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Background The aim of this ancillary study of the SARAH trial is to compare health-related quality of life (HRQoL) in patients with locally advanced or inoperable hepatocellular carcinoma (HCC) treated with transarterial radioembolisation (TARE) or sorafenib. Methods This study included randomised patients who received either TARE or at least one dose of sorafenib with no major deviation in the protocol and who had at least one QoL follow-up assessment in addition to the baseline evaluation. QoL was assessed from the date of randomisation using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire, until disease progression or other reasons for stopping study participation. Data were analysed using linear mixed and time-dependent models. Results A total of 285 patients were included (122 and 163, in the TARE and sorafenib groups, respectively). Questionnaire completion rates were similar (77.5% versus 80.4%, in the TARE and sorafenib groups, respectively, p = 0.25). Longitudinal HRQoL analysis showed a significant treatment and time effects for fatigue and global health status, and significant treatment, time and treatment by time interaction effects for appetite loss, diarrhoea and social functioning. The median time to deterioration for the global health status was 3.9 months (95% confidence interval [CI] 3.7–4.3) versus 2.6 months (95% CI 2.0–3.0) in the TARE and sorafenib groups, respectively. Conclusions HRQoL was preserved longer with TARE than with sorafenib in locally advanced HCC. These data could be used to optimise management of patients with advanced or inoperable HCC.

International audience; Background & aims: Noninvasive tests (NITs) of liver fibrosis have been suggested to be less accurate in type 2 diabetes mellitus (T2DM). We aimed to compare the accuracy of 6 NITs between patients with or without T2DM, explain any differences, and adapt diagnostic algorithms for clinical practice accordingly.Methods: We included 1051 patients with nonalcoholic fatty liver disease with liver biopsy, blood fibrosis tests (Nonalcoholic Fatty Liver Disease Fibrosis Score, FIB4, Fibrotest, FibroMeter), vibration-controlled transient elastography (VCTE), and the combinatory elasto-blood test FibroMeterVCTE. The study endpoint was advanced fibrosis on liver biopsy.Results: NIT areas under the receiver operating characteristic curve were significantly lower in patients with T2DM, mostly because of a decrease in specificity. For FIB4, this decrease in specificity was only related to the higher age of patients with T2DM enrolled. For Fibrotest, FibroMeter, and FibroMeterVCTE, the decrease in specificity was related to age but also to higher alpha2-macroglobulin level, which is known to increase in T2DM. Sensitivity was unaffected by T2DM, but it masked a doubled raw number of false negatives because of the 2-fold higher prevalence of advanced fibrosis in that setting. The sequential algorithm FIB4-vibration-controlled transient elastography had 90.3% accuracy in patients without T2DM vs 79.0% in those with (P < .001). Algorithms using first-line specialized tests maintained a low rate of false negatives and false positives in T2DM.Conclusions: The decrease in NIT accuracy observed in T2DM is partly biased by the different characteristics of the groups studied, but also linked to T2DM itself through modification of the levels of some NIT biomarkers. Specialized tests should be used first-line to diagnose advanced liver fibrosis in T2DM.

The European Association for the Study of the Liver (EASL) has recently proposed an algorithm for the diagnosis of advanced liver fibrosis. We aimed to evaluate the diagnostic accuracy of this algorithm in nonalcoholic fatty liver disease (NAFLD).One thousand fifty-one patients with NAFLD, liver biopsy, and four noninvasive tests (NITs; Fibrosis-4 [FIB4], vibration controlled transient elastography [VCTE], FibroMeter, Fibrotest) were included. The enhanced liver fibrosis (ELF) score was available in 396 patients. A cohort of 230 patients from primary care/diabetes clinics had FIB4, VCTE, and ELF. Compared with the performance of single NITs, agreement between two NITs (FIB4 and VCTE, VCTE and patented serum tests) increased specificity and positive predictive value by 20%, thus justifying the sequential use proposed in the EASL algorithm. The FIB4/VCTE/FibroMeter and FIB4/VCTE/Fibrotest algorithms performed similarly, providing 85% diagnostic accuracy and a liver biopsy requirement rate of only 10%. The FIB4/VCTE/ELF algorithm performed similarly in the subgroup where ELF was available. Simulations of algorithm accuracies at different prevalence showed that positive predictive values rapidly increased, reaching a plateau above 75% starting at 15% prevalence. Negative predictive values remained higher than 90% up to 25% prevalence. The rate of liver biopsy requirement remained stable, increasing by only 5% between low and high prevalence settings. When the EASL algorithm was applied in the primary care/diabetes clinic cohort, liver biopsy requirement was only 3%, and the agreement among the three steps provided 75% positive predictive value.Our study validates the algorithm proposed by the EASL in its latest 2021 guidelines for the diagnosis of advanced fibrosis in the setting of NAFLD.

Alcohol-related cirrhosis is a frequent and difficult-to-treat disease. Despite the low hepatic metabolism of baclofen, data on its use in this subgroup are scarce. The French multicenter Observatory of patients treated with Baclofen for Alcohol DEpendence real-life cohort assessed: (a) prescription modalities of baclofen in liver units; (b) safety profile of baclofen; and (c) declared alcohol intake, biological markers of excessive alcohol intake and hepatic function at 12 months.All consecutive patients with cirrhosis who received baclofen to reduce alcohol consumption or maintain abstinence were prospectively included. Psychosocial management was always associated. Clinical and biological data were collected every 3 months for 1 year.Between November 2013 and December 2016, 71 in- or outpatients were included from 10 liver units. Of the patients, 25% had ascites. After 12 months, 52 patients (73%) were still being followed, and 41 (57.7%) were still receiving baclofen at a mean dosage of 75 mg/day (r30-210). The overall declared consumption decreased from 100.2 to 14.7 g/day (P 0.0001), and 29 patients (40.8%) reached abstinence. Significant improvement in the usual biomarkers of excessive alcohol intake (AST, GGT and MCV) and liver function (Prothrombin ratio (PTr), albumin levels) were observed. The usual side effects such as drowsiness were frequent (22%) but no serious adverse events (AEs) or overt encephalopathy related to baclofen was reported.In this 1-year follow-up series, baclofen was combined with psychosocial treatment in patients with cirrhosis and was well tolerated. This treatment was associated with a significant decrease in declared alcohol consumption as well as improvement in hepatic function.

Background & Aims: Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics. Methods: This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM. Results: Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF. Conclusions: The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population. Impact and implications: Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved

International audience; Purpose: The SARAH (Sorafenib Versus Radioembolization in Advanced Hepatocellular Carcinoma) trial (ClinicalTrials.gov Identifier NCT01482442) did not show a significant survival benefit for patients treated with transarterial radioembolization (TARE) compared with continuous oral sorafenib. The improved toxicity profile of patients treated with TARE in the trial, however, could result in a quality of life benefit in economic evaluations. Our objective was to perform a cost-utility analysis of TARE versus sorafenib for locally advanced and inoperable hepatocellular carcinoma.Methods: This study used patient-level data of the SARAH trial regarding resource use, progression-free and overall survival, and quality of life for the within-trial period for the patients who received at least 1 dose of sorafenib or 1 treatment with TARE according to their randomization arm. Data were extrapolated by using a partitioned survival model that incorporated costs and health outcomes, measured in life-years and quality-adjusted life-years (QALYs).Findings: The use of TARE resulted in an average loss of 0.036 life-year and a gain of 0.006 QALY compared with sorafenib. The aerage cost for the TARE arm was €17,179 (95% CI, 9,926-24,280) higher than the sorafenib arm, for an incremental cost-effectiveness ratio of €3,153,086/QALY. The probabilistic sensitivity analysis revealed a 50% risk that the TARE strategy was dominated. TARE was consistently dominated by sorafenib or had an incremental cost-effectiveness ratio more than €450,000/QALY in all sensitivity analyses.Implications: This economic evaluation of SARAH found that using radioembolization with yttrium-90 microspheres for the treatment of hepatocellular carcinoma was not a cost-effective option at the usually accepted willingness-to-pay thresholds.

Background This study assessed the prognostic value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in the prediction of MVI and early recurrence following resection. Method This prospective study (ClinicalTrials.gov ID: NCT02145013) included 78 consecutive HCC patients who underwent 18F-FDG PET/CT before curative-intent resection from 2014 to 2017. Prognostic factors available before surgery for predicting MVI and early recurrence (≤2 years) were identified by univariate and multivariate analyses. Results The 18F-FDG PET/CT result was positive in 30 (38%) patients. MVI was present in 33% (26/78) of specimens. Early recurrence occurred in 19% (14/74) of surviving patients. PET/CT positivity was the sole independent predictor of MVI (odds ratio [OR] = 3.6, 95% confidence interval [CI] = 1.1–11.2; p = 0.03), with a specificity and sensitivity for predicting MVI of 73% and 62%, respectively. Analysis of variables available before surgery showed that PET/CT positivity (hazard ratio [HR] = 5.8, 95% CI = 1.6–20.4; p = 0.006) and the male sex (HR = 6.6; 95% CI = 1.8–24.2; p = 0.005) were independent predictors of early recurrence. Conclusion 18F-FDG PET/CT predicts MVI and early recurrence after surgery for HCC and could be used to select patients for neoadjuvant treatment.

There is limited data regarding the role for systemic treatment in patients with Hepatocellular Carcinoma with Child-Pugh B cirrhosis.PRODIGE 21 was a multicentric prospective non-comparative randomized trial. Patients were randomized to receive sorafenib (Arm A), pravastatin (Arm B), sorafenib-pravastatin (Arm C) combination, or best supportive care (Arm D). Primary endpoint was time to progression (TTP), secondary endpoints included safety and overall survival (OS).160 patients were randomized and 157 patients were included in the final analysis. 86% of patients were BCLC C and 55% had macrovascular invasion. The safety profiles of the drugs were as expected. Median TTP was 3.5, 2.8, 2.0 and 2.2 months in arms A, B, C and D, respectively, but analysis was limited by the number of patients deceased without radiological progression (59%). Median OS was similar between the four arms: 3.8 [95% CI: 2.4-6.5], 3.1 [95% CI: 1.9-4.3], 4.0 [95% CI: 3.2-5.5] and 3.5 months [95% CI: 2.2-5.4] in arms A, B, C and D, respectively. Median OS was 4.0 months [95% CI: 3.3-5.5] for patients treated with sorafenib, vs 2.9 months [95% CI: 2.2-3.9] for patients not treated with sorafenib. In patients with ALBI grade 1/2, median OS was 6.1 months [95% CI: 3.8-8.3] in patients treated with sorafenib vs 3.1 months [95% CI: 1.9-4.8] for patients not treated with sorafenib.In the overall Child-Pugh B population, neither sorafenib nor pravastatin seemed to provide benefit. In the ALBI grade 1/2 sub-population, our trial suggests potential benefit of sorafenib.The study was referenced in clinicaltrials.gov (NCT01357486).

Background & Aims Hepatocellular carcinoma (HCC) staging according to the Barcelona Clinical Liver Cancer (BCLC) classification is based on conventional imaging. The aim of our study was to assess the impact of dual-tracer 18F-fluorocholine and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on tumor staging and treatment allocation. Methods A total of 192 dual-tracer PET/CT scans (18F-fluorocholine and 18F-fluorodeoxyglucose PET/CT) were performed in 177 patients with HCC. BCLC staging and treatment proposal were retrospectively collected based on conventional imaging, along with any new lesions detected, and changes in BCLC classification or treatment allocation based on dual-tracer PET/CT. Results Patients were primarily men (87.5%) with cirrhosis (71%) due to alcohol ± non-alcoholic steatohepatitis (26%), viral infection (62%) or unknown causes (12%). Among 122 patients with PET/CT performed for staging, BCLC stage based on conventional imaging was 0/A in 61 patients (50%), B in 32 patients (26%) and C in 29 patients (24%). Dual-tracer PET/CT detected new lesions in 26 patients (21%), upgraded BCLC staging in 14 (11%) and modified treatment strategy in 17 (14%). In addition, dual-tracer PET/CT modified the final treatment in 4/9 (44%) patients with unexplained elevation of alpha-fetoprotein (AFP), 10/25 patients (40%) with doubtful lesions on conventional imaging and 3/36 patients (8%) waiting for liver transplantation without active HCC after tumor response following bridging therapy. Conclusion When used for HCC staging, dual-tracer PET/CT enabled BCLC upgrading and treatment modification in 11% and 14% of patients, respectively. Dual-tracer PET/CT might also be useful in specific situations (an unexplained rise in AFP, doubtful lesions or pre-transplant evaluation of patients without active HCC). Lay summary Using a combination of tracers 18F-fluorocholine and 18F-fluorodeoxyglucose when performing positron emission tomography/computed tomography (PET/CT), often called a PET scan, helps to identify new tumor lesions in patients with hepatocellular carcinoma. This technique enabled staging modification of patients' tumors and led to changes in treatment allocation in certain patients.

BACKGROUND Recent data suggest that alcohol-related hepatocellular carcinoma (HCC) is diagnosed at a later stage. The aim of this study was to compare HCC characteristics and outcomes in an alcohol-related group (group A) and a non-alcohol-related group (group NA). METHODS A total of 1207 patients with newly diagnosed HCC were prospectively included between May 2008 and October 2009. Patients with multiple causes (alcohol plus another cause) were excluded. Patients were followed every year for 5 years. Recorded variables, including etiologies were tested as prognostic factors of survival in a multivariate Cox model after adjustments for a lead-time bias. RESULTS In all, 894 patients were analyzed: 582 (65.1%) were in group A, and 312 (34.9%) were in group NA. Alcohol-related HCC was more likely to be diffuse and detected in patients with a worse performance status and worse liver function. After adjustments for a lead-time bias, the median overall survival (OS) was 9.7 and 5.7 months in groups NA and A, respectively (P = .0002), and 5.8 and 5.0 months in alcohol-abstinent and alcohol non-abstinent groups, respectively (P = .09). The prognostic role of alcohol disappeared when survival was assessed at each Barcelona Clinic Liver Cancer (BCLC) stage. Patients with HCC detected during a cirrhosis follow-up program (n = 199 [22.3% of the whole cohort]) had increased lead time-adjusted median OS in comparison with patients with HCC diagnosed incidentally (11.7 vs 5.4 months; P < .0001). CONCLUSIONS In comparison with patients with non-alcohol-related HCC, patients with alcohol-related HCC have reduced OS, mainly because of worse liver function and tumor characteristics at diagnosis, as attested by similar survival within each BCLC stage. Cancer 2018;124:1964-72. © 2018 American Cancer Society.

Resume Le carcinome hepatocellulaire represente un probleme de sante publique majeur avec une mortalite globale parmi les plus elevees comparee a celle des autres cancers. La mediane de survie observee en France dans une population hospitaliere avec carcinome hepatocellulaire est de 9,4 mois. De nombreuses equipes ont rapporte un impact positif du depistage du carcinome hepatocellulaire sur le diagnostic a un stade precoce, sur l’eligibilite a un traitement curatif et sur la survie globale. Cependant, l’identification des patients a risque de carcinome hepatocellulaire devant entrer dans un programme de depistage, et l’application des recommandations de depistage sont insuffisantes. D’autres travaux suggerent un impact potentiellement negatif sur le pronostic des patients du retard au diagnostic ou a la mise en route du traitement. Enfin, des variations marquees entre les regions et les departements francais ont ete decrites en ce qui concerne l’acces au traitement curatif et la survie globale. Dans cet article de synthese, nous nous proposons de faire un etat des lieux sur le parcours de soins du patient atteint de carcinome hepatocellulaire en France avec pour objectifs d’identifier les potentiels points de rupture pouvant avoir un impact sur le pronostic des patients et d’elaborer des propositions d’amelioration.

Background and aim Sorafenib is the standard of care for patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI), with limited survival. Retrospective surgical studies have reported prolonged survival in this situation. This study aimed to compare the overall survival of patients with HCC and MVI treated with surgical resection or sorafenib. Methods 143 patients with HCC and MVI but no extra-hepatic spread, treated with surgical resection (SR-patients; n=75) or sorafenib (SOR-patients; n=68) in four French centres between 1990 and 2013 were reviewed retrospectively. A propensity score analysis was performed to reduce bias. Results SR-patients were significantly younger and had a lower tumour burden than SOR-patients. Median overall survival (OS) rates were 10.1 months [95% CI: 4.1-16.1] in SR-patients and 12.9 months [95% CI: 7.9-17.9] in SOR-patients (p=0.959). The 90-day mortality rate was 16% (n=12) in SR-patients and 7.5% (n=5) in SOR-patients (p=0.196). SR-patients had a median disease-free survival of 4.60 months [95% CI: 3.3-5.9]. Under the propensity analysis, median OS was 12.0 months [95% CI: 5.5-18.5] in SR-patients versus 9.7 months [95% CI: 6.1-13.3] in SOR-patients (p = 0.682). Under multivariate analysis, extensive MVI (HR=1.956, p=0.024) and bilirubin >17 μmol/l (HR=1.738, p=0.011) were the two factors significantly associated with mortality. Conclusion Under a propensity score analysis, the overall survival of patients with HCC and MVI undergoing surgical resection was similar to that achieved with sorafenib. We were not able to identify a patient subgroup experiencing a surgery-related improvement in survival, and quality of life was not evaluable. This article is protected by copyright. All rights reserved.

This meta-analysis compared the effects of liver transplantation (LT) and liver resection (LR) on overall survival (OS) and disease-free survival (DFS) in patients with hepatocellular carcinoma (HCC) small transplantable HCC or within Milan criteria. Articles comparing LR with LT for HCC, based on Milan criteria or small size, published up to June 2015 were selected, and a meta-analysis was performed. No randomized controlled trial has been published to date comparing survival outcomes in patients with HCC who underwent LR and LT. Nine studies were identified, including 570 patients who underwent LR and 861 who underwent LT. For HCC within the Milan criteria, the 1-year OS rates following LR and LT were 84.5% (473/560) and 84.4% (710/841), respectively (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.71-1.33; P = 0.8), and the 5-year OS rates were 47.9% (273/570) and 59.3% (509/858), respectively (OR, 0.60; 95% CI, 0.35-1.02; P = 0.06). One-year DFS rates were similar (OR, 1.00; 95% CI, 0.39-2.61; P = 1.00), whereas the 3-year DFS rate was significantly lower in the LR group (54.4%, 210/386) than in the LT group (74.2%, 317/427; OR, 0.24; 95% CI, 0.07-0.80; P = 0.02), and the 5-year DFS rate was significantly lower for LR than LT (OR, 0.18; 95% CI, 0.06-0.53; P

Points essentiels La mortalite globale associee au carcinome hepatocellulaire est parmi les plus elevees comparee aux autres cancers. Quatre-vingt-dix pour cent des carcinomes hepatocellulaires se developpent sur une cirrhose. La cirrhose est decouverte en meme temps que le carcinome hepatocellulaire dans 25 % des cas, malgre la presence de facteurs de risque. Le carcinome hepatocellulaire est decouvert dans le cadre d’un programme de depistage dans moins de 25 % des cas. Le depistage par echographie hepatique semestrielle augmente les chances de diagnostic precoce, de traitement a visee curative et ameliore la survie. Un intervalle de plus de 7 mois entre les echographies de depistage diminue significativement la survie globale des patients. Tout patient cirrhotique doit beneficier d’une echographie de depistage avec un delai entre les echographies de 6 mois maximum.

To compare the added values of hepatobiliary phase (HBP) MRI and contrast-enhanced ultrasound (CEUS) in addition to inconclusive extracellular gadolinium-based contrast-enhanced MRI (CE-MRI) to characterize benign hepatocellular tumors (BHT). Eighty-three BHT-46 focal nodular hyperplasia (FNH) and 37 hepatocellular adenomas (HCA)-with inconclusive CE-MRI in 54 patients (43 women and 11 men, mean age 42 years old ± 14.8) were retrospectively analyzed. All patients underwent both HBP-MRI and CEUS. Two radiologists independently reviewed 2 sets of images, SET-1: CE-MRI and HBP-MRI; SET-2: CE-MRI and CEUS, and classified lesions as “definite FNH,” “possible FNH,” or “definitely not FNH.” Sensitivity (Se) and specificity (Spe) were compared between the two sets; subgroup analyses according to the lesion’s size were performed. Regardless of lesion size, the respective Se and Spe of both datasets were not statistically different (95.7 and 100% vs. 76.1 and 94.6% for set-1 and -2 respectively; p = 0.18). For lesions larger than 35 mm, although both sets had similar specificity (100%), sensitivity was higher for SET-1 (100% vs. 40%); p = 0.04. Tumor classifications using SET-1 and SET-2 could have changed patient management in 35/54 (64.8%) and 33/54 (61.1%) of all patients, respectively. HBP-MRI or CEUS should be performed after an inconclusive CE-MRI. Both can change patient management by avoiding unnecessary biopsy or surveillance. The use of HBP-MRI should be advocated over CEUS in larger (>35 mm) lesions.

We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.NCT01246986 at ClinicalTrials.gov.

Context: The management of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is challenging, especially if it is not treatable by surgery or embolization. Objectives: The present study aims to compare the survival rates of liver transplanted patients receiving sorafenib or best supportive care (BSC) for HCC recurrence not amenable to curative intent treatments. Design: This is a retrospective comparative study on a prospectively maintained database. Participants: Liver transplanted patients with untreatable HCC recurrence receiving BSC (n = 18) until 2007 or sorafenib (n = 15) thereafter were compared. Results: No group difference was observed for demographic characteristics at the time of transplantation and at the time of HCC recurrence. On the explant pathology of the native liver, 81.2% patients were classified within the Milan criteria, and 53.1% presented with microvascular invasion. Hepatocellular carcinoma recurrence was diagnosed 17.8 months (standard deviation: 14.5) after LT, with 17 (53.1%) patients presenting with early recurrence (≤12 months). The 1-year survival from untreatable progression of HCC recurrence was 23.9% for the BSC and 60% for the sorafenib group ( P = .002). The type of treatment (sorafenib vs BSC) was the sole independent predictor of survival (hazard ratio: 2.98; 95% confidence interval: 1.09-8.1; P = .033). In the sorafenib group, 8 (53.3%) patients required dose reduction, and 2 (13.3%) patients discontinued the treatment due to intolerable side effects. Conclusion: Sorafenib improves survival and is superior to the BSC in cases of untreatable posttransplant hepatocellular carcinoma recurrence.

Background Anthropometric measurements have been linked to resistance to anti-angiogenic treatment and survival. Methods Patients with advanced hepatocellular carcinoma treated with sorafenib or brivanib in 2008–2011 were included in this retrospective study. Anthropometric measurements were assessed using computed tomography and were correlated with drug toxicity, radiological response, and overall survival. Results 52 patients were included, Barcelona Clinic Liver Classification B (38%) and C (62%), with a mean value of α-fetoprotein of 29,554 ± 85,654 ng/mL, with a median overall survival of 10.5 months. Sarcopenia was associated with a greater rate of hand–foot syndrome ( P = 0.049). Modified Response Evaluation Criteria In Solid Tumours (mRECIST) and Choi criteria were significantly associated with survival, but RECIST criteria were not. An absence of hand–foot syndrome and high-visceral fat area were associated with progressive disease as assessed by RECIST and mRECIST criteria. In multivariate analyses, high visceral fat area (HR = 3.6; P = 0.002), low lean body mass (HR = 2.4; P = 0.015), and presence of hand–foot syndrome (HR = 1.8; P = 0.004) were significantly associated with overall survival. In time-dependent multivariate analyses; only high visceral fat area was associated with survival. Conclusion Visceral fat area is associated with survival and seems to be a predictive marker for primary resistance to tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma.

Purpose To determine whether texture features on pretreatment contrast material-enhanced computed tomographic (CT) images can help predict overall survival (OS) and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Materials and Methods This retrospective study included 92 patients with advanced HCC treated with sorafenib between January 2009 and April 2015 at two independent university hospitals. Sixty-four of the 92 patients (70%) (six women, 58 men; median age, 66 years) were included from institution 1 and constituted a training cohort; 28 patients (30%) (five women, 23 men; median age, 64 years) were included from institution 2 and constituted a validation cohort. Pretreatment CT texture analysis was performed on late arterial and portal venous phase HCC images. Mean gray-level intensity, entropy, kurtosis, skewness, and standard deviation values were derived from the pixel distribution histogram before and after spatial filtration at different anatomic scales ranging from fine to coarse texture. Lesion heterogeneity was also visually graded on a 4-point scale. Correlations between visual analysis and texture parameters were assessed with the Spearman rank correlation. Univariate Kaplan-Meier and multivariate Cox proportional hazards regression analyses were performed in the training cohort to identify independent predictors of OS and TTP. Their predictive capacity was tested on the validation cohort by using Kaplan-Meier analysis. Results Visual analysis of tumor heterogeneity correlated with entropy at both arterial (P = .012) and portal venous (P = .038) phases. Portal phase-derived entropy at fine (hazard ratio [HR], 5.08; P = .0033), medium (HR, 2.23; P = .019), and coarse (HR, 2.26; P = .0032) texture scales was identified as an independent predictor of OS and confirmed in the validation cohort (P.05). The difference in median survival between patients in the validation cohort with entropy values below and above the identified threshold was 272 days (with fine texture) and 741 days (with medium and coarse textures). Arterial phase-derived texture parameters (P.085) and visual analysis (P.11) were not associated with changes in survival. Conclusion Pretreatment portal venous phase-derived tumor entropy may be a predictor of survival in patients with advanced HCC treated with sorafenib.

We recently identified a histological subtype of hepatocellular carcinoma (HCC), designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this variant, we investigated its prognostic value in two large series of patients with HCC treated by either surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM-HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than six cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, alpha-fetoprotein level, satellite nodules, and vascular invasion). Multivariate analysis showed that MTM-HCC subtype was an independent predictor of early and overall recurrence (surgical series: hazard ratio, 3.03; 95% confidence interval, 1.38-6.65; P = 0.006; and 2.76; 1.63-4.67; P < 0.001; RFA series: 2.37; 1.36-4.13; P = 0.002; and 2.19; 1.35-3.54; P = 0.001, respectively). Its prognostic value was retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness. No other baseline parameter was independently associated with recurrence in the RFA series. CONCLUSION The MTM-HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. (Hepatology 2018;68:103-112).

The original version of this article unfortunately contained a mistake. There was an error in the last sentence of the summary and the last sentence of the discussion. It should read as "On HBP, all FNH appeared hyper- or iso-intense compared to adjacent liver while close to 97% of HCA appeared hypointense".

Summary Background Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 ( 90 Y) resin microspheres in patients with hepatocellular carcinoma. Methods SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90 Y-loaded resin microspheres 2–5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. Findings Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9–33·6) in the SIRT group and 28·1 months (20·0–35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7–9·9) in the SIRT group versus 9·9 months (8·7–11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94–1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [ vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. Interpretation In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. Funding Sirtex Medical Inc.

To assess the value of Hepatobiliary phase MRI (HPB-MRI) to differentiate FNH and HCA, and evaluate its impact on diagnostic accuracy, diagnostic confidence, inter-observer variability, and patient clinical management.Forty-nine patients referred for Gd-BOPTA-enhanced MRI were retrospectively included in this IRB-approved study, with a total of 119 lesions-90 FNH and 29 HCA. Two observers separately assessed in 2 distinct randomized reading sessions the performance of MRI with (HBP-MRI) or without (conventional MRI) the use of HBP images. Each lesion was ranked with a 5-point scale (from 1 Typical FNH to 5 Certainly not a FNH). Sensitivity, specificity, overall accuracy, and inter-observer agreement for the differentiation of FNH from HCA were calculated and compared between conventional and HBP-MRI.Both sensitivity (respective values of 38.9% and 97.8%), overall accuracy (respective values of 53.8% and 98.3%), and inter-observer agreement (respective values of Kappa 0.56 and 0.88) were significantly higher using HBP-MRI than with conventional MRI, with unchanged specificity (100%). The sensitivity of conventional MRI for the diagnosis of FNH was significantly lower in lesions ≤ 3 cm (20% vs. 88%). Overall, HBP could have changed lesion management in 59/119 cases (49.5%), including 53 FNH and 6 HCA with no impact in 60/119 lesions (50.5%) including all 35 lesions classified as scores 1 and 2 for the diagnosis of FNH.The clinical impact of HBP-MRI is mostly important for smaller than 3-cm FNH, and more limited in larger FNH lesions as well as for HCA diagnosis for which conventional MRI is already accurate. The use of extracellular contrast agents upfront could limit the required use of linear HBP contrast agents for benign hepatocellular lesion characterization. On HBP, all FNH appeared hypointense compared to adjacent liver while close to 97% of HCA appeared hypointense.

Purpose To determine the value of quantitative analysis of the hepatobiliary phase (HBP) in gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) to differentiate focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). Materials and Methods Thirty-eight patients bearing 67 lesions (40 FNH; 27 HCA) were retrospectively included in this Institutional Review Board-approved study. The same volumetric interpolated breath-hold examination (VIBE) T1-weighted sequences were performed before and after contrast injection on a 1.5T MRI, with HBP images acquired with a mean delay of 80 minutes (range 60–120 min). After a visual assessment of lesions enhancement (qualitative HBP analysis), the HBP signal intensity ratio (SIR) and the lesion-to-liver contrast enhancement ratio (LLCER) were calculated for each lesion by two observers (Mann-Whitney test). The sensitivities, specificities (receiver operating characteristic [ROC] curve analysis) and interobserver correlation (intraclass coefficient, ICC) of quantitative HBP analysis were determined. Results All FNH and 44.4% of HCA appeared hyper- or isointense relative to the adjacent liver on qualitative HBP analysis. The mean SIR (P

BACKGROUND Several studies have suggested the efficacy of baclofen in reducing alcohol consumption, leading to a temporary recommendation for use in France. AIM Our aim was to report our experience in using baclofen in alcohol-dependant patients with or without liver cirrhosis. PATIENTS AND METHODS Consecutive patients from two liver and alcohol units were recruited over a 3-year period and received increasing doses of baclofen associated with social, psychological, and medical care. RESULTS One hundred patients were treated, of whom 65 were cirrhotic. After 1 year, 86 patients were still being followed up. At a mean dosage of 40 mg/day (extremes: 30-210), the median daily alcohol consumption reduced from 80 to 0 g/day (P

Hepatocellular carcinoma is a major public health problem with one of the highest overall mortality compared to other cancers. The median overall survival in France in a hospital population with hepatocellular carcinoma is 9.4 months. Several publications reported a positive impact of hepatocellular carcinoma screening on diagnosis at an early-stage, eligibility for curative treatment and overall survival. However, the identification of patients to be included in a hepatocellular carcinoma screening program and the application of screening recommendations are not optimal. Other studies suggest a potentially negative impact of delayed diagnosis or treatment initiation on the patient's prognosis. Finally, marked variations between French regions and departments have been described in terms of access to curative treatment and overall survival. In this review article, we propose a state of play of the hepatocellular carcinoma patient's care pathway in France with the aim of identifying potential breaking points with negative impact on prognosis and of developing proposals for improvement.

The purpose of this study was to assess the diagnostic performance of contrast-enhanced sonography (CEUS) for the differentiation of focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA) according to lesion size. Forty patients with a definite diagnosis of FNH or HCA who underwent CEUS were included in this institutional review board (IRB)-approved study. A total of 43 FNHs and 20 HCAs, including 15 inflammatory HCAs and five unclassified HCAs, were analysed. Two radiologists reviewed the diagnostic CEUS parameters separately and in consensus, including the presence or absence of centrifugal filling and central vessels. The sensitivity (Se), specificity (Sp), and inter-observer confidence (Kappa) of CEUS diagnostic parameters were assessed. Inter-observer agreement of CEUS for FNH diagnosis was high (kappa = 0.81) with an overall Se of 67.4 % [29/43 (CI 95 %: 51.4–80.1 %)] and an Sp of 100 % [20/20 (CI 95 %: 81–100 %)]. Significantly higher Se figures were found for lesions ≤ 35 mm than for lesions > 35 mm [respectively, 93 % (28/30) (CI 95 %: 77.6–99.2) vs. 7.7 % (1/13) (CI 95 %: 0.2–36 %), p = 0.002] with unchanged specificity. CEUS is highly specific for the diagnosis of FNH, with very good inter-observer agreement, whatever the size, but its sensitivity is significantly reduced in diagnosing lesions larger than 35 mm. • CEUS is highly specific for the diagnosis of FNH, regardless of lesion size • CEUS shows reduced sensitivity in diagnosing FNH lesions larger than 35 mm • The filling patterns of hepatocellular adenomas are not affected by lesion size

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma.

Hepatocellular carcinoma related mortality is one of the highest among all cancers. Ninety percent of all hepatocellular carcinoma develop in the context of liver cirrhosis. Liver cirrhosis is not recognized prior to the diagnosis of hepatocellular carcinoma in 25 % of the cases, despite the existence of risk factors. Hepatocellular carcinoma is diagnosed within a surveillance program in less than 25 % of the cases. Ultrasound screening for hepatocellular carcinoma every 6 months increases chances to diagnose HCC at an early stage amenable to curative treatment, and increases survival. Interval greater than 7months between ultrasound imaging has a significant negative impact on survival. All patients diagnosed with cirrhosis have to perform an ultrasound screening for hepatocellular carcinoma and comply with the six months rule.

Management of patients with a benign hepatocellular tumor relies largely on imaging data; the diagnosis of focal nodular hyperplasia (FNH) must be made with certainty using MRI, because no other clinical or laboratory data can help diagnosis. It is also essential to identify adenomas to manage them appropriately. The radiological report in these situations is therefore of major importance. However, there are diagnostic traps. The aim of this paper is to present the keys to the diagnosis of benign lesions and to warn of the main diagnostic pitfalls.

The prognosis of hepatocellular carcinoma (HCC) remains poor, with only one third of patients eligible for curative treatments and very limited survival benefits with the use of sorafenib, the current standard of care for advanced disease. Recently, agents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) immune checkpoint were shown to display impressive antitumor activity in various solid or hematological malignancies, including HCC. PD-L1 immunohistochemical expression is thought to represent a biomarker predictive of drug sensitivity. Here, we investigated PD-L1 expression in a series of 217 HCCs and correlated our results with clinical and histological features and immunohistochemical markers (PD-1, cytokeratin 19, glutamine synthetase, and β-catenin expression). PD-L1 expression by neoplastic cells was significantly associated with common markers of tumor aggressiveness (high serum alpha-fetoprotein levels, P = 0.038; satellite nodules, P

Background To compare the apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) with the standardized uptake values (SUV) measured by18F-FDG-PET/CT in naïve hepatocellular carcinoma (HCC) nodules, and to determine whether these markers are associated with tumours at high-risk of aggressiveness. Methods From 2007 to 2010, all patients with HCC on the waiting list for liver transplantation and who underwent both FDG-PET/CT and 1.5-T DWI-MRI (b values: 0, 200, 400, and 800 s/mm2) were included in this institutional review board-approved retrospective study. Tumour size, tumour ADC, tumour-to-liver ADC ratio (ADCT/L), maximal tumour SUV and tumour-to-liver SUV ratio (SUVT/L) were measured and compared to serum alpha-fetoprotein (AFP) levels, tumour size and differentiation grade on explanted specimens. Results A total of 37 HCC nodules in 28 patients were available for correlation between MRI and PET/CT, 7 of which (in 7 patients) showed a SUVT/L > 1.15. We did not find any correlation between tumour ADC or ADCT/L and tumour SUV or SUVT/L. To note, SUVT/L was positively correlated with AFP levels (R = 0.95, P ≤ 0.0001), while ADCT/L was not (P = 0.73). Twenty-four patients (with 32 nodules) underwent liver transplantation. In this subgroup, an increased SUVT/L ratio was associated with larger tumours (average size, 32 ± 14 mm; range, 18–60 mm; P