Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study.

BACKGROUND & AIMS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes. METHODS: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared. RESULTS: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22). CONCLUSION: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup. IMPACTS AND IMPLICATIONS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup.

AFP-DIAM Score to Predict Survival in Patients with Hepatocellular Carcinoma Before TACE: A French Multicenter Study.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended as a palliative treatment for patients of the B stage of the Barcelona Clinic Liver Cancer (BCLC) classification. AIMS: To identify clinical, biological, and radiological predictors of survival in patients undergoing TACE and develop a pre-therapeutic prognostic score. METHODS: 191 adult cirrhotic patients treated for HCC with TACE at the University Hospital (UH) of Clermont-Ferrand (France) from 2007-2017 were retrospectively included. We investigated the impact of baseline liver function, patient characteristics, and tumor burden on overall survival and developed a prognostic score. RESULTS: Patients had a median age of 66 years and 126 patients were Child A. The AFP-DIAM score distinguishes two groups with a significant difference in survival time (median OS 28.3 months in patients with a score = 0 versus 17.7 months in patients with a score > 0). AFP-DIAM was validated on an external cohort, is well calibrated, and has the best discrimination capacity (C-index) as compared to NIACE, HAP, STATE, and SIX TO TWELVE. AFP-DIAM and SIX TO TWELVE are the more easy-to-use scores. When AFP-DIAM and the SIX TO TWELVE scores were tested in the same statistical model, results confirmed a better AFP-DIAM performance. CONCLUSIONS: The AFP-DIAM is an easy-to-use score which allows to distinguish two groups with different prognosis before the first TACE session. Its use could provide further support to BCLC system to guide the therapeutic strategy of patients with HCC.

Phase 3, Multicenter Open-Label study to investigate the efficacy of elbasvir and grazoprevir fixed-dose combination for 8 weeks in treatment-naïve, HCV GT1b-infected patients, with non-severe fibrosis.

BACKGROUND: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naïve patients, with non-severe fibrosis. METHODS: HCV mono-infected and treatment naïve patients with non-severe fibrosis (Fibroscan® <9.5 kPa and Fibrotest®  < 0.59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non-1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12). FINDINGS: Mean age was 54 ± 13 years, 31% were men and viral load was higher than 800.000 IU/mL in 70 of 112 patients (63%). Using Fibroscan® , 100 had F0-1 fibrosis score. FIB-4 lower than 1.45 and APRI less than 1 was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance-associated substitution). Then, modified intention-to-treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow-up week 24. INTERPRETATION: Naïve patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for 8 weeks.

Prospective study comparing hepatic steatosis assessment by magnetic resonance imaging and four ultrasound methods in 105 successive patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem, resulting in hepatic, metabolic and cardio-vascular morbidity. AIM: To evaluate new ultrasonographic tools to detect and measure hepatic steatosis. METHODS: We prospectively included 105 patients referred to our liver unit for NAFLD suspicion or follow-up. They underwent ultrasonographic measurement of liver sound speed estimation (SSE) and attenuation coefficient (AC) using Aixplorer MACH 30 (Supersonic Imagine, France), continuous controlled attenuation parameter (cCAP) using Fibroscan (Echosens, France) and standard liver ultrasound with hepato-renal index (HRI) calculation. Hepatic steatosis was then classified according to magnetic resonance imaging proton density fat fraction (PDFF). Receiver operating curve (ROC) analysis was performed to evaluate the diagnostic performance in the diagnosis of steatosis. RESULTS: Most patients were overweight or obese (90%) and had metabolic syndrome (70%). One third suffered from diabetes. Steatosis was identified in 85 patients (81%) according to PDFF. Twenty-one patients (20%) had advanced liver disease. SSE, AC, cCAP and HRI correlated with PDFF, with respective Spearman correlation coefficient of -0.39, 0.42, 0.54 and 0.59 (P < 0.01). Area under the receiver operating characteristic curve (AUROC) for detection of steatosis with HRI was 0.91 (0.83-0.99), with the best cut-off value being 1.3 (Se = 83%, Sp = 98%). The optimal cCAP threshold of 275 dB/m, corresponding to the recent EASL-suggested threshold, had a sensitivity of 72% and a specificity of 80%. Corresponding AUROC was 0.79 (0.66-0.92). The diagnostic accuracy of cCAP was more reliable when standard deviation was < 15 dB/m with an AUC of 0.91 (0.83-0.98). An AC threshold of 0.42 dB/cm/MHz had an AUROC was 0.82 (0.70-0.93). SSE performed moderately with an AUROC of 0.73 (0.62-0.84). CONCLUSION: Among all ultrasonographic tools evaluated in this study, including new-generation tools such as cCAP and SSE, HRI had the best performance. It is also the simplest and most available method as most ultrasound scans are equipped with this module.

Non-invasive biomarkers of non-alcoholic fatty liver disease in patients with Metabolic Syndrome: insights from the RESOLVE study.

BACKGROUND: The aim of the present study was to evaluate i) the presence of liver steatosis using Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI) and Liver Fat Score (LFS) in patients suffering from MS and ii) the association of FLI, HSI and LFS with the cardiometabolic risks. METHODS: A total of 91 patients with MS (MS; 39 men, 52 women) and 44 age matched healthy subjects (Control; 23 men and 21 women) were enrolled in the study. A continuous cardiometabolic score (MetsScore) and the noninvasive tests of hepatic steatosis were calculated for comparison and association analysis. RESULTS: Liver steatosis was detected in 86%, 84% and 80% of people diagnosed with MS using FLI, HSI and LFS respectively and MetsScore increases with FLI severity (p<0,05). Also, FLI and LFS were positively associated with MetsScore (p<0.01 and p<0.05 respectively) but not HSI. Multivariate linear regression models revealed that FLI has a stronger association with MetsScore compared with HSI and LFS (p<0,001). CONCLUSIONS: FLI is associated with the severity of MS and represent a good indicator to assess the relation between liver steatosis and a cardiometabolic disorders in clinical routine.

Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity.

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

Assessment of Malnutrition, Sarcopenia and Frailty in Patients with Cirrhosis: Which Tools Should We Use in Clinical Practice?

Malnutrition is a common comorbidity in patients with cirrhosis. Its prognostic value is indisputable as it greatly affects the evolution of liver diseases. It has a major impact on both morbi-mortality before and after liver transplantation. Being now integrated in the definition of malnutrition and recognized as a new entity in the international classification of diseases, physicians have taken great interest in sarcopenia. Its negative consequences on the fate of patients with cirrhosis are well-demonstrated. The concept of frailty has recently been enlarged to chronic liver diseases as symptoms of impaired global physical functioning. In this article, we will discuss the definitions of malnutrition and emphasize its links with sarcopenia and frailty. We will show the relevance of frailty and sarcopenia in the course of liver diseases. The emerging role of muscle depletion on the cardiorespiratory system will also be highlighted. The importance of body composition will be demonstrated and the main tools reviewed. Finally, we adapted the definition of malnutrition to patients with cirrhosis based on the assessment of sarcopenia together with reduced food intakes.