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Background: A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear., Objective: This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC., Patients and Methods: This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed., Results: After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007)., Conclusions: ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN., (© 2022. The Author(s).)

Health state utilities are global measurements of quality of life and have been used to evaluate health outcomes for the cost-utility analysis. This study aimed to estimate the health state utilities of patients with hepatitis B (HB), hepatitis C (HC), and hepatitis-related diseases in Japan. We distributed a self-administered questionnaire, including the EuroQol 5-Dimension 5-Level (EQ-5D-5L), to 9,952 outpatients with several clinical conditions caused by HB or HC virus infection (such as asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis) and estimated the condition-specific utilities of patients with HB or HC. In patients with more severe conditions (patients with acute hepatitis, fulminant hepatitis, and hepatocellular carcinoma and patients undergoing post-liver transplantation), the utilities of these severe conditions were estimated by three hepatitis experts using the EQ-5D-5L. The means of the utilities for acute hepatitis, fulminant hepatitis, asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, compensated cirrhosis, hepatocellular carcinoma stage I/II, hepatocellular carcinoma stage III/IV, and post-liver transplantation were 0.529, - 0.111, 0.904, 0.868, 0.845, 0.722, 0,675, 0,428, and 0.651 and 0.876, 0.821, 0.737, 0.671, 0.675, 0.428, and 0.651 in HB and HC, respectively. To the best of our knowledge, this is the first study that comprehensively assessed the health state utilities of patients with HB, HC and hepatitis-related conditions from a nationwide survey in Japan using the EQ-5D-5L., (© 2022. The Author(s).)

Background: Direct-acting antiviral (DAA) therapy enables a high rate of sustained virologic response (SVR) in patients with hepatitis C virus associated cirrhosis. However, the impact of DAA therapy on liver-related events in patients with cirrhosis is unclear., Methods: A total of 350 patients with compensated and decompensated cirrhosis administered DAA therapy at 29 Japanese hospitals were enrolled (Child-Pugh class A [CP-A]: 195 patients, CP-B: 131 patients and CP-C: 24 patients)., Results: The SVR rates of patients with CP-A, CP-B and CP-C were 96.9%, 93.1% and 83.3%, respectively (p = 0.006). Seventy patients developed hepatocellular carcinoma (HCC), and male sex, previous HCC treatment, platelet counts < 10.0 × 10 4 /µl, alpha-fetoprotein levels ≥ 5.0 ng/ml and CP-C were identified as significant factors in the multivariate analysis. The cumulative HCC occurrence/recurrence rates at 1 year were 6.6%/45.2%. The cumulative rate of decompensated cirrhotic events requiring hospital admission at 1 year was 9.1%. In the multivariate analysis, CP-B and CP-C were identified as significant factors. During the median observation period of 14.9 months, 13 patients died and one patient received liver transplant. The overall survival rates at 1 year were 98.4% in patients with CP-A, 96.4% in those with CP-B and 85.6% in those with CP-C (CP-A vs. CP-B: p = 0.759, CP-A vs. CP-C: p = 0.001 and CP-B vs. CP-C: p = 0.005)., Conclusions: HCC development and mortality in patients with CP-B were not different from those with CP-A. On the other hand, in patients with CP-C, the development of HCC and decompensated cirrhotic events requiring hospital admission, and death were frequent., Trial Registration: University Hospital Medical Information Network (UMIN000036150)., (© 2022. Japanese Society of Gastroenterology.)

Background: The age of patients with advanced hepatocellular carcinoma (HCC) eligible for molecular-targeted drug treatment is increasing. We assessed liver function after lenvatinib administration according to age in patients with advanced HCC., Patients and Methods: In this retrospective, multicenter, observational study, we reviewed the records of patients with HCC who received lenvatinib treatment (March 2018-March 2020). Liver function was measured using the Albumin-Bilirubin Index (ALBI)., Results: Of 119 patients, with a median age of 72.0 years, median overall survival was 15.3 months. Overall survival was significantly better in the group which maintained liver function (p=0.02). Older age (≥72 years) was associated with liver-function deterioration within 8 weeks (odds ratio=2.47, 95% confidence interval=1.06-5.75, p=0.035). The ALBI score was significantly higher in the older group at 4 and 8 weeks after lenvatinib administration., Conclusion: Lenvatinib administration was more likely to adversely affect liver function in older patients; dose adjustment should be considered in such patients., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: We examined serum kynurenine levels in patients with chronic hepatitis C virus infection, and the relationship between serum kynurenine and prognosis in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C., Methods: We retrospectively analyzed 604 patients with HCC diagnosed between January 1999 and December 2015, and 288 patients without HCC who were seen at the National Hospital Organization Nagasaki Medical Center between October 2014 and November 2017. The association between serum kynurenine and prognosis was evaluated using the Cox's proportional hazards regression analysis., Results: Patients with HCC had significantly higher values of serum kynurenine than patients without HCC (median: 557.1 vs. 464.2 ng/mL, p<0.001). Five-year survival rates of HCC patients with serum kynurenine ≥900 (n = 65), 600-899 (n = 194), and <600 ng/mL (n = 345) were 30.6%, 47.4%, and 61.4%, respectively (p = 0.001, log-rank test). Multivariate analysis identified serum kynurenine as an independent predictor for prognosis of HCC patients. The hazard ratio of serum kynurenine ≥900, and 600-899 compared with serum kynurenine <600 ng/mL were 1.91 (p<0.001) and 1.37 (p = 0.015), respectively., Conclusions: A high level of serum kynurenine correlated with poor prognosis of HCC. Serum kynurenine levels may be a novel biomarker to predict the prognosis of patients with HCC. The development of drugs that inhibit kynurenine production is expected to help improve the prognosis of patients with HCC., Competing Interests: The authors have declared that no competing interests exist.

Background: While achieving sustained virological response (SVR) following interferon-based or direct-acting antiviral agent (DAA) treatments reduces the incidence of hepatocellular carcinoma (HCC), an increase in unexpected early occurrence or recurrence of HCC after hepatitis C virus elimination by DAA treatments has been reported. We prospectively investigated the incidence and risk factors of HCC after DAA treatment in a large multicenter cohort in Japan., Methods: Patients with chronic hepatitis C with or without cirrhosis who were treated with DAAs and obtained SVR were enrolled. DAAs were administered for 3 or 6 months. A total of 2552 patients were enrolled., Results: Of these, 70 patients (2.7%) developed HCC. The 12-, 24-, and 36-month cumulative HCC incidences were 1.3%, 2.9%, and 4.9% in all patients; 2.5%, 5.2%, and 10.0% in those with cirrhosis; and 0.9%, 2.1%, and 2.9% in those without cirrhosis, respectively. Multivariate analysis revealed age, sex, gamma-glutamyl transpeptidase level, and fibrosis-4 index to be independent factors associated with HCC. Patients with these four factors had an approximately six-to-sevenfold increased risk for HCC development. Five patients with large and early tumor occurrence did not receive contrast imaging examinations before treatment., Conclusion: Although the results of our prospective study suggested that achieving SVR by DAA treatment reduces the incidence of HCC, HCC development still occurs. Careful follow-up is important in patients with risk factors.

Background: Previous studies have suggested an association between the use of direct-acting antiviral agents (DAAs) for treating hepatitis C virus (HCV) infection and the resulting decrease in the incidence of hepatocellular carcinoma (HCC); however, it is unclear whether DAAs prevent the recurrence of HCC after curative treatment for HCC. This study aimed to prospectively investigate HCC recurrence and its predictors after curative treatment for HCC., Methods: A total of 3012 patients with chronic HCV infection, with or without cirrhosis, who were treated with DAAs were enrolled between January 1, 2015 and January 31, 2017 as per the institutional review board approved study protocol at 15 institutions, including 10 university hospitals and five high-volume centers in the Kyusyu area of Japan. Of the 3012 patients, 459 patients who had HCC but were cured with surgery or ablation therapy (curative treatment) before the use of DAAs were included in the analysis., Results: During a mean follow-up period of 29.4 months, 217 (47.2%) patients developed HCC recurrence. The median time to recurrence was 34.0 months, and the 1-, 2-, and 3-year cumulative HCC recurrence rates were 27.1%, 43.4%, and 50.8%, respectively. The risk factors for HCC recurrence were the α-fetoprotein (AFP) level before DAA therapy (P = 0.0047) and the number of curative treatments for HCC before DAA therapy (P < 0.0001)., Conclusions: A high AFP level and multiple occurrences of HCC before DAA therapy are associated with a high risk for HCC recurrence after curative treatment. Follow-up after DAA therapy should include special attention to the abovementioned risk factors., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: We previously reported that the incidence of hepatocellular carcinoma (HCC) with non-viral etiologies increased rapidly between 1991 and 2010 in Japan., Methods: To update this investigation, we enrolled patients who were initially diagnosed as having non-B, non-C HCC at participating hospitals between 2011 and 2015. In addition to the patient characteristics investigated in the previous report, we also investigated the duration of alcohol consumption. The overall survival rate was analyzed using the Kaplan-Meier method, and the hazard function against the body mass index (BMI) was plotted using cubic splines., Results: A total of 2087 patients were enrolled. The proportion of patients with non-viral etiologies has continued to increase from 10.0% in 1991 to 32.5% in 2015. Patients were also older (median ages, 70-73 years) and more obese (median BMIs, 23.9-24.2 kg/m 2 ), and the proportions of patients with diabetes mellitus (46.1% to 51.6%), hypertension (42.7% to 58.6%), dyslipidemia (14.6% to 22.9%), and fatty liver (24.0% to 28.8%) had all increased significantly. There was a significant inverse relationship between the duration and the amount of daily alcohol consumption. The improvement in the overall survival was relatively small, with a decreased proportion of patients under surveillance (41.3% to 31.6%). A hazard function plot showed a curve similar to that in our previous report, with a lowest hazard of ~ 26 kg/m 2 ., Conclusions: The proportion of HCC patients with non-viral etiologies continues to increase in Japan. Lifetime total amount of alcohol consumption may be a risk factor.

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10 -4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10 -12 ; rs1110446: OR = 1.79, P = 1.66 × 10 -13 ; and rs3094137: OR = 1.73, P = 7.09 × 10 -9 ). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10 -4 ) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A * 33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

Measurement of Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) in serum was recently shown to be a noninvasive method to assess liver fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP values to predict the development of hepatocellular carcinoma (HCC) in patients who achieved a sustained virological response (SVR) by interferon treatment. For this purpose, we retrospectively analyzed 238 patients with SVR who were treated with interferon in our department. Serum WFA+-M2BP values were measured at pre-treatment (pre-Tx), post-treatment (24 weeks after completion of interferon; post-Tx), the time of HCC diagnosis, and the last clinical visit. Of 238 patients with SVR, HCC developed in 16 (6.8%) patients. The average follow-up period was 9.1 years. The cumulative incidence of HCC was 3.4% at 5 years and 7.5% at 10 years. The median pre-Tx and post-Tx WFA+-M2BP values were 1.69 (range: 0.28 to 12.04 cutoff index (COI)) and 0.80 (range: 0.17 to 5.29 COI), respectively. The WFA+-M2BP values decreased significantly after SVR (P < 0.001). The median post-Tx WFA+-M2BP value in patients who developed HCC was significantly higher than that in patients who did not (P < 0.01). Multivariate analysis disclosed that age (> 60 years), sex (male), pre-Tx platelet count (< 15.0×10(3)/μL), and post-Tx WFA+-M2BP (> 2.0 COI) were associated with the development of HCC after SVR. Conclusion: Post-Tx WFA+-M2BP (> 2.0 COI) is associated with the risk for development of HCC among patients with SVR. The WFA+-M2BP values could be a new predictor for HCC after SVR.

Unlabelled: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We evaluated the ability of WFA+-M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+-M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA+-M2BP, and the response to interferon (IFN) therapy. Serum WFA+-M2BP levels were significantly increased according to the progression of liver fibrosis stage (P<0.001). In each distinctive stage of fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+-M2BP. Multivariate analysis identified age>57 years, F4, AFP>20 ng/mL, WFA+-M2BP ≥4, and WFA+-M2BP 1-4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time-dependent areas under the receiver operating characteristic curve demonstrated that the WFA+-M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP., Conclusion: WFA+-M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy., (© 2014 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The incidence of hepatocellular carcinoma (HCC) continues to increase in Japan, but the clinical characteristics of Japanese patients with HCC have not been well described. The aim of this study was to determine the frequencies and utilities of elevated a-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels as biomarkers in cryptogenic HCC., Material/methods: A total of 2638 patients with HCC diagnosed between 1999 and 2010 in the Nagasaki Association Study of Liver (NASLD) were recruited for this study. The cause of HCC was categorized into 4 groups; HCC-B, HCC-C, HCC-BC, and HCC-nonBC. The significance of factors was examined for HCC-nonBC using logistic regression analysis in all patients., Results: Multivariate analysis identified age, sex, BMI, alcohol consumption, platelet count, AST, ALT, AFP, DCP, and TNM stage as independent and significant risk factors for HCC-nonBC. According to TNM stage, the median AFP levels in HCC-nonBC with TNM stages I, II, and III were significantly lower than in either HCC-B or HCC-C. In TNM stage IV, the median AFP level in HCC-nonBC was significantly lower than in either HCC-B or HCC-BC. The median DCP levels in HCC-nonBC with TNM stages I and II were significantly higher than those in either HCC-B or HCC-C. In TNM stage III, the median DCP level in HCC-nonBC was significantly higher than that in HCC-C., Conclusions: DCP was more sensitive than AFP for the diagnosis of early stage cryptogenic HCC. DCP should be used as the main serum test for cryptogenic HCC detection.

Background: We investigated whether the administration of maintenance doses of interferon prevented hepatocellular carcinoma (HCC) in patients with chronic hepatitis C., Methods: Study 1: A multicenter, retrospective, cooperative study was carried out to determine whether long-term administration of low-dose peginterferon alpha-2a (PegIFNα-2a) prevented HCC development in patients with chronic hepatitis C. In total, 594 chronic hepatitis C patients without a history of HCC were enrolled and treated with 90 μg PegIFNα-2a administered weekly or bi-weekly for at least 1 year. Study 2: HCC developed in 16 of 99 additional patients without PegIFNα-2a treatment during 3.8 years of observation. A propensity-matched control study was then carried out to compare the incidence of HCC between the 59 patients who received low-dose PegIFNα-2a (PegIFNα-2a group) and 59 patients who did not receive PegIFNα-2a treatment (control group), matched for sex, age, platelet count, and total bilirubin levels., Results: Study 1: HCC developed in 49 patients. The risk of HCC was lower in patients with undetectable hepatitis C virus RNA, ≤40 IU/L alanine aminotransferase (ALT), or ≤10 ng/L alpha-fetoprotein (AFP) 24 weeks after the start of therapy. Study 2: The incidence of HCC was significantly lower in the PegIFNα-2a group than in the control group., Conclusions: Low-dose and long-term maintenance administration of PegIFNα-2a decreased the incidence of HCC in patients with normalized ALT and AFP levels at 24 weeks compared with patients without normal ALT and AFP levels.

Background/aims: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH., Methods: The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years., Results: Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis., Conclusions: Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan., (© 2011 John Wiley & Sons A/S.)

Background: Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV)., Methods: A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received., Results: The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6-20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6-20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively., Conclusions: Not only high (>20 ng/mL), but also even slightly elevated (6-20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.

A 47-year-old otherwise healthy woman, presented elevation of alpha fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels at a general health checkup. Both HCV antibody and hepatitis B surface antigen were negative. A screening abdominal CT revealed no abnormal change. An abdominal MRI and repeated CT, however, revealed a 20-mm tumor adjacent to the inferior vena cava and adjacent to or involving the liver. A surgical resection of the tumor was performed. The tumor was adjacent to, but distinct from, the liver. The Capsule of the tumor was connected to the liver but it was distinct from hepatic, renal, and adrenal tissue. A histological examination yielded a diagnosis of moderately differentiated hepatocellular carcinoma, with positive staining of hepatocyte-specific antigen and AFP.

The incidence of hepatocellular carcinoma (HCC) in Japan is still increasing. The aim of the present study was to analyze the epidemiological trend of HCC in the Western area of Japan, Nagasaki. A total of 1,807 patients with HCC diagnosed at our two hospitals between 1981 and 2005 were consecutively recruited for this study. Cohorts of patients with HCC were categorized into five-year intervals. The etiology of HCC was categorized into four groups: HCC-B: HBsAg positive, HCVAb negative, HCC-C: HCVAb positive, HBsAg negative, HCC-BC: both of HBsAg and HCVAb positive and HCC-nonBC: both of HBsAg and HCVAb negative. The number and proportion of HCC-B cases decreased from 1986 to 1990 and thereafter stabilized, whereas those of HCC-C reached the peak from 1995 to 2000 and thereafter decreased. On the other hand, the number and ratio of the HCC-nonBC cases continued to increase in the whole period. The male/female ratio of HCC-C patients decreased from 6.4 in the period 1981-1985 to 1.9 in 2001-2005, indicating clearly the increase of female patients. On the other hand, the male/female ratio of other types of HCC patients did not change during the period. HCC patients rapidly increased from 1981 to 2000 and this increase was originated from that of HCC-C. The increase of the median age and the number of female patients with HCC-C was also demonstrated. The increase in the number and the proportion of the HCC-nonBC patients was also significant.

Hepatitis B virus (HBV) genotypes/subgenotypes and their related mutations in the HBV genome have been reported to be associated with hepatocellular carcinoma (HCC). To determine the HCC-associated mutations of the HBV genome in the entire X, core promoter, and precore/core regions, a cross-sectional control study was conducted comparing 80 Japanese patients infected with HBV C2 and suffering from HCC with 80 age-, sex-, and hepatitis B e antigen (HBeAg) status-matched patients without HCC (non-HCC group). Each HBeAg-positive group (31 with HCC; 29 without HCC) and HBeAg-negative group (49 with HCC; 51 without HCC) was also matched with respect to age and sex. The C1479, T1485, H1499, A1613, T1653, V1753, T1762/A1764, and A1896 mutations were frequent in this population. The prevalences of the T1653 mutation in the box alpha region and the V1753 and T1762/A1764 mutations in the basal core promoter region were significantly higher in the HCC group than in the non-HCC group (56% versus 30%, 50% versus 24%, and 91% versus 73% [P = 0.0013, P = 0.0010, and P = 0.0035, respectively]). The platelet count was significantly lower for the HCC group than for the non-HCC group (10.7 x 10(4) +/- 5.1 x 10(4) versus 17.3 x 10(4) +/- 5.1 x 10(4) platelets/mm(3) [P < 0.0001]). Regardless of HBeAg status, the prevalence of the T1653 mutation was higher in the HCC group (52% versus 24% [P = 0.036] for HBeAg-positive patients and 59% versus 33% [P = 0.029] for HBeAg-negative patients). In the multivariate analysis, the presence of T1653, the presence of V1753, and a platelet count of < or =10 x 10(4)/mm(3) were independent predictive factors for HCC (odds ratios [95% confidence intervals], 4.37 [1.53 to 12.48], 7.98 [2.54 to 25.10], and 24.39 [8.11 to 73.33], respectively). Regardless of HBeAg status, the T1653 mutation increases the risk of HCC in Japanese patients with HBV/C2.

Background/aims: The objective of this study was to evaluate the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in hepatocellular carcinoma (HCC) tissues., Methods: Forty surgically resected HCC tissues with adjacent non-tumorous liver tissues and 14 surgically resected, histologically normal liver tissues were used. The immunohistochemical expressions of the mPGES-1 protein in these HCC tissues and normal control livers were analysed. mPGES-1 mRNA expression was also analysed by the real-time polymerase chain reaction method using the same tissues., Results: Microsomal prostaglandin E synthase-1 was not expressed in hepatocytes but instead in vascular endothelial cells and bile duct epithelial cells in normal liver tissues. The mPGES-1 expression in HCC tissues was significantly greater than its expression in the non-tumorous tissues. All types of HCC expressed more mPGES-1 than normal or hepatitis livers, and the levels of mPGES-1 expression in poorly differentiated HCC were similar to the levels in well-differentiated HCC. The mPGES-1 mRNA expression paralleled its protein expression in these tumorous and non-tumorous tissues., Conclusions: The present study is the first to demonstrate a high expression of mPGES-1 in well-differentiated HCC as well as in poorly differentiated HCC. These findings suggest that mPGES-1 may play a role in the advanced as well as early stage of hepatocarcinogenesis.

Background and Aim: This study investigated the clinical features of hepatocellular carcinoma in patients with sustained virological response to interferon for hepatitis C viral (HCV) infection., Methods: A total of 7,715 patients with HCV infection were treated with interferon and followed up for more than 1 year after withdrawal of interferon in 64 Japanese hospitals and clinics between July 1988 and August 2001. Sustained virological response was obtained in 2,515 (32.6%) patients. Of these 2,515 patients, clinical data were collected for 38 patients in whom hepatocellular carcinoma developed. Sustained virological response was defined as HCV RNA negativity more than 6 months after the termination of interferon., Results: All patients were HCV RNA negative at the time of diagnosis of hepatocellular carcinoma. The median period until the detection of hepatocellular carcinoma was 4.7 years (range 1.4-9.0 years). There were significant improvements in hepatic function including serum albumin, aspartate aminotransferase, alanine aminotransferase, indocyanine green test, platelet count and histological activity grade in comparison with those before interferon therapy and at the onset of hepatocellular carcinoma. The maximum tumor size in patients without medical follow-up for 1 year or more (median: 60 mm) was significantly larger than in patients who were periodically followed up for 6 months or less (median: 25 mm) (P=0.002)., Conclusions: The present findings emphasize the importance of regular medical follow up of patients with HCV infection, as even patients showing a sustained virological response to interferon and in whom hepatic function has improved have the potential to develop hepatocellular carcinoma.

Aim: The beta-catenin has been recognized as a critical member of the Wnt signaling pathway and plays an important role in the generation/differentiation of many tissues. Inappropriate activation of this pathway has been implicated in carcinogenesis. The mechanism underlying the development as well as its prognosis of hepatocellular carcinoma (HCC) has remained unclear. The purpose of this study is to analyze the expression of beta-catenin in HCC in relation to histological grades and viral hepatitis backgrounds., Methods: Thirty-two sections were selected at random from autopsy and surgical cases of HCC. Immunohistologically, the location and positivity of beta-catenin expression in HCC was examined., Results: Normal hepatocytes did not express beta-catenin. In 78% of HCC beta-catenin was expressed at the membrane of the cells, with or without cytoplasmic and/or nuclear expression. The tumor cells with well- and moderately-differentiated grades expressed frequently at the membrane and cytoplasm compared with poorly-differentiated type. Nuclear expression of beta-catenin was prone to occur in the tumor cells of poorly-differentiated grade. There were 15% of hepatitis C virus (HCV) backgrounds with nuclear expression. In contrast, there was 38% with nuclear expression in hepatitis B virus (HBV) backgrounds. In nonB-nonC hepatitis, no case expressed nuclear beta-catenin., Conclusion: The beta-catenin expression in HCC cells was heterogeneous among types of hepatitis viral infection. Wnt signaling pathway might be deeply involved in less-differentiated HCC and HBV background.

Background/aims: In this study, we determined the frequencies of the genotypes associated with the polymorphism of the cytokines genes, and investigated their association with the risk of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers., Methods: Genetic polymorphism in the cytokines TNF-alpha, IFN-gamma, TGF-beta1, IL-6, and IL-10 were studied in 236 Japanese patients with HBV infection. The genetic polymorphisms of these cytokines were analyzed by polymerase chain reaction-sequence-specific primer (SSP)., Results: There was no statistically significant difference in the genetic polymorphisms of TNF-alpha, IFN-gamma, and IL-10 genes between HBV carriers with HCC and those without HCC. However, the TGF-beta1+29 (codon 10) C/C genotype was lower in HBV carriers with HCC than in those without HCC (HCC 14.6% vs non-HCC 31.9%). The association of HCC was significantly lower in HBV carriers with C/C genotype than in those with T/C or T/T genotype in position +29 of the TGF-beta1 gene., Conclusions: Our findings suggest that the genetic polymorphism in codon 10 of the TGF-beta1 gene may play a role in HCC development in patients with chronic HBV infection.

Background: Interferon (IFN) is expected to prevent the progression of hepatitis C virus infection to cirrhosis and the development of hepatocellular carcinoma (HCC), but there have been several reports of the development of HCC after a sustained response to IFN. Our aim was to elucidate the incidence and clinical features of, and risk factors for, HCC in sustained responders to IFN, taken for the treatment of chronic hepatitis C., Methods: We designed a retrospective cohort study conducted at 16 major Hospitals. The subjects were a total of 1056 patients showing sustained responses, 29 of whom developed HCC., Results: The incidence of HCC per 100 person-years was 0.56 (95% confidence interval, 0.35-0.76) in sustained responders. By the Cox proportional hazard model, we found that older age, higher serum aspartate aminotransferase level, and lower platelet count before IFN therapy were independent risk factors associated with the development of HCC. A risk index of HCC development, based on the coefficients of these risk factors, was used to classify patients into three groups, with low, intermediate, and high risk. The incidence rates of HCC for these three groups were 0.11, 0.44, and 1.98 per 100 person-years, respectively. The median period to the development of HCC was 4.6 years (range, 1.4-9.0 years), and there were no other specific clinical features of the HCC that developed in these patients., Conclusions: This study suggests that the risk of development of HCC is not completely eliminated in sustained responders to IFN. These findings may be useful in determining a follow-up strategy after a sustained response to IFN.

Background: Des-gamma-carboxy prothrombin (DCP) has been reported to be an important prognostic factor in patients with hepatocellular carcinoma (HCC). Recently, a monoclonal antibody, 19B7, which recognizes the Gla domain of DCP, has been identified. The 19B7 antibody recognizes an epitope different from that recognized by MU-3, which is another antibody against DCP. In this study, the authors investigated the measurement of DCP using the antibodies MU-3 and 19B7, respectively, as a prognostic factor for patients with HCC who had solitary, small tumors and or Child Stage A HCC., Methods: One hundred four patients with HCC who had solitary, small tumors or Child Stage A tumors were enrolled in the study between 1991 and 2001. All patients were treated and were followed for a mean of 3.2 years. The authors analyzed the correlation between the DCP Index (DCP measured by MU-3 and DCP measured by 19B7) and patient prognosis. The patients were classified into 3 groups based on their DCP Index: 1) DCP negative (DCP < 40 milli arbitrary unit (mAU)/mL)); 2) low DCP Index (DCP > or = 40 mAU/mL; MU-3:19B7 ratio, < 3.0; and 3) high DCP Index (DCP > or = 40 mAU/mL; MU-3:19B7 ratio, > or = 3.0)., Results: The survival rate for patients in the high DCP Index group was lower compared with the survival rate for patients in the DCP-negative group and was significantly lower compared with the survival rate for patients in the low DCP Index group. In a univariate Cox proportional hazards model, the positive factors were high DCP Index and low DCP Index. Among the positive predictive factors that were analyzed using a multivariate Cox proportional hazards model were age (hazard ratio, 3.27; P = 0.006), low DCP Index (hazard ratio, 2.87; P = 0.012), and high DCP Index (hazard ratio, 12.3; P < 0.0001)., Conclusions: The prognosis of patients who had a high DCP Index score was poorer compared with patients who had a low DCP Index score and patients who were classified as DCP negative. The authors concluded that the DCP Index is a prognostic indicator for patients with HCC., (Copyright 2003 American Cancer Society.)

Background: Hepatitis C virus (HCV) infection is a heterogeneous disease, the natural history of which remains controversial. There is solid evidence that chronic HCV infection is responsible for the occurrence of hepatocellular carcinoma (HCC). The aim of the current cohort study was to determine the rate of the development of HCC from the time of primary HCV infection and to assess the risk factors for the development of HCC in chronic posttransfusion hepatitis C patients., Methods: Four hundred sixty-nine patients with clinically compensated HCV, who had undergone a single blood transfusion comprised the current study cohort. Patients with other risk factors for chronic liver disease were excluded. All patients were referred to the liver center at the National Nagasaki Medical Center between December 1980 and December 1998 and were followed prospectively until the end of the analysis (June 2000)., Results: Follow-up data were obtained for 445 patients. The mean duration from HCV infection to the end of the observation was 28 years. Fifty-two patients (11.1%) progressed to HCC. The mean duration from the time of blood transfusion to the diagnosis of HCC was 31 years. Multivariate Cox regression analyses revealed age, fibrosis, duration from HCV infection to study entry, and alcohol consumption to be the independent factors affecting the development of HCC. The risk of developing HCC in patients age > or = 56 years was increased 7.8-fold compared with that in patients age < 56 years. The mean age of patients at the time of HCC diagnosis was 65 years (range, 58-79 years)., Conclusions: At the time of diagnosis, 92% of the 52 HCC patients were age > 60 years and 38 of the HCC patients (73%) were in their 60s. There was a significantly negative correlation between the duration from HCV infection to the development of HCC and the age of the patient at the time of infection (correlation coefficient = 0.702; P < 0.0001; Y = 61.1-0.82X), indicating that the age of patients, rather than the duration of HCV infection, is more significant for HCC development in patients with posttransfusion HCV. Moreover, these data may contribute to the design of an optimal follow-up schedule for patients with posttransfusion HCV., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10662)

Chronic hepatitis C virus (HCV) infection is associated with a spectrum of liver diseases and a proportion of chronic cases progress through cirrhosis to hepatocellular carcinoma (HCC). The viral and host factors that are important in the clinical and histological progression of HCV infection are unclear. We investigated the effect of moderate (<80 g/day) and heavy (>80 g/day) alcohol intake on the histological and clinical progression of HCV infection and their associated risk of hepatic cancer in a group of Japanese patients. A number of other variables were assessed to evaluate their impact on disease progression. We recruited 120 patients with HCV infection and categorized them into four groups, based on alcohol consumption pattern. All clinical and biochemical profiles were collected from recorded files. Liver biopsies were analysed for the degree of fibrosis, presence of cirrhosis and histological activity of necroinflammation. Hepatic tumours were detected by the follow-up imaging analysis. There was no difference in the age, length of exposure to HCV infection and HCV RNA serum levels in the alcohol and alcohol-free groups. The histological grading of necroinflammation, serum levels of alanine aminotransferase and HCV RNA did not have any correlation with each other in the alcohol and alcohol-free group. There was a 1.5-2. 5-fold greater risk of liver cirrhosis and hepatocellular carcinoma in the alcohol intake group compared to the alcohol-free group. Kruskal-Wallis analysis among four groups demonstrated a significant transition to fibrosis (P < 0.05) for alcoholics with HCV infection. The increased risk of liver cancer in the alcohol group is independent of size and growth of tumours. The clinical manifestations of gastro-oesophageal variceal bleeding, ascites, and encephalopathy were also higher in the alcohol intake group. Alcohol consumption is an important risk factor in the histological and clinical progression of HCV infection and has no relation with HCV replication. Chronic HCV carriers should avoid excessive alcohol intake to reduce the acceleration of liver disease and risk of liver cancer.

Background/aim: Time-dependent intrahepatic recurrence of hepatocellular carcinoma is frequent after different treatment modalities, including percutaneous ethanol injection. We attempted to prospectively analyze the possible risk factors for early intrahepatic recurrence of hepatocellular carcinoma after percutaneous ethanol injection., Methods: Sixty-five patients with 65 solitary hepatocellular carcinoma nodules < or =6 cm in diameter underwent initial treatment with percutaneous ethanol injection and were examined to ascertain the factors related to recurrence, local and distant, within the liver. A number of clinical and tumor parameters were analyzed., Results: Cumulative overall recurrence rates 12 and 24 months after percutaneous ethanol injection were 15.6% and 45.1%, respectively, irrespective of clinical and tumor parameters. Overall recurrence rates 12 and 24 months after percutaneous ethanol injection were 40% and 67.5%, for tumor > or =3 cm and 7.5% and 37.5%, for tumor <3 cm. Cumulative local recurrence rates at 12 and 24 months were 26.3% and 43.5%, respectively, for tumor > or =3 cm and 11.7% and 18.2%, respectively, for tumor <3 cm. The log-rank test indicated that a tumor size of > or =3 cm and the presence of capsule for a tumor of <3 cm in diameter were significant risk factors for intrahepatic recurrence. A pretreatment serum PIVKA-II level of > or =0.02 AU/ml was the only clinical parameter associated with overall recurrence (p=0.0041) and distant intrahepatic recurrence (p=0.0307). Distant intrahepatic recurrence rates 12 and 24 months after percutaneous ethanol injection were 22.5% and 31.4%, respectively, for PIVKA-II levels of > or =0.02 AU/ml and 8% and 17.8%, for PIVKA-II of <0.02 AU/ml. Cox's proportional hazard model identified that tumor size, tumor capsule and baseline serum PIVKA-II levels were independently related to intrahepatic recurrence., Conclusions: These data demonstrate that tumor size and peritumoral capsule were associated with overall and local recurrence of hepatocellular carcinoma. Moreover, pretreatment serum levels of PIVKA-II can indicate the risk of early intrahepatic recurrence and may assist in patient selection and appropriate therapy.