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AIM To validate the utility of hepatic resection combined with complementary radiofrequency ablation (RFA) compared with resection alone for patients with multiple hepatocellular carcinoma (HCC), and to compare these results with those of a previous report. MATERIALS AND METHODS A total of 78 HCC patients with multiple (≤5) tumours who were initially treated with hepatic resection only (Resection group) or with combined hepatic resection and RFA (Combination group) were included. Overall and disease-free survival were analysed. RESULTS There were 21 women and 57 men with a median age of 72.5 (64.3–76.8) years. Fifty-three patients were treated with resection alone and 25 received combination therapy. The 3-, 5-, and 7-year cumulative overall survival rates were 81.2%, 68.2%, and 57.1%, respectively, in the Resection group, and 81.3%, 59.6%, and 42.4%%, respectively, in the Combination group (hazard ratio [HR], 1.462; 95% confidence interval [CI], 0.682–3.136; p=0.329). The 1-, 3-, and 5-year cumulative disease-free survival rates were 61.4%, 45.7%, and 39.8%, respectively, in the Resection group, and 53.1%, 18.6%, and 0%, respectively, in the Combination group (HR, 2.080; 95% CI, 1.157–3.737; p=0.014). The overall survival rate was not significantly different between the Resection and Combination groups in patients within the up-to-seven HCC criteria (n=56; HR, 2.101; 95% CI, 0.805–5.486; p=0.130) or those beyond these criteria (n=22; HR, 0.804; 95% CI, 0.197–3.286; p=0.761). CONCLUSIONS The combination of hepatic resection and RFA therapy may be an effective strategy for HCC patients with multiple tumours.

Background/aim Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple. Material/methods From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child-Pugh 5:6=68:27, TNM stage II:III=17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Results Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR) and disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/42.5% and 84.7%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Conclusion Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition. This article is protected by copyright. All rights reserved.

Background/Aim: With the development of systemic treatment methods for unresectable hepatocellular carcinoma (uHCC), the concept of unsuitable for transcatheter arterial chemoembolization (TACE) has become important. This study aimed to establish a simple predictive scoring system for determining TACE unsuitable status. Materials/Methods: From 1998 to 2015, 196 patients with intermediate-stage uHCC with Child-Pugh A (score 5:6 = 108:88) and given TACE as the initial treatment were enrolled. At the baseline, tumor burden (Milan criteria-out, up-to-7 in/out, and up-to-11 in/out: 0–2 points) and modified albumin-bilirubin grade 1/2a or 2b (0–1 point) were added to determine the score for TACE unsuitable (CITRUS-MICAN score; low Results: Median survival time (MST) was better for low compared to high CITRUS-MICAN score (42.0 vs. 26.4 months) (p = 0.002). A 2-step evaluation using the combination of CITRUS-MICAN and TM scores showed an MST of 43.2 months for low CITRUS-MICAN/TM score 0/1 (rank-A) and 39.6 months for low CITRUS-MICAN/TM score ≥2 (rank-B2), while it was 46.8 months for high CITRUS-MICAN/TM score 0 (rank-B1), 28.8 months for high CITRUS-MICAN/TM score 1 (rank-B2), and 22.8 months for high CITRUS-MICAN/TM score ≥2 (rank-C). For rank-A cases (n = 51), MST was 43.2 months, while it was 46.8 months for rank-B1 (n = 12), 31.2 months for rank-B2 (n = 82), and 22.8 months for rank-C (n = 51) (p = 0.001). Conclusion: The results showed that rank-C indicates absolute TACE unsuitable status. For rank-A patients, good prognosis with TACE can be expected, while TACE refractoriness status during the clinical course should be carefully evaluated so as to anticipate the appropriate timing for switching to systemic treatment in rank-B1 and -B2 patients.

AIMS Data on the long-term outcomes of individuals with hepatitis B virus (HBV) infection who are hepatitis envelope antigen (HBeAg)-negative inactive carriers (ICs) are limited due to small numbers. We compared the long-term prognosis of well-defined ICs with that of age- and gender-matched general population controls. METHODS A total of 526 HBeAg-negative patients who demonstrated alanine aminotransferase (ALT) level ≤40 U/L and HBV DNA level ≤4.3 log IU/ml at least three times within 1 year after the start of follow-up were enrolled as ICs. Inactive carriers were divided into two groups: Group A (n = 332), whose ALT level was ≤30 U/L and HBV DNA level was ≤3.3 log IU/ml, and Group B (remaining patients, n = 194). We determined the long-term prognosis of ICs and compared it with that of general population controls. We also analyzed factors associated with hepatitis B surface antigen (HBsAg) clearance and phase transition in ICs. RESULTS There were no significant differences in hepatocellular carcinoma development or all-cause, liver-related, or non-liver-related mortality between Groups A and B. There was no significant difference in all-cause mortality between ICs and the general population. Low HBsAg level (≤3.0 log IU/ml) and the presence of fatty liver were associated with HBsAg clearance and high alpha-fetoprotein level was associated with phase transition. CONCLUSIONS The long-term prognosis of well-defined ICs was similar to that of general population controls. In addition, the ICs had a high HBsAg clearance rate and low phase transition rate.

Non-hypervascular hypointense nodules (NHHNs) on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of hypervascularization progressing to typical hypervascular hepatocellular carcinoma (HCC). NHHNs that were present before the start of anti-hepatitis C virus (HCV) therapy is a risk marker for HCC development after achieving sustained virologic response (SVR). In this report, we show a patient without a previous history of HCC in whom HCC developed by hypervascularization of NHHN after SVR. This patient achieved SVR more than 8 years before NHHN developed into HCC, and during this time NHHN had been present but had remained unchanged in size and imaging features as shown by repeated EOB-MRI. Hepatocarcinogenic potential of NHHNs persist for a long time after SVR, despite the eradication of HCV.

Background and Aim Hepatic angiography procedures such as transarterial chemoembolization (TACE) are essential procedures for managing patients with hepatocellular carcinoma (HCC), and are usually performed with femoral access. However, femoral access causes patient discomfort and may be associated with the risk of hematoma or pseudoaneurysm at puncture site. We evaluated the safety, feasibility, and patient comfort of hepatic angiography procedures performed with radial access. Methods In this single‐institution, retrospective, time‐frame study, a total of 206 patients who underwent hepatic angiography procedures with radial access, which were first used on October 2017 at our institution, were compared with 240 patients who underwent the same procedures with femoral access before this period. Several measures were assessed, including procedure time and safety. In addition, a questionnaire was used to compare the access types regarding procedure‐associated discomfort. Results Hepatic angiography procedures performed with radial access, including TACE, were completed in all patients without complications. The procedure time was comparable between radial access and femoral access. Most patients preferred radial to femoral access. Patients taking anticoagulants were able to complete the procedures without discontinuing these drugs. Conclusions Hepatic angiography procedures with radial access resulted in less discomfort than those with femoral access, and the two approaches showed similar feasibility and safety. Radial access can be introduced as a routine technique for hepatic angiography procedures., Hepatic angiography procedures with radial access resulted in less discomfort than those with femoral access, and the two approaches showed similar feasibility and safety. Radial access can be introduced as a routine technique for hepatic angiography procedures.

The impact of antiviral therapy on clinical outcomes in patients with hepatitis C virus (HCV) infection and mild liver fibrosis (FIB-4 score

We investigated the impact on survival of modified albumin–bilirubin (mALBI) grade versus Child–Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child–Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944–3.141 and HR, 2.178; 95%CI, 1.591–2.982]. In patients with a Child–Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083–3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child–Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child–Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child–Pugh classification in patients with unresectable HCC who received lenvatinib therapy.

Hepatocellular carcinoma (HCC) can de novo develop in patients with chronic hepatitis C even after the achievement of sustained virologic response (SVR). We characterized de novo HCC after SVR, comparing it with HCC that developed in patients during persistent hepatitis C virus (HCV) infection. Characteristics, survival rates, and recurrence rates after curative treatment in 178 patients who developed initial HCC after SVR diagnosed between 2014 and 2020 were compared with those of 127 patients with initial HCC that developed during persistent HCV infection diagnosed between 2011 and 2015; HCC was detected under surveillance in both groups. HCC was less advanced and liver function worsened less in patients with SVR than in patients with persistent HCV. The survival rate after diagnosis was significantly higher for patients with SVR than for patients with persistent HCV (1-, 3-, and 5-year survival rates, 98.2%, 92.5%, and 86.8% versus 89.5%, 74.7%, and 60.8%, respectively; P < 0.001). By contrast, the recurrence rate after curative treatment was similar between groups (1-, 3-, and 5-year recurrence rates, 11.6%, 54.6%, and 60.4% versus 24.0%, 46.7%, and 50.4%, respectively; P = 0.7484). Liver function improved between initial HCC diagnosis and recurrence in patients with SVR (P = 0.0191), whereas it worsened in the control group (P < 0.001). In addition, patients with SVR could receive curative treatment for recurrence more frequently than patients with persistent HCV (80.4% versus 47.8%, respectively; P = 0.0008). Conclusion: Survival of patients with de novo HCC after SVR was significantly higher than that of patients in whom HCC developed during persistent HCV infection, despite similar rates of recurrence after curative treatment. A higher prevalence of curative treatment for recurrent HCC and improved liver function contributed to this result.

BACKGROUND Identification of risk factors for the development of hepatocellular carcinoma (HCC) after a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection is urgently needed for HCC surveillance. AIMS To evaluate whether the presence of non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) before direct-acting antivirals (DAAs) therapy is a risk factor for de novo HCC development after SVR. METHODS The presence of NHHNs was examined with EOB-MRI before the start of DAA therapy in 383 patients with HCV infection who achieved SVR. The incidence of de novo HCC after SVR was compared between patients with versus without NHHNs. RESULTS NHHNs were detected before DAA therapy in 32 patients (8.4%). The incidence of de novo HCC after SVR was significantly higher in patients with NHHNs than in those without (1-, 3-, 5-year incidence, 9.8%, 24.2% and 41.6% vs. 0%, 1.2% and 4.4%, P

In patients with hepatitis C virus (HCV) infection and decompensated cirrhosis (DC), it is uncertain whether viral clearance is clinically meaningful and whether it decreases liver-related and non-liver-related mortality. The aim of this study was to assess whether viral eradication reduced liver-related and non-liver-related mortality in patients with HCV infection and DC. To clarify the impact of viral eradication on liver-related and non-liver-related mortality, 364 patients with DC who received direct-acting antivirals (DAAs) and achieved sustained virological response (SVR) in the UK (DAA group) were compared with 249 patients with DC who did not receive DAAs and who underwent symptomatic treatment in Japan (non-DAA group). Propensity score matching and inverse probability weighting (IPW) were performed to adjust the baseline characteristics in the DAA and non-DAA groups. Liver-related and non-liver-related mortality were analyzed using the competing risks IPW cumulative incidence functions estimator. The cumulative all-cause mortality rate in the DAA group was significantly lower than that in the non-DAA group (p

AIM Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development. METHODS Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH). RESULTS Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval, 3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p

To investigate the long-term prognosis of liver disease in patients with hepatitis C virus (HCV) eradication after antiviral therapy versus those with persistent HCV infection. Four hundred and eighty patients (5259 person-years [PYs]) who received interferon-based therapy and achieved sustained virologic response and 848 patients (3853 PYs) with persistent HCV infection were included. In the analysis of 1-year liver disease state transition probability matrices using Markov chain models, progression to cirrhosis from the chronic hepatitis state was observed (0.00%-0.63%) in patients with HCV eradication. Among patients with chronic hepatitis or cirrhosis and HCV eradication, hepatocellular carcinoma (HCC) development was observed in males aged ≥ 50 years (0.97%-1.96%) and females aged ≥ 60 years (0.26%-5.00%). Additionally, in patients with cirrhosis and HCV eradication, improvement to chronic hepatitis was also observed (4.94%-10.64%). Conversely, in patients with chronic hepatitis and persistent HCV infection, progression to cirrhosis was observed in males aged ≥ 30 years and female aged ≥ 40 years (0.44%-1.99%). In males aged ≥ 40 years and female aged ≥ 50 years with cirrhosis, the transition probability for HCC was relatively high (4.17%-14.02%). Under the assumption of either chronic hepatitis or cirrhosis at age 40 or 60 years as the starting condition for simulation over the next 30 or 40 years, respectively, the probability of HCC was higher in patients with persistent HCV infection than those with HCV eradication. In conclusion, HCV eradication can reduce the risk of developing cirrhosis or HCC in patients with chronic HCV infection.

Introduction The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2. Methods A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. Results The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2–92.6) (110/126) and 97.3% (95% CI 92.4–99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5–96.9) (105/113), 99.1% (95% CI 95.2–100.0) (112/113), and 100.0% (95% CI 97.4–100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment. Conclusion The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection. Trial Registration UMIN registration no. 000038604.

Background and Aim Although tenofovir alafenamide (TAF), as well as entecavir (ETV), is widely used as first‐line treatment for patients with chronic hepatitis B, there are only a few studies comparing sequential therapy from ETV to TAF and continuous ETV monotherapy in patients with maintained virologic response to ETV. Methods In a retrospective multicenter study, we investigated the efficacy and safety of sequential therapy from ETV to TAF (ETV‐TAF group) and compared them with continuous ETV monotherapy (ETV group), using propensity score matching, in chronic hepatitis B patients. Results From 442 patients, we analyzed 142 patients from each group comprising 71 patients matched for several data, including age, HBV genotype, hepatitis B envelope antigen, cirrhosis, alanine aminotransferase, platelet count, prior ETV monotherapy period, and hepatitis B surface antigen (HBsAg) change during prior ETV monotherapy. In the ETV‐TAF group, HBsAg levels significantly decreased from baseline to 48 weeks after switching to TAF (−0.02 log IU/mL, P = 0.038). HBcrAg levels also significantly decreased after switching to TAF (−0.1 log IU/mL, P = 0.004). However, there were no significant differences in the reduction of HBsAg and HBcrAg levels between the ETV‐TAF and ETV groups. There was no significant difference in the change of estimated glomerular filtration rate levels from baseline to 48 weeks between the two groups. Conclusions The present study indicated that the efficacy, especially of the HBsAg‐reducing action, and safety of sequential therapy from ETV to TAF were similar to those of continuous ETV monotherapy among chronic hepatitis B patients with maintained virologic response to ETV., In a retrospective, multicenter study involving 17 institutions, we investigated the efficacy and safety of sequential therapy from entecavir (ETV) to tenofovir alafenamide (TAF) (ETV‐TAF group). The present study indicated that the efficacy, especially of the hepatitis B surface antigen‐reducing action, and safety of sequential therapy from ETV to TAF were similar to those of continuous ETV monotherapy.

Background and Aim This study aimed to elucidate the clinical importance of muscle volume loss (pre‐sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u‐HCC). Methods Of 437 u‐HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre‐sarcopenia was diagnosed based on a previously reported cut‐off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm2)/height (m)2]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre‐sarcopenia. Results Cox hazard multivariate analysis showed alpha‐fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P

Background Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment. Methods Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner. Results The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was −2.19. Of the 28 patients, 23 were male, 21 were classified as Child–Pugh A and 7 as Child–Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2. Conclusions The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.

The albumin–bilirubin (ALBI) score is calculated using only serum albumin and bilirubin levels, and was developed as a simple method to assess hepatic function. In this study, a total of 409 patients with primary biliary cholangitis (PBC) were enrolled between March 1990 and October 2018. The predictive performances of the ALBI score and other well-established prognostic scores were compared using time-dependent receiver operating characteristic (ROC) analysis. During the follow-up period, 60 patients died, 45 due to liver-related diseases and 15 due to non-liver-related diseases, and 16 patients underwent liver transplantation. Time-dependent ROC analysis showed that the ALBI score has higher the areas under the ROC curves (AUROCs) than the Child–Pugh (C–P) score at each time point; AUROCs at 3, 5, and 10 years after the start of follow-up were 0.94, 0.91, and 0.90 for the ALBI score, and 0.89, 0.88, and 0.82 for the C–P score, respectively. The ALBI score showed the highest AUROCs within 2 years after the start of observation; beyond 2 years, however, the Mayo score had better prognostic ability for mortality and liver transplantation. The ALBI score/grade, derived from objective blood tests, and the Mayo score were superior prognostic tools in PBC patients.

Introduction Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. Methods A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. Results The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child–Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5–13). The albumin–bilirubin (ALBI) score ranged from − 3.01 to − 0.45 (median − 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child–Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child–Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10−4 and 2.42 × 10−4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. Conclusion Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. Trial Registration UMIN registration no, 000038587. Electronic supplementary material The online version of this article (10.1007/s40121-020-00329-y) contains supplementary material, which is available to authorized users.

OBJECTIVE Chronic liver diseases are associated with zinc (Zn) deficiency. However, no previous studies have examined the relationship between serum Zn levels and hepatic pathological findings in patients with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the serum Zn levels in NAFLD patients based on pathological/laboratory findings. METHODS We evaluated a total of 191 NAFLD patients who underwent liver biopsy with the goal of identifying laboratory markers and pathological findings associated with serum Zn levels. RESULTS Zn levels significantly decreased along with progression of hepatic fibrosis (P = 0.039), but there were no significant differences among inflammatory grades. Zn levels were most strongly correlated with albumin levels (r = 0.410, P

BACKGROUND AND AIMS Survival data among patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after achieving sustained virologic response (SVR) with interferon-free direct-acting antivirals (DAAs) in both Asian and western countries are limited. Survival rates were compared between patients with HCV-related HCC who were untreated for HCV and those who achieved SVR. APPROACH AND RESULTS Using data from two U.S. and six Asian centers from 2005 to 2017, we categorized 1,676 patients who were mono-infected with HCV-related HCC into patients untreated for HCV (untreated group) and DAA-treated patients with SVR (SVR group) and matched by propensity score matching (PSM); multivariable Cox regression with HCV treatment status as a time-varying covariate was used to determine mortality risk and landmark analysis to avoid immortal time bias. There were 1,239 untreated patients and 437 patients with SVR. After PSM, background risks of the 321 pairs of matched patients were balanced (all P > 0.05). After time-varying adjustment for HCV treatment initiation compared with untreated patients, patients with SVR had significantly higher 5-year overall survival (87.78% vs. 66.05%, P

BACKGROUND AND AIM Hepatitis B core-related antigen (HBcrAg) has been shown to correlate with various viral markers in chronic hepatitis B, but its role in defining natural history is not well studied. We aimed to investigate the use of HBcrAg to define different phases of chronic hepatitis B. METHODS Stored residual serum samples from longitudinal cohorts of chronic hepatitis B patients in Hong Kong and Japan were studied. Viral markers were measured in three serial serum samples for each patient. Patients were divided into six groups for analysis: hepatitis B e antigen (HBeAg)-positive chronic infection (EPI), HBeAg-positive chronic hepatitis (EPH), HBeAg seroconversion (ES), HBeAg-negative chronic hepatitis (ENH), HBeAg-negative chronic infection (ENI), and HBsAg seroclearance (SS). RESULTS In total, 166 patients followed up for 100 (76-113) months were included. HBcrAg was correlated with hepatitis B virus DNA and HBsAg levels in both HBeAg-positive and HBeAg-negative patients. HBcrAg cut-off of ≥ 6.0 log U/mL could best differentiate HBeAg-positive from HBeAg-negative patients (area under receiver operating characteristic curve of 0.99, P

Objective Lenvatinib, a newly developed molecularly targeted agent, has become available as a first-line therapy in patients with unresectable hepatocellular carcinoma (HCC). The platelet-to-lymphocyte ratio (PLR) has been associated with poor outcome in various malignancies, including HCC. In this study, we investigated the ability of PLR to predict outcomes in patients with unresectable HCC who received lenvatinib. Methods Multivariate survival analysis was performed in 283 patients with unresectable HCC who received lenvatinib. In addition, the utility of PLR for predicting survival was clarified using an inverse probability weighting (IPW) analysis. Results Cumulative overall survival at 100, 200, 300, 400, and 500 days was 95.2, 83.8, 68.3, 60.3, and 49.9%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that PLR (≥150) [hazard ratio, 1.588; 95% confidence interval (CI), 1.039-2.428; P = 0.033], α-fetoprotein level, and Barcelona clinic liver cancer stage were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high PLR (P = 0.029). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that PLR (≥150) (hazard ratio, 1.396; 95% CI, 1.051-1.855; P = 0.021) was significantly associated with overall survival. Conversely, univariate analysis with Cox proportional hazards modeling adjusted only by IPW showed that PLR (≥150) (hazard ratio, 1.254; 95% CI, 1.016-1.549; P = 0.035) was significantly associated with progression-free survival. PLR values were not independently associated with therapeutic responses before or after IPW-adjusted logistic regression analysis. Conclusions PLR predicted overall survival in patients with unresectable HCC who received lenvatinib.

OBJECTIVE Tenofovir alafenamide is a new prodrug of tenofovir that allows for the treatment of patients with hepatitis B virus (HBV) at a lower dose than with tenofovir disoproxil fumarate, due to the more efficient delivery of tenofovir to hepatocytes. In this study, we compared entecavir and tenofovir alafenamide in terms of their ability to reduce hepatitis B surface antigen (HBsAg) in the same group of patients with HBV infection. METHODS During March and June 2018, 129 patients who received entecavir were switched to tenofovir alafenamide. Every 3- 6 months for 1 year before and after switching to tenofovir alafenamide, all patients underwent measurements of HBsAg, hepatitis core-related antigen (HBcrAg), calcium (Ca), inorganic phosphorus, and estimated glomerular filtration rate (eGFR). RESULTS The percent decline rate during the entecavir and tenofovir alafenamide phases at 6 months were 2.38% (-3.57 to 0.00) and -3.57% (-7.14 to 0.00), respectively, and those at 12 months were 3.03% (-6.57 to 0.00) and -5.56% (-7.41 to -2.50), respectively. HBsAg levels were reduced significantly more during the tenofovir alafenamide phase than during the entecavir phase (P

Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naive patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10–5; genotype 2 vs. 3, p = 3.28 × 10–5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4–5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512–148.550), p value (p = 4.06 × 10–5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153–13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% [79/190]) than CKD stage 1–3 (26.1% [319/1220]) patients (p = 2.00 × 10–5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10–18) patients. G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Tenofovir alafenamide (TAF), a new tenofovir prodrug, has been developed to circumvent the less favorable safety profile of tenofovir disoproxil fumarate (TDF). We investigated reductions in hepatitis B surface antigen (HBsAg) levels in patients with HBV infection who received continuous entecavir (ETV) monotherapy or sequential therapy with ETV and TAF.This retrospective cohort study included 286 patients who were divided into two groups: continuous ETV monotherapy (ETV group, n = 168) and sequential therapy with ETV and TAF (ETV-TAF group, n = 108). Factors associated with a 90% reduction in HBsAg levels were analyzed by a Cox proportional hazards model using a time-dependent covariate in both groups.In the multivariate Cox proportional hazards model, the ETV-TAF group [adjusted hazard ratio (aHR) 2.750; 95% confidence interval (CI), 1.265-3.405; P = 0.0038] and BMI ≤ 25.0 kg/m2 (aHR 0.520, 95% CI, 0.308-0.875; P = 0.0139) demonstrated a 90% reduction in HBsAg levels. HBsAg levels of patients in the TAF phase in the ETV-TAF group showed greater yearly percent reductions than those in the ETV group and those in the ETV phase in the ETV-TAF group (P = 0.0361 and P = 0.0022, respectively, Steel-Dwass test).HBsAg levels decreased more rapidly after patients switched from ETV to TAF. Switching to TAF may be an effective treatment option to reduce HBsAg levels.

We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2–22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495–2.452), Eastern Cooperative Oncology Group performance status ≥1 (HR, 1.429), and α-fetoprotein ≥400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p

AIM Direct-acting antivirals (DAAs) are currently available even for patients with decompensated cirrhosis. Reportedly, hepatic functional reserve improved in the short term after achievement of sustained virologic response (SVR). We aimed to clarify the outcomes after achievement of SVR in patients with decompensated cirrhosis who were treated by DAAs in real-world clinical practice. METHODS A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted in 86 patients with decompensated cirrhosis, who were evaluated for 48 weeks post-treatment. RESULTS The cohort included 8 patients with Child-Pugh class A, 56 with B, and 22 with C. The proportion of Child-Pugh class A patients increased from 9.1% at baseline to 44.1% at 48 weeks post-treatment, while that of class B and C patients decreased from 66.2% to 35.1% and from 24.7% to 14.3%, respectively. Among the patients with Child-Pugh class B and C, univariate analysis identified low total bilirubin, Child-Pugh score, Child-Pugh class B, ALBI score, and high serum albumin as factors associated with improvement to Child-Pugh class A. The optimal cut-off value of the factors for predicting improvement to Child-Pugh class A were 1.4 mg/dL for total bilirubin, 2.9 g/dL for serum albumin, 8 points for Child-Pugh score, and -1.88 for ALBI score. CONCLUSION Achievement of SVR with sofosbuvir/velpatasvir improved the liver functional reserve at 12 weeks post-treatment and maintained the stable effects until 48 weeks post-treatment in patients with decompensated cirrhosis. Specifically, the patients with less advanced conditions had the likelihood of improving to Child-Pugh class A at 48 weeks post-treatment. This article is protected by copyright. All rights reserved.

Ultrasound-guided attenuation parameter (UGAP) is recently developed for noninvasive evaluation of steatosis. However, reports on its usefulness in clinical practice are limited. This prospective multicenter study analyzed the diagnostic accuracy of grading steatosis with reference to magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), a noninvasive method with high accuracy, in a large cohort.Altogether, 1010 patients with chronic liver disease who underwent MRI-PDFF and UGAP were recruited and prospectively enrolled from 6 Japanese liver centers. Linearity was evaluated using intraclass correlation coefficients between MRI-PDFF and UGAP values. Bias, defined as the mean difference between MRI-PDFF and UGAP values, was assessed by Bland-Altman analysis. UGAP cutoffs for pairwise MRI-PDFF-based steatosis grade were determined using area under the receiver-operating characteristic curve (AUROC) analyses.UGAP values were shown to be normally distributed. However, because PDFF values were not normally distributed, they were log-transformed (MRI-logPDFF). UGAP values significantly correlated with MRI-logPDFF (intraclass correlation coefficient = 0.768). Additionally, Bland-Altman analysis showed good agreement between MRI-logPDFF and UGAP with a mean bias of 0.0002% and a narrow range of agreement (95% confidence interval [CI], -0.015 to 0.015). The AUROCs for distinguishing steatosis grade ≥1 (MRI-PDFF ≥5.2%), ≥2 (MRI-PDFF ≥11.3%), and 3 (MRI-PDFF ≥17.1%) were 0.910 (95% CI, 0.891-0.928), 0.912 (95% CI, 0.894-0.929), and 0.894 (95% CI, 0.873-0.916), respectively.UGAP has excellent diagnostic accuracy for grading steatosis with reference to MRI-PDFF. Additionally, UGAP has good linearity and negligible bias, suggesting that UGAP has excellent technical performance characteristics that can be widely used in clinical trials and patient care. (UMIN Clinical Trials Registry, Number: UMIN000041196).

OBJECTIVE Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD). METHODS A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH. RESULTS The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4%, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7% (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of

Background/Aim: Few studies have examined the details of nutritional status in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing systemic chemotherapy with lenvatinib. We evaluated the prognostic/predictive value of nutritional status using Onodera’s prognostic nutritional index (O-PNI) for overall survival among patients with u-HCC treated with lenvatinib. Methods: Three-hundred and seventy-five u-HCC patients treated with lenvatinib were enrolled (median age 72 years; Child-Pugh class A/B/C: n = 312/60/3; BCLC stage A/B/C/D: n = 2/159/212/2). We examined median survival time (MST) and time to progression (TTP) in all patients (n = 375), prognosis according to the O-PNI (high/low: >40/≤40) in 298 patients with lymphocyte findings, and the prognostic/predictive values of Child-Pugh stage, albumin-bilirubin (ALBI)/modified ALBI (mALBI) grade, and O-PNI for Chemotherapy grade (OPNIC grade 1/2/3: O-PNI >40/≤40 to >36/≤36). Results: The MST and TTP were 16.6 and 8.0 months, respectively. The MST and TTP according to the O-PNI (>40/≤40) were “not reached” (NR)/12.4 months (p < 0.001) and 10.0/6.1 months (p = 0.012), respectively. There was a good correlation noted between ALBI score and O-PNI (r = −0.939, p < 0.001). The predictive value of the O-PNI for mALBI grade 2a was 36.0 (specificity/sensitivity = 0.894/0.942; area under the curve [AUC] = 0.978), while that for mALBI grade 1 was 39 (specificity/sensitivity = 0.920/0.929; AUC = 0.972), which was very similar to a high O-PNI. The MST analyzed with the OPNIC in the 298 patients was NR/16.2/10.4 months for OPNIC grade 1/2/3 (p < 0.001), respectively, and the c-index was 0.632, the same as that for mALBI grade (0.632), while that for Child-Pugh class was 0.571. Conclusions: OPNIC grading might have a potential for easy substitution of mALBI grading. A good nutritional status (OPNIC grade 1) or mALBI grade 1 is the best indication for lenvatinib use, while with an OPNIC grade 3, lenvatinib might be not suitable.

Glypican‐3 (GPC3) is a cancer antigen expressed in approximately 80% of hepatocellular carcinomas (HCC) and is secreted into the blood. To confirm the effectiveness of GPC3 as a biomarker in HCC, we analyzed the relationship between GPC3 expression levels in cancer cells and in blood in 56 patients with HCC. Preoperative plasma GPC3 levels were determined with an immunoassay, and expression of GPC3 in resected tumors was analyzed by immunohistochemical staining. Median plasma GPC3 level in all HCC cases was 4.6 pg/mL, and tended to be higher in patients with hepatitis C virus (HCV)‐related HCC (HCV group) (9.9 pg/mL) than in patients with hepatitis B virus (HBV)‐related HCC (HBV group) (2.6 pg/mL) or in those without virus infection (None group) (3.0 pg/mL), suggesting that the virus type most likely influences GPC3 secretion. Median percentage of GPC3+ cells in tumors was also higher in the HCV (26.2%) and HBV (11.1%) groups than in the None group (4.2%). In the HCV group, there was a positive correlation between the two parameters (r = 0.66, P 10% GPC3+ cells in a tumor if the cut‐off value was 6.8 pg/mL (sensitivity 80%, specificity 100%; area under the curve 0.875, 95% confidence interval 0.726‐1) in the HCV group. Plasma concentration of GPC3 could be a predictive marker of tumoral GPC3 expression in patients with HCV‐related HCC, suggesting a useful biomarker for immunotherapies targeting GPC3, although larger‐scale validations are needed., Glypican‐3 (GPC3) is a cancer antigen expressed in approximately 80% of hepatocellular carcinomas (HCC) and is secreted into the blood. We analyzed the relationship between GPC3 expression levels in cancer cells and in blood in 56 patients with HCC. In conclusion, plasma concentration of GPC3 could be a predictive marker of tumoral GPC3 expression in patients with HCV‐related HCC, suggesting a useful biomarker for immunotherapies targeting GPC3.

BACKGROUND In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. METHODS In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. RESULTS Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. CONCLUSION The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naive, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

Background: Transcatheter arterial chemoembolization (TACE) is the standard therapy for intermediate-stage (IM) hepatocellular carcinoma (HCC). However, IM-HCC includes various clinical conditions, and various therapies were conducted in practice. In this study, we retrospectively analyzed the actually conducted treatments for IM-HCC and their efficacies to elucidate the treatment strategies suitable for IM-HCC. Methods: This study included 627 IM-HCC of 5,260 HCC from 9 hospitals. We examined the treatment strategies of these patients and analyzed the efficacy of each therapy with the Cox proportional hazard model and propensity score-matched analysis. Results: Liver resection, radiofrequency ablation (RFA), and TACE were performed in 165, 108, and 351 patients, respectively. Liver resection and RFA were preferably selected in cases of Barcelona Clinic Liver Cancer (BCLC)-B1/B2, and patient survival was significantly longer than in those treated with TACE (p< 0.0001). However, no beneficial effect of these active therapies was observed in cases of BCLC-B3/B4. Multivariate analysis revealed that surgical resection (hazard ratio = 0.384) and RFA (hazard ratio = 0.597) were negative risk factors for survival. Propensity score-matching analysis revealed that ­survival of RFA-treated patients was longer than that of TACE-treated patients (p = 0.036). Conclusion: RFA and surgical resection were effective for IM-HCC, particularly in BCLC-B1/B2 cases.

Background/Aim: Post-progression treatment following tyrosine-kinase inhibitor (TKI) failure in patients with unresectable hepatocellular carcinoma (u-HCC) is important to prolong post-progression survival (PPS), which has a good correlation with overall survival (OS). This study aimed to elucidate the clinical features of progressive disease (PD) in patients treated with lenvatinib (LEN). Materials/Methods: From March 2018 to June 2019, 156 u-HCC patients with Child-Pugh A were enrolled (median age: 71 years, Child-Pugh score 5:6 = 105:51, BCLC A:B:C = 8:56:92, modified albumin-bilirubin grade (mALBI) 1:2a:2b = 59:42:55, past history of sorafenib:regorafenib = 57:17). Clinical features were retrospectively evaluated. Results: The median observation period was 8.5 months. Median OS was not obtained, while median time to decline to Child-Pugh B (CPB) was 11.4 months, median time to progression (TTP) was 8.4 months, and the period of LEN administration was 7.3 months. When we compared predictive values for time to decline to CPB based on Child-Pugh score and mALBI, values for Akaike information criterion (AIC) score and c-index of mALBI were superior as compared to Child-Pugh score (AIC: 592.3 vs. 599.7) (c-index: 0.655 vs. 0.597). Of the 73 patients with PD, 32 (43.8%) showed no decline to CPB or death. After excluding 3 without alpha-fetoprotein data at PD determination, only 14 (20.0%) of 70 showed REACH-2 eligibility. Non-mALBI 1/2a at the start of LEN was a significant risk factor for decline to CPB during LEN treatment (HR 2.552, 95% CI: 1.577–4.129; p < 0.001). Conclusion: Introduction of TKI therapy including LEN for u-HCC patients with better hepatic function (mALBI 1/2a: ALBI score ≤–2.27), when possible, increases the chance of undergoing post-progression treatment, which can improve PPS.

INTRODUCTION:It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).METHODS:This retrospective cohort study analyzed an international consortium that encompas

Background Intrahepatic non-hypervascular hypointense nodules (NHHNs) detected during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have the potential to transition into typical hypervascular hepatocellular carcinoma (HCC). However, the incidence and risk factors for the emergence of these nodules in patients with chronic hepatitis C virus (HCV) infection are unknown. Aim To investigate the incidence and risk factors for NHHNs in patients with chronic HCV infection in a longitudinal follow-up study METHODS: EOB-MRI was performed in 608 patients with chronic HCV infection and no history of HCC. The characteristics of patients with and without NHHNs were compared. In patients without NHHNs at baseline, the incidence of NHHN emergence and associated risk factors were analysed. Results NHHNs were detected at baseline in 93 of 608 patients (15.3%). Among 515 patients without NHHNs at baseline, the 1-year, 3-year and 5-year incidence of NHHN emergence was 1.8%, 9.8% and 16.4%, respectively. Only FIB-4 index was independently associated with the emergence of NHHNs in multivariate analyses. Whereas NHHNs emerged in 24.1% of patients with FIB-4 index ≥ 3.25 at 5 years, none emerged in patients with FIB-4 index Conclusion In patients with chronic HCV infection, advanced liver fibrosis is an important risk factor for the presence or emergence of NHHNs.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan.

Background Long‐term prognosis of patients with chronic hepatitis C infection (HCV) remains incompletely characterized. We investigated the long‐term prognosis of liver disease in patients with chronic HCV infection who have not received antiviral therapy. Methods A total of 2304 patients with chronic HCV who were not received interferon‐based therapy were included. Results In the assessment of 1‐year disease state of liver transition probabilities, progression to chronic hepatitis occurred in 12% to 14% of patients across all age groups in male asymptomatic carriers. In male patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (7.6%) and ≥70 age groups (9.6%). In addition, in male patients with cirrhosis, HCC development occurred in approximately 5% of patients over the age of 40. In female asymptomatic carriers, progression to chronic hepatitis was observed in 6% to 14% of patients across all age groups. In female patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (8.7%) and ≥70 (7.4%) age groups. In addition, in female patients with cirrhosis, HCC development occurred in 0.9% to 3.3% of patients over the age of 50. Under assumptions of either chronic hepatitis or asymptomatic carrier state at age 40 as the starting condition for simulation over the following 40 years, the probability of HCC gradually increased with age and was higher in male patients. Conclusions There is a risk of cirrhosis or HCC development in HCV patients with not only chronic hepatitis but the asymptomatic carrier state as well., Highlight Yearly transition probabilities for each liver state (asymptomatic carrier, chronic hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]) were calculated using a Markov chain model.Poor liver disease outcomes such as the development of cirrhosis or HCC are possible not only in patients with chronic hepatitis but also in patients who are asymptomatic carriers at age ≥40 years.

The severity of liver fibrosis is strongly associated with prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated clinical risk factors for progression of liver fibrosis in patients with NAFLD.This study included 1562 middle-aged (36-64 years) patients with NAFLD and less severe liver fibrosis (fibrosis-4 index 1.3).During follow-up, 186 patients progressed to advanced fibrosis (fibrosis-4 index 2.67). The 3-, 5-, 7-, and 10-year cumulative incidence of progression to advanced fibrosis was 4.4%, 6.7%, 11.0%, and 16.7%, respectively. In the univariate analysis, age, albumin concentration, and type 2 diabetes mellitus (T2DM) were significantly associated with progression to advanced fibrosis. Multivariate analysis with adjustment for age, smoking, body mass index, albumin, estimated glomerular filtration rate, dyslipidemia, T2DM, and steatosis showed that age ≥ 50 years (hazard ratio [HR], 2.121; 95% confidence interval [CI], 1.462-3.076; P 0.001), albumin concentration 4.2 g/dL (HR, 1.802; 95% CI, 1.285-2.528; P 0.001), and the presence of T2DM (HR, 1.879; 95% CI, 1.401-2.520; P 0.001) were independently associated with progression to advanced fibrosis. Conversely, degree of steatosis was not associated with progression to advanced fibrosis. The respective 3-, 5-, 7-, and 10-year cumulative incidence of progression to advanced fibrosis was 3.6%, 5.0%, 8.2%, and 12.9% in patients without T2DM (n = 1077) and 6.1%, 10.4%, 16.7%, and 24.0% in patients with T2DM (n = 485) (P 0.001).Type 2 diabetes mellitus is associated with progression to advanced liver fibrosis in middle-aged NAFLD patients, even those with less severe liver fibrosis.

Little is known about the course of elderly patients with persistent hepatitis C virus (HCV) infection. We investigated the course of HCV infection in this patient population. Among 9,126 HCV antibody-positive patients who visited our hospital between 1995 and 2015, there were 453 patients with continuous follow-up who survived to age 80. They were included in the study following the inclusion criteria: confirmed persistent detection of HCV RNA, no HCV eradication if anti-HCV therapy occurred before enrollment, and no development of hepatocellular carcinoma (HCC) before enrollment. For all study patients, baseline was defined as the date when they turned 80. Mortality rates after the age of 80 years and cause of death were analyzed. During the study period, 155 patients (34.2%) died. Median survival time (MST) after age 80 was 8.8 years, which was comparable to that of the general population (10.1 years). Among 155 deceased patients, the majority (115 patients, 74.2%) died due to non-liver-related disease, followed by HCC (28 patients, 18.1%) and liver-related disease other than HCC (12 patients, 7.7%). Patients with advanced liver fibrosis (FIB-4 index > 3.25, n = 245) had shorter MST than patients with mild liver fibrosis (FIB-4 index ≤ 3.25, n = 208) (7.1 vs. 10.2 years; p = 0.020) due to a higher mortality rate from liver-related complications, including HCC. Most elderly HCV patients die from non-liver-related disease, especially those with less advanced liver fibrosis.

Background/aim We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u‐HCC) by investigating real‐world clinical features of patients. Materials/methods One hundred fifty two u‐HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child‐Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin‐bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively. Results Overall‐response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine‐kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649‐13.02, P = 0.004) in Cox‐hazard multivariate analysis. In patients with Child‐Pugh A, c‐index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m2, P

AIMS Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. METHODS We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription-polymerase chain reaction (PCR). RESULTS Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P

Hepatocellular Carcinoma (HCC) is the fourth most common cause of cancer deaths worldwide, and its early detection is a critical determinant of whether curative treatment is achievable. Early stage HCC is typically asymptomatic. Thus, screening programmes are used for cancer detection in patients at risk of tumour development. Radiological screening methods are limited by imperfect data, cost and associated risks, and additionally are unable to detect lesionsuntil they have grown to a certain size. Therefore, some screening programmes use additional blood/serum biomarkers to help identify individuals in whom to target diagnostic cancer investigations. The GALAD score, combining the levels of several blood biomarkers, age and sex, has been developed to identify patients with early HCC. Here we propose a Bayesian hierarchical model for an individual's longitudinal GALAD scores whilst in HCC surveillance to identify potentially significant changes in the trend of the GALAD score, indicating the development of HCC, aiming to improve early detection compared to standard methods. An absorbent two-state continuous-time hidden Markov model is developed for the individual level longitudinal data where the states correspond to the presence/absence of HCC. The model is additionally informed by the information on the diagnosis by standard clinical practice, taking into account that HCC can be present before the actual diagnosis so that there may be false negatives within the diagnosis data. We fit the model to a Japanese cohort of patients undergoing HCC surveillance and show that the detection capability of this proposal is greater than using a fixed cut-off point.

The impact of age on survival after hepatic resection for hepatocellular carcinoma (HCC) has not been thoroughly examined. We reviewed the data of a nationwide follow-up survey to determine the outcomes of hepatectomy for HCC in elderly patients.Management of malignant diseases in elderly patients has become a global clinical issue because of the increased life expectancy worldwide. Advancements in surgical techniques and perioperative management have reduced age-related contraindications for liver surgery.In all, 12,587 patients with HCC who underwent curative hepatic resection were included in this cohort study and classified according to age group [40-59 years (n = 2991), 60-74 years (n = 7576,), and ≥75 years (n = 2020)]. Clinicopathological features, long-term survival, and cumulative incidences of death after hepatic resection were compared among the groups. The cause-specific subdistribution hazard ratios for 3 types of death depending on age were also estimated.Preoperative liver function tests showed that the prothrombin activity and platelet count were higher in the ≥75-year age group than in the other age groups. The overall survival was significantly lower in the elderly than younger patients. However, recurrence-free survival was almost identical among the 3 groups. The cumulative incidence of HCC-related or liver-related death was almost identical among the 3 groups; however, the cumulative incidence of other causes of death was significantly different. The 60-year subdistribution hazard ratio for other causes of death increased remarkably with increasing age.Elderly patients in this nationwide survey had significantly worse overall survival after hepatectomy than middle-aged and young patients. The cumulative incidence of other causes of death in elderly patients was significantly different from that of HCC-related or liver-related death among the 3 groups.

BACKGROUND Patients with chronic hepatitis C are often complicated by chronic kidney disease (CKD). AIM To evaluate the efficacy, safety and pharmacokinetics of glecaprevir/pibrentasvir in patients with severe renal impairment. METHODS In a prospective, multicentre study involving 35 medical institutions, 832 genotype 1-3 patients were treated with glecaprevir/pibrentasvir. The efficacy and safety of glecaprevir/pibrentasvir were analysed for patients with CKD stage 4 or 5. Multivariate analysis was performed to identify the factors associated with the most frequently observed adverse event. In patients undergoing haemodialysis, a pharmacokinetic study was conducted to investigate the dialysability of the drugs: plasma samples were obtained from the arterial and venous sides of a dialyser to serially measure drug concentrations. RESULTS The subjects comprised 141 patients (32 with CKD stage 4 and 109 with CKD stage 5), of whom 100 were undergoing haemodialysis. All but one stage 5 CKD patients undergoing haemodialysis achieved sustained virologic response (99.3%). Adverse events were observed in 39.7% of subjects: pruritus was the most frequent (30.5%), and was significantly associated with haemodialysis. In the pharmacokinetic study, no arterial-venous differences in the plasma concentrations of glecaprevir/pibrentasvir were detected during the haemodialysis sessions. CONCLUSIONS Glecaprevir/pibrentasvir was highly effective and safe in chronic hepatitis C patients with severe renal impairment. Haemodialysis was associated with increased incidence of pruritus, which was the most frequent adverse event, but had little or no influence on the drug concentrations, which indicated that their dialysability is very low and that no dose modification is required in patients undergoing haemodialysis. (UMIN registration no. 000032073).

AIM Transient elastography (TE) is the gold standard for measurement of liver stiffness. The usefulness of shear wave elastographies (SWE) is well accepted. However, the measurement values cannot be equivalently compared because cut-off values for the diagnosis of liver fibrosis are different among those devices. We aimed to clarify correlations, to generate the regression equations between TE and SWEs, and to compare the diagnostic ability of each device to diagnose liver fibrosis. METHODS A total of 109 patients with chronic liver disease who underwent liver biopsy and same-day evaluation of liver stiffness using six ultrasound devices were analyzed. The diagnostic ability of liver stiffness from each ultrasound device and correlations between TE and each SWE were analyzed. RESULTS Liver stiffness measured by all six ultrasound devices increased significantly as liver fibrosis stage advanced (P