location in segment VIII (p < 0.01). The average increase in bilirubin at 6 months was higher in the group with biliary changes (+2.9 vs. +0.4 µg/mL; p = 0.03). There were no significant differences in terms of complications, cirrhosis decompensation at 1 year (p = 0.95), local and distant tumor progression (p = 0.91 and 0.14 respectively), and overall survival (p = 0.4) between the two groups., Conclusion: Bile duct changes are common after mbpRFA for HCC, especially in tumors with an infiltrative aspect or those located in segment VIII. These changes do not appear to negatively impact the course of cirrhosis at 1 year or overall survival., Clinical Relevance Statement: Bile duct changes following mbpRFA for HCC are relatively common. Nevertheless, they do not raise clinical concerns in terms of complications, deterioration in liver function, or survival rates. Consequently, specific monitoring or interventions for these bile duct changes are not warranted., Key Points: • Bile duct changes are frequently observed after multibipolar radiofrequency ablation for hepatocellular carcinoma, occurring in 33% of cases in our study. • Patients with bile duct changes exhibited a higher increase in bilirubin levels at 6 months but no more cirrhosis decompensation or liver abscesses. • Biliary changes following multibipolar radiofrequency ablation for hepatocellular carcinoma are not alarming and do not necessitate any specific monitoring or intervention., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background & Aims: Despite its growing incidence, hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) in non-cirrhotic livers remains poorly characterized. We compared the characteristics, management, survival, and trends of MASLD-related HCC in patients with or without underlying cirrhosis in a large multicenter cohort., Methods: A total of 354 cases of MASLD-related HCC presented at the liver tumor meetings of four French university hospitals between 2007 and 2018 were included in the study. Data were extracted from the meetings' databases and from the French Birth and Death Registry., Results: Of HCC cases, 35% occurred in the absence of cirrhosis. HCC was diagnosed through screening in 60% of patients with cirrhosis, and incidentally in 72% of patients without it. Patients without cirrhosis were older, had a greater tumor burden, but also better liver function than patients with cirrhosis. Patients without cirrhosis showed better overall survival than those with cirrhosis ( p = 0.043). However, cirrhosis was not independently associated with overall survival, the independent predictors were age, liver function, tumor burden and BCLC classification. Patients without cirrhosis underwent surgery more frequently than patients with cirrhosis (41% vs. 11%, p < 0.001), even in cases where the largest tumors were ≥5 cm (42% vs. 14%, p = 0.002) or there were four or more lesions (19% vs. 2%, p = 0.024). Among the patients (with/without cirrhosis) who underwent surgery, survival was not significantly different. The cirrhosis/no cirrhosis ratio remained stable over the study period., Conclusions: In MASLD-related HCC, patients without cirrhosis account for 35% of cases and have poor prognostic factors (higher age and larger tumors) but also better liver function, resulting in more aggressive management of advanced tumors and better survival compared to patients with cirrhosis., Impact and Implications: The incidence of hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is projected to increase by 47% to 130% by year 2030 with one-third of cases occurring in non-cirrhotic livers, making them inaccessible to screening and therefore more likely to be diagnosed at an advanced stage. Our study shows that survival in patients with MASLD-related HCC depends on age, tumor burden and underlying liver function and the preserved liver function of these non-cirrhotic patients allows them to be managed surgically. A better understanding of the pathophysiological processes driving HCC occurrence in patients with non-cirrhotic MASLD will help guide the screening and early management of these patients., (© 2024 The Author(s).)

Introduction: We aim to assess the long-term outcomes of percutaneous multi-bipolar radiofrequency (mbpRFA) as the first treatment for hepatocellular carcinoma (HCC) in transplant-eligible cirrhotic patients, followed by salvage transplantation for intrahepatic distant tumour recurrence or liver failure., Materials and Methods: We included transplant-eligible patients with cirrhosis and a first diagnosis of HCC within Milan criteria treated by upfront mbp RFA. Transplantability was defined by age <70 years, social support, absence of significant comorbidities, no active alcohol use and no recent extrahepatic cancer. Baseline variables were correlated with outcomes using the Kaplan-Meier and Cox models., Results: Among 435 patients with HCC, 172 were considered as transplantable with HCCs >2 cm (53%), uninodular (87%) and AFP >100 ng/mL (13%). Median overall survival was 87 months, with 75% of patients alive at 3 years, 61% at 5 years and 43% at 10 years. Age (p = .003) and MELD>10 (p = .01) were associated with the risk of death. Recurrence occurred in 118 patients within Milan criteria in 81% of cases. Local recurrence was observed in 24.5% of cases at 10 years and distant recurrence rates were observed in 69% at 10 years. After local recurrence, 69% of patients were still alive at 10 years. At the first tumour recurrence, 75 patients (65%) were considered transplantable. Forty-one patients underwent transplantation, mainly for distant intrahepatic tumour recurrence. The overall 5-year survival post-transplantation was 72%, with a tumour recurrence of 2.4%., Conclusion: Upfront multi-bipolar RFA for a first diagnosis of early HCC on cirrhosis coupled with salvage liver transplantation had a favourable intention-to-treat long-term prognosis, allowing for spare grafts., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: HCC surveillance is challenged by the detection of hepatic focal lesions (HFLs) of other types. This study aimed to describe the incidence, characteristics, outcomes, and costs of non-HCC HFL detected during surveillance., Approach and Results: We retrospectively analyzed nonstandardized workup performed in French patients included in HCC surveillance programs recruited in 57 French tertiary centers (ANRS CirVir and CIRRAL cohorts, HCC 2000 trial). The overall cost of workup was evaluated, with an estimation of an average cost per patient for the entire population and per lesion detected. A total of 3295 patients were followed up for 59.8 months, 391 (11.9%) patients developed HCCs (5-year incidence: 12.1%), and 633 (19.2%) developed non-HCC HFLs (5-year incidence: 21.8%). Characterization of non-HCC HFL required a median additional of 0.7 exams per year. A total of 11.8% of non-HCC HFLs were not confirmed on recall procedures, and 19.6% of non-HCC HFLs remained undetermined. A definite diagnosis of benign liver lesions was made in 65.1%, and malignant tumors were diagnosed in 3.5%. The survival of patients with benign or undetermined non-HCC HFL was similar to that of patients who never developed any HFL (5-year survival 92% vs. 88%, p = 0.07). The average cost of the diagnostic workup was 1087€ for non-HCC HFL and €1572 for HCC., Conclusions: Non-HCC HFLs are frequently detected in patients with cirrhosis, and do not impact prognosis, but trigger substantial costs. This burden must be considered in cost-effectiveness analyses of future personalized surveillance strategies., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Aggressive intrasegmental recurrence (AIR) is a form of local recurrence associated with a dismal prognosis and defined by multiple nodules or by an infiltrative mass with a tumor thrombus, occurring in the treated segment, after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). We aimed to identify radiological and/or histological characteristics of tumor biopsy predictive of AIR. We retrospectively analyzed patients treated by No-Touch multi-bipolar RFA (mbpRFA) for a first HCC with a systematic per-procedural tumor biopsy positive for diagnosis of HCC. The first recurrence was classified as non-aggressive local recurrence, AIR or intrahepatic distant recurrence. 212 patients were included (168 men; mean age 67.1 years; mean tumor size 28.6 mm, 181 cirrhosis). AIR occurred in 21/212 patients (10%) and was associated with a higher risk of death (57% in patients with AIR vs 30% without AIR, p = 0.0001). Non-smooth tumor margins, observed in 21% of the patients and macro-trabecular massive histological subtype, observed in 12% of the patients were independently related to a higher risk of AIR (HR: 3.7[1.57;9.06], p = 0.002 and HR:3.8[2.47;10], p = 0.005 respectively). Non smooth margins at imaging and macro-trabecular massive histological subtype are associated with AIR and could be considered as aggressive features useful to stratify therapeutic strategy., (© 2022. The Author(s).)

Background: The ABO blood group system may influence tumorigenesis, but its prognostic value in liver transplantation (LT) for hepatocellular carcinoma (HCC) has never been assessed., Methods: All consecutive patients who underwent LT for HCC between 2013 and 2017 at 9 centers were analyzed. Predictors of tumor recurrence were identified using multivariable analysis, while comparison between group A and non-A recipients was performed after propensity score matching., Results: Among 925 LT recipients, 406 were blood group A, 94 group B, 380 group O, and 45 group AB. On multivariable analysis, group A was associated with tumor recurrence (hazard ratio [HR] = 1.574 [95% confidence interval; 95% CI = 1.034-2.394] P = 0.034). After propensity score matching, 1- and 5-y recurrence rates were 7.4% and 20.1% in group A recipients versus 3.3% and 13.2% in non-A recipients (HR = 1.66 [95% CI = 1.12-2.45], P = 0.011). One and 5-y recurrence-free survivals were 85.2% and 66.8% in group A recipients versus 88.5% and 71.3% in non-A recipients (HR = 1.38 [95% CI = 1.01-1.90], P = 0.045). Among recipients within Milan criteria (n = 604), 1- and 5-y recurrence rates were 5.8% and 12.7% in group A recipients versus 3.1% and 12.2% in non-A recipients (HR = 1.197 [95% CI = 0.721-1.987], P = 0.485). Among recipients outside Milan criteria (n = 182), 1- and 5-y recurrence rates were 12.1% and 43.8% in group A recipients versus 3.9% and 15.6% in non-A recipients (HR = 3.175 [95% CI = 1.526-6.608], P = 0.002)., Conclusions: ABO blood system influences the oncological outcome of recipients undergoing LT for HCC. Its incorporation in the prognostication model of LT for HCC may allow improving the management of LT candidates., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%., Methods: French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs . ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs., Results: Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective., Conclusions: In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection., Lay Summary: The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes., Competing Interests: Pr Nahon has received honoraria from and/or consults for AstraZeneca, Abbvie, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen, MSD and Roche. He received research grants from AstraZeneca, AbbVie, Bristol-Myers Squibb and Eisai. Pr Ganne-Carrié consults for and/or received personal fees from Abbvie, Bayer, Gilead, Ipsen, and Shionogi, outside the submitted work. Pr Pol has received grants from Gilead, Roche, Abbvie. He consults for BMS, Janssen Cilag, Gilead, Roche, Merck/Schering-Plough, Abbvie, Vivv, Shinogui, Biotest, LFB. Pr Durand-Zaleski consults for AbbVie, Bristol-Myers Squibb, Janssen and MSD. All other authors report no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Background & Aims: In this study we aimed to analyse the impact of the aetiology of cirrhosis on the incidence, characteristics and prognosis of hepatocellular carcinoma (HCC) diagnosed during a surveillance program., Methods: Individual data from a randomized trial and 2 prospective cohorts of patients with compensated histologically proven cirrhosis recruited between 2000 and 2016 were pooled. The influence of cirrhosis aetiology on survival after HCC detection was assessed using multivariable regression models., Results: Among 3,533 patients (1,926 virus [VIR], 1,167 alcohol [ALC], 440 combined [MIX]), 431 were diagnosed with HCC after a median follow-up of 57.1 months. The 5-year HCC incidence was lowest in ALC (VIR 12.6%, ALC 9.1%, MIX 14.3%, p  = 0.04). At the time of diagnosis, tumour burden and Child-Pugh score were comparable across aetiology groups, but early BCLC stages (0/A) were significantly less frequent in ALC (VIR 80%, ALC 37%, MIX 72%) as a result of worse ECOG performance status. However, similar access to first-line curative HCC treatment was reported across aetiology groups ( p  = 0.68). Median survival after HCC diagnosis was significantly reduced in ALC (VIR 39, ALC 21, MIX 34 months, p  = 0.02). However, when adjusting for tumour size, ECOG and Child-Pugh score, the aetiology of the underlying cirrhosis no longer had a significant impact., Conclusion: Compared to patients with virus-related cirrhosis, patients with alcohol-related compensated cirrhosis enrolled in a surveillance program have: i) the lowest 5-year HCC incidence; ii) worse overall prognosis, mostly driven by a poor general condition, despite similar access to first-line curative treatment., Lay Summary: It has been suggested that early detection of hepatocellular carcinoma (HCC) may be futile in patients with alcohol-related cirrhosis. By comparing outcomes in more than 3,000 patients with compensated cirrhosis included in surveillance programs, this study suggests that HCC surveillance enables early diagnosis in most patients with alcohol-related cirrhosis despite a higher competing risk of death in these patients. We also report similar access to first-line curative HCC treatment in these patients compared to those with viral cirrhosis, despite higher rates of comorbidities and impaired liver function. Following HCC detection, the later parameters were major drivers of death irrespective of the cause of cirrhosis., Registration: CHC2000 (NCT00190385) and CIRRAL (NCT01213927) cohorts were registered at ClinicalTrials.gov and the full protocols are available at the following links (https://clinicaltrials.gov/ct2/show/NCT00190385) and https://clinicaltrials.gov/ct2/show/NCT01213927, respectively). The full CirVir protocol is available via the ANRS Web site (http://anrs.fr)., Competing Interests: Prof. Ganne-Carrié received honoraria from Bayer, Gilead, Ipsen and Shionogi. Prof Nahon has received honoraria/grants from 10.13039/100006483Abbvie, 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, 10.13039/100002491Bristol-Myers Squibb, 10.13039/100005564Gilead and 10.13039/501100014382Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Purpose: The percutaneous ablation of subcapsular hepatocellular carcinoma (S-HCC) may involve a risk of complications such as hemorrhage and tumor seeding, mainly linked to the direct tumor puncture often inevitable with mono-applicator ablation devices. The purpose of this study was to assess the efficacy and safety of no-touch multi-bipolar radiofrequency ablation (NTMBP-RFA) for the treatment of S-HCC ≤ 5 cm not puncturable via the non-tumorous liver parenchyma., Materials and Methods: Between September 2007 and December 2014, 58 consecutive patients (median age: 63 years [46-86], nine females) with 59 S-HCC ≤ 5 cm (median diameter: 25 mm [10-50 mm]), not puncturable via the non-tumorous liver parenchyma, were treated with NTMBP-RFA. Response and follow-up were assessed by CT or MRI. Complications were graded using the Cardiovascular and Interventional Radiological Society of Europe classification. Overall local tumor progression (OLTP)-free survival was assessed using the Kaplan-Meier method. A Cox proportional model evaluated the factors associated with OLTP. Signs of peritoneal or parietal tumor seeding were noted during follow-up imaging studies., Results: A complete ablation was achieved in 57/58 patients (98.3%) after one (n = 51) or two (n = 6) procedures. Three patients (5.2%) experienced complications (sepsis, cirrhosis decompensation; CIRSE grade 2 or 3). After a median follow-up period of 30.5 months [1-97], no patients had tumor seeding. The 1, 2 and 3-year OLTP-free survival rates were 98%, 94% and 91%, respectively. No factors were associated with OLTP., Conclusion: NTMBP-RFA is a safe and effective treatment for S-HCC not puncturable via the non-tumorous liver parenchyma.

Background : Percutaneous radiofrequency ablation (RFA) is one of the main treatments of small hepatocellular carcinoma (HCC). However, it remains unclear whether this local treatment can induce systemic immune variations. Methods : We conducted a prospective study in a tertiary center including consecutive cirrhotic patients with unifocal HCC<5 cm treated by a first RFA between 2010 and 2014. Peripheral blood mononuclear cells were isolated on the day before (D0), day after (D1) and month after RFA (M1). Frequencies and phenotypes of myeloid cells, T cells, and NK cells were compared between timepoints. Overall recurrence and associated variables were estimated using Kaplan-Meier, log-rank and Cox proportional-hazards models. Results : 80 patients were included (69% male, median age: 67 years old). Main aetiologies of HCC were alcohol (51%), hepatitis C virus (45%), non-alcoholic steatohepatitis (36%) and hepatitis B virus (9%). Median overall survival was 55 months (M); median progression-free survival was 29.5M. Among innate immune populations, we observed variations between D0, D1 and M1 in NKp30+ NK cells (p < .0001) and in plasmacytoid dendritic cells (pDC, p < .01). Concerning adaptive immunity, we observed variations in CD8 Central Memory (p < .05) and CD28+ CD8 Central Memory (p < .01). An early dynamic (D0/D1) of activated NKp30 + NK cells was associated with a decreased overall recurrence (log-rank, p = .016, median delay 25.1 vs 40.6 months). In contrast, a late dynamic (D1/M1) of immature NK cells (CD56 bright ) and altered myeloid DC (PDL1 + ) was associated with an increased overall recurrence (log-rank, p = .011 and p = .0044, respectively). In multivariate analysis, variation of immature NK cells predicts tumor recurrence independently of classical clinical prognostic features (HR = 2.41, 95% CI: 1.15-5.057), p = .019). Conclusions : Percutaneous RFA of small HCC leads to systemic modifications of innate and adaptive immunity closely linked with overall tumor recurrence.

Aims and Background: Only few patients with cirrhosis and hepatocellular carcinoma (HCC) larger than 5 cm are amenable to resection or straight liver transplantation, and in such circumstances, multibipolar radiofrequency ablation (mbp-RFA) could be a reliable alternative. This study was aimed to assess the long-term outcome in patients treated with mbp-RFA for unresectable HCC > 5 cm., Methods: Eighty-three consecutive patients with cirrhosis (median age 70 years [37-93 years], 67 males, BCLC A/B/C: 54/21/8, 74 naive) with up to three HCCs, the largest > 5 cm in diameter (median: 6.2 cm, 5.1-9 cm, 22 infiltrative forms, 12 with segmental portal invasion of which 10 were infiltrative forms) were treated with mbp-RFA. Overall (OS) and recurrence-free (RFS) survival and their associated predictive factors were assessed., Results: Complete ablation was observed in 78/83 (94%) patients. Thirty-one side effects occurred, including 6 (7%) severe complications. After a median follow-up of 26.1 months (1-112 months), in naive patients the 3- and 5-year OS was 51% (38-62) and 24% (13-36), 63 and 30% for mass-forming and 25 and 6% for infiltrative form, respectively. Infiltrative form (HR: 2.5 [1.33-4.69], p = 0.004) was the only independent OS predictor. In naive patients with mass-forming and infiltrative form, the 3- and 5-year RFS were 47 and 17 and 18 and 18%, respectively. Alpha-fetoprotein (HR: 2.86 [1.32-6.21], p = 0.008), multinodular form (HR: 2.74 [1.4-5.38], p = 0.003) and infiltrative form (HR: 3.43 [1.67-7.01], p = 0.0007) were independent RFS predictors., Conclusions: mbp-RFA offers good OS in inoperable patients with cirrhosis and large HCC, with acceptable safety profile. For infiltrative forms, although mbp-RFA leads to complete responses in more than 80% cases, few only remain tumor progression-free in long-term.

Aims: To evaluate the diagnostic performance of CT, MRI and CEUS alone and in combination, for the diagnosis of HCC between 10 and 30 mm, in a large population of cirrhotic patients., Patients and Methods: In a multicentre prospective trial, 442 patients have been enrolled. Within a month, CEUS, CT and MRI were performed for all patients. A composite algorithm was defined to obtain the more accurate gold standard., Results: A total of 544 nodules in 381 patients have been retained for the performance analysis. Eighty-two percent of the patients were male, mean age was 62 years. For the 10-20 mm nodules (n=342), the sensitivity (Se) and specificity (Sp) for the diagnosis of HCC were, respectively, 70.6% and 83.2% for MRI, 67.9% and 76.8% for CT and 39.6% and 92.9% for CEUS. For the 20-30 mm nodules (n=202), the Se and Sp were, respectively, 72.3% and 89.4% for MRI, 71.6% and 93.6% for CT and 52.9% and 91.5% for CEUS. THE BEST COMBINATION FOR THE 10-20 MM NODULES WAS MRI + CT (SE: 55.1%, SP: 100.0%).: After a first inconclusive technique, CEUS as second image technique allowed the highest specificity with only a slight drop of sensitivity for 10-20 mm nodules and the highest sensitivity and specificity for 20-30 mm nodules., Conclusion: This large multicentre study validates the EASL/AASLD recommendations in daily practice. Specificity using CT or MRI in 10-20 mm HCC was low, but we do not recommend combined imaging at first as sensitivity would be very low. The best sequential approach combined MRI and CEUS., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose To assess the safety and efficacy of irreversible electroporation (IRE) in the treatment of patients with inoperable hepatocellular carcinoma (HCC) who are ineligible for thermal ablative techniques. Materials and Methods This retrospective study was approved by an ethics review board, and the requirement to obtain informed written consent was waived. From March 2012 to June 2015, 58 patients (median age, 65.4 years; range 41.6-90 years) with cirrhosis received IRE for the treatment of 75 HCC tumors. The median tumor diameter was 24 mm (range, 6-90 mm). IRE was selected because of tumor location (48 patients) or the patient's poor general condition (10 patients). Treatment response was assessed with magnetic resonance (MR) imaging 1 month after treatment and every 3 months thereafter. Overall local tumor progression-free survival (PFS) per nodule (including initial treatment failures) was assessed by using the Kaplan-Meier method. The marginal Cox proportional hazards model was used to assess the factors associated with overall local tumor PFS. Complications were recorded and graded according to the Clavien-Dindo classification. Results Of 75 tumors, 58 (77.3%), 67 (89.3%), and 69 (92%) were completely ablated after one, two, and three IRE procedures, respectively. After a median follow-up of 9 months (range, 3 days to 31 months), the 6- and 12-month overall local tumor PFS rates for the 75 treated nodules were 87% (95% confidence interval [CI]: 77%, 93%) and 70% (95% CI: 56%, 81%), respectively. A preablative serum α-fetoprotein level higher than 200 ng/mL (hazard ratio: 9.94 [95% CI: 2.82, 35.06], P = .0004) was the only factor linked with overall local tumor PFS. Complications occurred in 11 of the 58 patients (19%) and were classified as grade I in three patients, grade II in five patients, grade IV in two patients, and grade V in one patient. The three (5.2%) complications classified as grade III or higher were liver failures occurring in patients with Child-Pugh class B disease; one led to death. Conclusion IRE offers safe, complete ablation of HCC tumors in patients with contraindications to other commonly used ablative techniques. © RSNA, 2017 Online supplemental material is available for this article.

Background & Aims: The primary aim of this study was to compare the rate of global radiofrequency ablation (RFA) failure between monopolar RFA (MonoRFA) vs. no-touch multi-bipolar RFA (NTmbpRFA) for small hepatocellular carcinoma (HCC) ⩽5cm in cirrhotic patients., Methods: A total of 362 cirrhotic patients were included retrospectively across four French centres (181 per treatment group). Global RFA failure (primary RFA failure or local tumour progression) was analysed using the Kaplan-Meier method after coarsened exact matching. Cox regression models were used to identify factors associated with global RFA failure and overall survival (OS)., Results: Patients were well matched according to tumour size (⩽30/>30mm); tumour number (one/several); tumour location (subcapsular and near large vessel); serum AFP (<10; 10-100; >100ng/ml); Child-Pugh score (A/B) and platelet count (30mm and HCC near large vessel were independent factors associated with global RFA failure. Five-year OS was 37.2% following MonoRFA vs. 46.4% following NTmbpRFA p=0.378., Conclusions: This large multicentre case-matched study showed that NTmbpRFA provided better primary RFA success and sustained local tumour response without increasing severe complications rates, for HCC ⩽5cm., Lay Summary: Using no-touch multi-bipolar radiofrequency ablation for hepatocellular carcinoma ⩽5cm provide a better sustained local tumour control compared to monopolar radiofrequency ablation., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Within 5 years after percutaneous ablation of hepatocellular carcinoma, roughly 70% of patients experience tumor recurrence. Relapses beyond curative options affected patients' survival. Ablation shares with resection common predictive factors of recurrence as size of the tumor, multinodularity and presence of vascular invasion. High serum α-fetoprotein level and markers of severity of underlying liver disease have also been found to be associated with recurrence and even survival. However, predictive values for recurrence of technical factors, histopathological and molecular tumors' features have been rarely studied. Few comparative studies have shown that ablation techniques impact recurrence rates. Moreover, although ablation does not allow analysis of the whole tumor, some reports suggest that biopsies allow histopathological and even molecular testing of the risk of recurrence., Competing Interests: Financial & competing interests disclosure O Seror is advisor for Celon, Olympus and Bayer Schering Pharma; J-C Trinchet and M Beaugrand are advisors for Bayer Schering Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Purpose: To compare histopathologically the completeness of radiofrequency (RF) ablation to treat hepatocellular carcinoma (HCC) with monopolar or multipolar technique., Materials and Methods: Thirty-five consecutive patients (mean age, 59 y) with cirrhosis and HCC (n = 59) within Milan criteria received RF ablation and subsequently underwent liver transplantation (LT) for tumor progression or liver failure. Data were extracted retrospectively from a prospective database. Thirty nodules were treated with a monopolar device with internally cooled (n = 17) or perfused (n = 13) electrodes, and 29 were treated with a multipolar technique with internally cooled electrodes based on the "no-touch" concept. This consisted of inserting two or three straight electrodes around the nodule to avoid intratumor puncture to the greatest extent possible. Effectiveness of the three devices was compared by histopathologic examination of explants. Fisher exact and χ(2) tests and multivariate logistic regression analysis were performed., Results: Mean sizes of nodules ablated (25, 22, and 21.6 mm) and median times from ablation to LT (11, 7.5, and 8.4 months) for patients treated with the monopolar internally cooled electrode device (MoICD), monopolar perfused electrode device (MoPED), and multipolar internally cooled electrode device (MuICD), respectively, were similar (P = .8 and P = .9, respectively). Pathologic examination showed complete necrosis for eight of 17 and six of 13 nodules treated with the MoICD and MoPED, respectively, versus 26 of 29 treated with the MuICD (P = .0019). In multivariate analysis, RF technique remained the predictive factor for complete necrosis (P = .005)., Conclusions: Ablation of small HCCs with multipolar RF ablation based on the no-touch concept improves the rate of complete necrosis during pathologic examination compared with monopolar techniques., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA., Methods: All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models., Results: 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-ß-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p=0.045) and ESM-1 expression (HR 1.56 [1.004; 2.43], p=0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 [1.02; 3.21], p=0.042)., Conclusions: ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Proteoglycans are involved in neoangiogenesis and transduction of oncogenic signals, two hallmarks of carcinogenesis., Methods: This study sought to assess the prognostic value of serum levels of three proteoglycans (endocan, syndecan-1, and glypican-3) and VEGF in 295 patients with alcoholic cirrhosis: 170 without hepatocellular carcinoma, 58 with early hepatocellular carcinoma, and 67 with advanced hepatocellular carcinoma at inclusion. We analyzed the association between proteoglycan levels and prognosis using Kaplan-Meier and Cox methods., Results: Serum levels of the three proteoglycans and VEGF were increased in patients with advanced hepatocellular carcinoma compared with those without hepatocellular carcinoma or with early hepatocellular carcinoma. In multivariate analysis, high levels of serum endocan (>5 ng/mL) were independently associated with death [HR, 2.84; 95% confidence interval (CI,) 1.18-6.84; P = 0.02], but not with hepatocellular carcinoma occurrence, in patients without hepatocellular carcinoma at baseline. High serum endocan (>5 ng/mL) and syndecan-1 (>50 ng/mL) levels were significantly associated with greater risk of tumor recurrence (P = 0.025) in patients with early hepatocellular carcinoma treated by radiofrequency ablation. In patients with advanced hepatocellular carcinoma, high serum levels of endocan (P = 0.004) and syndecan-1 (P = 0.006) were significantly associated with less favorable overall survival. However, only a high level of serum syndecan-1 (>50 ng/mL) was independently associated with greater risk of death (HR, 6.21 95% CI, 1.90-20.30; P = 0.0025)., Conclusion: Serum endocan and syndecan-1 are easily assessable prognostic serum biomarkers of overall survival in alcoholic cirrhosis with and without hepatocellular carcinoma., Impact: These new biomarkers will be useful to manage patients with hepatocellular carcinoma developed on alcoholic cirrhosis., (©2013 AACR)

Background & Aims: Genetic dimorphisms modulate the activities of several pro- or antioxidant enzymes, including myeloperoxidase (MPO), catalase (CAT), manganese superoxide dismutase (SOD2), and glutathione peroxidase 1 (GPx1). We assessed the role of the G(-463)A-MPO, T(-262)C-CAT, Ala16Val-SOD2, and Pro198Leu-GPx1 variants in modulating HCC development in patients with HCV-induced cirrhosis., Methods: Two hundred and five patients with HCV-induced, biopsy-proven cirrhosis but without detectable HCC at inclusion were prospectively followed-up for HCC development. The influence of various genotypes on HCC occurrence was assessed with the Kaplan-Meier method., Results: During follow-up (103.2±3.4 months), 84 patients (41%) developed HCC, and 66 died. Whereas the Ala16Val-SOD2 or Pro198Leu-GPx1 dimorphisms did not modulate the risk, HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7-4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank <0.0001) or the homozygous CC-CAT genotype (HR=1.74 [1.06-2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank=0.02). Compared to patients with neither of these two at risk factors, patients with only the CC-CAT genotype had a HR of 2.05 [0.9-4.6] (p=0.08) and patients with only the GG-MPO genotype had a HR of 3.8 [1.5-9.1] (p=0.002), while patients with both risk factors had an HR of 4.8 [2.2-10.4] (p<0.0001). However, only the GG-MPO genotype was independently associated with the HCC risk in multivariate Cox analysis., Conclusions: The high activity-associated GG-MPO genotype increases the rate of HCC occurrence in patients with HCV-induced cirrhosis., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma is responsible for around 6 000 deaths each year in France. About 90% of patients have underlying liver cirrhosis. The annual incidence rate in such patients is estimated at between 2% and 4%, but it is largely dependent on the cause and severity of the underlying liver disease, as well as on epidemiological factors such as age, sex, and the body mass index. Multiple genetic polymorphisms are also involved. Screening for hepatocellular carcinoma is indicated for patients with cirrhosis, based on ultrasonographic examination every six months. It allows early diagnosis and curative treatment in most cases but is still under-used.

Background & Aims: In patients with hepatocellular carcinoma (HCC) within the Milan criteria, liver transplantation (LT) may be the best therapeutic option. However, the shortage of grafts, leads to attempt liver resection (LR) or radiofrequency ablation (RFA) as a first-line treatment for patients with Child-Pugh A cirrhosis., Methods: We report results, obtained between 2000 and 2007 from a single center, involving 67 patients (mean age: 57 years) eligible for LT, who were treated with RFA, followed by LT if there was recurrence or liver failure., Results: Eighty three tumors were treated (mean size: 29±9 mm; 16 binodular forms). RFA achieved complete ablation in 96% of nodules. No mortality occurred. During a post-RFA median follow-up of 48 months, 38 patients experienced recurrence, corresponding to a 5-year recurrence rate of 58%. Of these, 14 patients did not receive a transplant because they fell outside the Milan criteria, 21 were transplanted, and 3 were treated by RFA after refusing LT. Binodularity (95% CI HR=2, 1.0-4.0; p=0.049) was the unique risk factor for recurrence. By the study's end-point, 24 patients had undergone LT (21 for HCC recurrence and three for liver failure). No HCC recurrence occurred after LT. Among the 43 non-transplant patients, 12 died due to HCC progression, and 27 were alive without detectable viable tumor. The probability rates for 5-year overall and tumor-free survival were 74% and 69%, respectively., Conclusions: First line RFA followed by salvage LT allows survival figures that are at least as good as a first-line LT, while limiting the number of grafts., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Gray's test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal-lesion incidence was not different between Gr3M and Gr6M groups (2-year estimates, 20.4% versus 13.2%, P = 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M, P = 0.002). No difference in either HCC incidence (P = 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%, P = 0.30) was observed between the randomized groups., Conclusion: US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Telomere shortening impairs liver regeneration in mice and is associated with cirrhosis formation in humans with chronic liver disease. In humans, telomerase mutations have been associated with familial diseases leading to bone marrow failure or lung fibrosis. It is currently unknown whether telomerase mutations associate with cirrhosis induced by chronic liver disease. The telomerase RNA component (TERC) and the telomerase reverse transcriptase (TERT) were sequenced in 1,121 individuals (521 patients with cirrhosis induced by chronic liver disease and 600 noncirrhosis controls). Telomere length was analyzed in patients carrying telomerase gene mutations. Functional defects of telomerase gene mutations were investigated in primary human fibroblasts and patient-derived lymphocytes. An increased incidence of telomerase mutations was detected in cirrhosis patients (allele frequency 0.017) compared to noncirrhosis controls (0.003, P value 0.0007; relative risk [RR] 1.859; 95% confidence interval [CI] 1.552-2.227). Cirrhosis patients with TERT mutations showed shortened telomeres in white blood cells compared to control patients. Cirrhosis-associated telomerase mutations led to reduced telomerase activity and defects in maintaining telomere length and the replicative potential of primary cells in culture., Conclusion: This study provides the first experimental evidence that telomerase gene mutations are present in patients developing cirrhosis as a consequence of chronic liver disease. These data support the concept that telomere shortening can represent a causal factor impairing liver regeneration and accelerating cirrhosis formation in response to chronic liver disease., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background & Aims: The expression of biliary lineage markers such as cytokeratin (K) 7 by hepatocytes is thought to reflect an altered regeneration pathway recruiting a stem cell compartment, more prone to carcinogenesis. We aimed to investigate the presence of these so-called intermediate hepatobiliary cells (IHC) in liver biopsies of patients with hepatitis C-related cirrhosis and their potential influence on the subsequent occurrence of hepatocellular carcinoma (HCC)., Methods: From a cohort of patients with hepatitis C-related cirrhosis, prospectively screened for HCC, we retrospectively selected those with a liver biopsy performed for the initial diagnosis of cirrhosis. Presence of IHC was recorded when foci of K7-positive, intermediate-sized hepatocytes were detected., Results: A total of 150 patients were included (87 men; mean age, 57 y; range, 19-84 y; body mass index, 25 kg/m(2)). After a median follow-up period of 4.85 years, HCC was diagnosed in 36 patients (24%). Baseline liver biopsy showed intermediate hepatobiliary cell foci in 61 patients (41%). Intermediate cells co-expressed both hepatocytes markers and the progenitor cell markers Ep-CAM and K19. The presence of intermediate hepatobiliary cells was associated independently with HCC occurrence (Fine and Gray model; hazard ratio, 2.48; 95% confidence interval, 1.24-4.96; P = .01). Other predictors of HCC were diabetes and low platelet count. The HCC annual incidence rate was significantly higher in patients with IHC compared with patients without (8.14% vs 3.12%, Gray's test, P = .003)., Conclusions: The aberrant expression of biliary K by hepatocytes in patients with hepatitis C virus-related cirrhosis is related independently to HCC occurrence., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The sole effective option for patients with advanced HCC is sorafenib and there is an urgent need to develop new therapeutic approaches. Immunotherapy is a promising option that deserves major investigation. In this open label, single arm clinical trial, we analyzed the effect of a low dose cyclophosphamide treatment in combination with a telomerase peptide (GV1001) vaccination in patients with advanced HCC., Methods: 40 patients with advanced HCC were treated with 300 mg/m2 cyclophosphamide on day -3 followed by GM-CSF + GV1001 vaccinations on days 1, 3, 5, 8, 15, 22, 36 followed by 4-weekly injections. Primary endpoint of this phase II trial was tumor response; secondary endpoints evaluated were TTP, TTSP, PFS, OS, safety and immune responses., Results: None of the patients had a complete or partial response to treatment, 17 patients (45.9%) demonstrated a stable disease six months after initiation of treatment. The median TTP was 57.0 days; the median TTSP was estimated to be 358.0 days. Cyclophosphamide, GV1001 and GM-CSF treatment were well tolerated and most adverse events, which were of grade 1 or 2, were generally related to the injection procedure and injection site reactions. GV1001 treatment resulted in a decrease in CD4+CD25+Foxp3+ regulatory T cells; however, no GV1001 specific immune responses were detected after vaccination., Conclusions: Low dose cyclophosphamide treatment followed by GV1001 vaccinations did not show antitumor efficacy as per tumor response and time to progression. Further studies are needed to analyze the effect of a combined chemo-immunotherapy to treat patients with HCC., Trial Registration: NCT00444782.

Unlabelled: Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 +/- 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1-10.1) for HCC and 3.6 (1.9-6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%., Conclusion: The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis.

Unlabelled: For the treatment of small hepatocellular carcinoma (HCC), radiofrequency ablation (RFA) is in some centers considered a first-line therapeutic option. However, such a strategy is still under debate with regard to tumor and patient characteristics. In this single-center study we assessed the 5-year survival and prognosis factors in 235 consecutive patients with cirrhosis (Child-Pugh A/B: 205/30) who received RFA as first-line treatment for up to three HCC