Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD.

BACKGROUND AND AIMS: 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). APPROACH AND RESULTS: 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. CONCLUSIONS: 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.

Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores.

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.

Impact of Type 2 Diabetes on the Accuracy of Noninvasive Tests of Liver Fibrosis With Resulting Clinical Implications.

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.

Validation of the Blood Test MACK-3 for the Noninvasive Diagnosis of Fibrotic Nonalcoholic Steatohepatitis: An International Study With 1924 Patients.

BACKGROUND & AIMS: Drug development in nonalcoholic steatohepatitis (NASH) is hampered by a high screening failure rate that reaches 60% to 80% in therapeutic trials, mainly because of the absence of fibrotic NASH on baseline liver histology. MACK-3, a blood test including 3 biomarkers (aspartate aminotransferase, homeostasis model assessment, and cytokeratin 18), recently was developed for the noninvasive diagnosis of fibrotic NASH. We aimed to validate the diagnostic accuracy of this noninvasive test in an international multicenter study. METHODS: A total of 1924 patients with biopsy-proven nonalcoholic fatty liver disease from 10 centers in Asia, Australia, and Europe were included. The blood test MACK-3 was calculated for all patients. FibroScan-aspartate aminotransferase score (FAST), an elastography-based test for fibrotic NASH, also was available in a subset of 655 patients. Fibrotic NASH was defined as the presence of NASH on liver biopsy with a Nonalcoholic Fatty Liver Disease Activity Score of 4 or higher and fibrosis stage of F2 or higher according to the NASH Clinical Research Network scoring system. RESULTS: The area under the receiver operating characteristic of MACK-3 for fibrotic NASH was 0.791 (95% CI 0.768-0.814). Sensitivity at the previously published MACK-3 threshold of less than 0.135 was 91% and specificity at a greater than 0.549 threshold was 85%. The MACK-3 area under the receiver operating characteristic was not affected by age, sex, diabetes, or body mass index. MACK-3 and FAST results were well correlated (Spearman correlation coefficient, 0.781; P < .001). Except for an 8% higher rate of patients included in the grey zone, MACK-3 provided similar accuracy to that of FAST. Both tests included 27% of patients in their rule-in zone, with 85% specificity and 35% false positives (screen failure rate). CONCLUSIONS: The blood test MACK-3 is an accurate tool to improve patient selection in NASH therapeutic trials.

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking. OBJECTIVES: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC. METHODS: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS. RESULTS: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival. CONCLUSIONS: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.

Baclofen Combined With Psychosocial Care is Useful and Safe in Alcohol-Related Cirrhosis Patients: A Real-Life Multicenter Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Alcohol-related hepatocellular carcinoma is a heterogenous condition: Lessons from a latent class analysis.

BACKGROUND: Alcohol-associated hepatocellular carcinoma (AL-HCC) poor prognosis has been attributed to diagnosis at a later stage. However, host factors and specific health trajectories have been associated with severe outcomes in alcohol-related liver disease. We hypothesize AL-HCC is not a homogeneous condition but encompasses subgroups yielding different outcomes. AIMS: Our aim was to provide a first attempt at a clinical phenotyping of AL-HCC. METHODS: We analysed data for the calendar years 2007-2013 from the French nationwide administrative hospital database. We selected patients with AL-HCC only. Clustering of AL-HCC phenotypes was performed by latent class analysis (LCA). RESULTS: The study included 11 363 patients with AL-HCC, mainly male (89.6%), median age 67 years [IQR: 61; 74] of which 71.2% had at least one metabolic comorbidity. Five phenotypes were identified. Phenotype 1 (41.4%) displayed high rates of unrecognized cirrhosis prior to HCC diagnosis (81%), low rates of metabolic comorbidities (diabetes 13%), and mostly compensated liver disease at HCC diagnosis while the four other phenotypes displayed high rates of metabolic comorbidities (diabetes up to 100%), various patterns of liver disease trajectories and overall 42% unrecognized cirrhosis. In adjusted survival analysis, compared to phenotype 1, risk of death after HCC diagnosis was significantly different for all phenotypes. CONCLUSION: LCA uncovers AL-HCC is a heterogeneous condition with distinct phenotypes yielding specific survival outcomes. Frequent unrecognized cirrhosis prior to HCC underlines the urgent need for implementing strategies to identify the underlying liver disease prior to HCC onset in patients with documented alcohol use disorders and metabolic comorbidities.

Patient preferences for advanced hepatocellular carcinoma treatment: a multicountry stated preference study.

The present study aimed to explore patient preferences for attributes of advanced hepatocellular carcinoma (HCC) treatments. A stated preference survey was completed by 150 patients with HCC living in Europe. Overall survival (OS) was the most important attribute, closely followed by risk of diarrhea and hypertension, and other adverse event (AE) risks. Patients were willing to trade OS to reduce AE risks. While less important than OS and AEs, patients also preferred shorter waiting times, and one-off administration of selective internal radiation therapy and oral tablets over intravenous infusions. Although patients placed the most value on extending OS, they were willing to forego OS to avoid risk of treatment-related AEs, to maintain their quality of life.

Lay abstract This study aimed to understand patient preferences for characteristics of advanced hepatocellular carcinoma (HCC) treatments. A total of 150 people with HCC in Europe were presented a series of questions asking them to choose between two hypothetical treatments. Overall, length of life was the most important issue for patients, followed by avoiding diarrhea and hypertension, and then other side effects and treatment risks. Patients were willing to forego some months of life to avoid side effects or risks. Patients preferred to be given their treatment via a single minimally invasive hospital procedure or oral daily tablets compared with intravenous drips. In conclusion, although patients placed the most value on overall length of life, side effects and treatment risks were also important.

Is It Time to Reconsider the Milan Criteria for Selecting Patients With Hepatocellular Carcinoma for Deceased-Donor Liver Transplantation?

Liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC) because it removes tumor as well as the underlying cirrhotic liver. Because of a global organ shortage, LT for patients with HCC is limited to patients with expected survival comparable to that of nonmalignant indications. Therefore, identifying patients with lower rates of HCC recurrence and higher rates of survival is critical. International guidelines have considered the Milan Criteria (MC) the standard for selecting patients with HCC for deceased-donor LT (DDLT). However, several alternative criteria have been reported in the Western world. Interestingly, the two most recent models combining α-fetoprotein level, number of nodules, and size of the largest nodule have been shown to outperform MC in identifying patients with low risk of HCC recurrence or those who will survive for 5 years after liver transplantation. In addition, new models overcome limitations of MC in improving classification of high- versus low-risk patients with HCC for DDLT. These recent scoring systems also provide clinicians with user-friendly tools to better identify patients at lower risk of recurrence. Conclusion: Although most Western countries still select patients based on MC, there is a mounting change in recent practice patterns regarding the selection of patients with HCC for DDLT. Herein, we describe how alternative criteria should lead to reconsideration of MC as it applies to selecting patients with HCC for DDLT in international guidelines.

Geographical Disparities of Outcomes of Hepatocellular Carcinoma in France: The Heavier Burden of Alcohol Compared to Hepatitis C.

BACKGROUND: Data on alcohol-related HCC are limited. AIMS: Our aim was to describe the incidence, management, and prognosis of alcohol compared to Hepatitis C (HCV)-related HCC at a national level. METHODS: Incident cases of HCC were identified in French healthcare databases between 2009 and 2012 and analyzed retrospectively. Demographic data, type, location, and annual HCC-caseload of the hospitals where patients were first managed were retrieved. Survival of incident cases was computed from the time of diagnosis and adjusted for potential confounding variables. RESULTS: The study population included 14,060 incident cases of alcohol and 2581 HCV-related HCC. Alcohol-related HCC was more frequent than HCV-related HCC (29.37 and 5.39/100,000 adults/year, respectively) with an heterogeneous distribution on the French territory. The optimal treatment was less frequently curative (20.5% vs 35.9%; p < 0.001), and survival was significantly shorter (9.5 [9.0-10.0] versus 16.8 [15.5-18.7] months p < 0.001) in alcohol compared to HCV-related HCC, with marked variations between regions for a given risk factor. In multivariable analysis in the whole study population, curative treatment was a strong predictor of survival (adjusted HR 0.28 [0.27-0.30] months p < 0.001). Being managed at least once in a teaching hospital during follow-up was independently associated with receiving a curative treatment and survival. CONCLUSION: In France, incidence of alcohol-related HCC is high and prognosis is poor compared to HCV-related HCC, with marked variations between regions. These results should guide future health policy initiatives pertaining to HCC care. Importantly, increasing patient' referral in expert centers could increase chances to receive curative treatment and improve outcomes.

Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study.

BACKGROUND & AIMS: Semi-annual surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. We aimed to determine how compliance with HCC surveillance guidelines affects survival times of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis who developed HCC. METHODS: We collected data from the prospective ANRS CO12 CirVir study, from March 2006 through June 2012, on 1671 patients with biopsy-proven viral cirrhosis and no previous liver complications who were undergoing surveillance for HCC at 35 centers in France. Only 216 patients who developed HCC during the follow-up period were included in the analysis. Patients were considered to be compliant with surveillance guidelines if the time between their last surveillance image evaluation and diagnosis of HCC were fewer than 7 months and noncompliant if this time was 7 months or longer. RESULTS: HCC was detected in 216 patients, at a median follow-up time of 59.7 months. Of these patients, 140 (80.5%) were Barcelona Clinic Liver Cancer stage 0/A, 135 (69.9%) received first-line curative treatment (15 underwent transplantation, 29 underwent resection, 89 received percutaneous ablation, and 2 received resection and percutaneous ablation), and 129 (60.0%) were compliant with surveillance guidelines. Seventy-nine of the patients with HCC died; 49 deaths were associated with tumor progression. After lead-time adjustment, overall survival (OS) time was longer in patients compliant with surveillance guidelines (median OS time, 53.2 months) than noncompliant patients (median OS time, 25.4 months) (P = .0107); this difference remained significant even when we changed lead time assumptions. In multivariate analysis adjusted for a propensity score, compliance with HCC surveillance guidelines was associated with low tumor burden, allocation of curative treatment, and increased OS time compared with noncompliance (hazard ratio for OS, 2.19; 95% confidence interval, 1.16-4.14; P = .0150). CONCLUSIONS: In an analysis of data from the ANRS CO12 CirVir cohort, we associated compliance with HCC surveillance guidelines (fewer than 7 months between image evaluations) with early diagnosis, allocation of curative treatment, and longer adjusted OS of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis and a diagnosis of HCC.

Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance.

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).

Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-ß1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP). METHODS: 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-ß1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS). RESULTS: 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-ß1 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). CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-ß1 levels (vs no response) correlated with longer survival. TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.

18F-FDG PET/CT predicts microvascular invasion and early recurrence after liver resection for hepatocellular carcinoma: A prospective observational study.

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.

Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients: Results of a prospective, nationwide study.

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.

Positron emission tomography/computed tomography with 18F-fluorocholine improve tumor staging and treatment allocation in patients with hepatocellular carcinoma.

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 ±â€¯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.

Advanced Hepatocellular Carcinoma: Pretreatment Contrast-enhanced CT Texture Parameters as Predictive Biomarkers of Survival in Patients Treated with Sorafenib.

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.

Early detection and curative treatment of hepatocellular carcinoma: A cost-effectiveness analysis in France and in the United States.

Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Patients outside clinical trials seldom benefit from evidence-based monitoring. The objective of this study was to estimate the cost-effectiveness of complying with HCC screening guidelines. The economic evaluation compared surveillance of patients with cirrhosis as recommended by the guidelines ("gold-standard monitoring") to "real-life monitoring" from the health care system perspective. A Markov model described the history of the disease and treatment course including current first-line curative treatment: liver resection, radiofrequency ablation (RFA), and liver transplantation. Transition probabilities were derived mainly from two French cohorts, CIRVIR and CHANGH. Costs were computed using French and U.S. tariffs. Effectiveness was measured in life years gained (LYG). An incremental cost-effectiveness ratio (ICER) was calculated for a 10-year horizon and tested with one-way and probabilistic sensitivity analyses. The cost difference between the two groups was $648 ($87,476 in the gold-standard monitoring group vs. $86,829 in the real-life monitoring group) in France and $11,965 ($93,795 vs. $81,829) in the United States. Survival increased by 0.37 years (7.18 vs. 6.81 years). The ICER was $1,754 per LYG in France and $32,415 per LYG in the United States. The health gain resulted from earlier diagnosis and access to first-line curative treatments, among which RFA provided the best value for money. CONCLUSION: Our results indicate that gold-standard monitoring for patients with cirrhosis is cost-effective, attributed to a higher probability of benefiting from a curative treatment and so a higher survival probability. (Hepatology 2017;65:1237-1248).

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

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 (90Y) 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 90Y-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 [<1%] 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.