The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan.

BACKGROUND: We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC). METHODS: Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases. RESULTS: In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased. CONCLUSIONS: Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.

Factors affecting the recovery of hepatic reserve after sustained virologic response by direct-acting antiviral agents in chronic hepatitis C virus-infected patients.

BACKGROUND AND AIM: Since the advent of direct-acting antiviral (DAA) therapy, the total eradication of hepatitis C virus has been achievable with the recovery of hepatic reserve after achievement of sustained virologic response (SVR). Hence, here, we examined the factors affecting the recovery of hepatic reserve. METHODS: We followed up 403 patients (male: 164, female: 239; genotype 1: 299, genotype 2: 104; median age: 69 years) for at least 3 years after they achieved SVR to DAA therapy. Of these patients, 75 (18.6%) had a history of hepatocellular carcinoma (HCC). Biochemical tests were periodically performed, and the hepatic reserve was evaluated based on the albumin-bilirubin grade. We examined background factors such as age, biochemical test results, HCC occurrence and portosystemic shunt by computed tomography. RESULTS: At the start of treatment, the albumin-bilirubin grades were grades 1, 2, and 3 in 241, 157, and 5 patients, respectively, and 3 years later, 117 of 162 (72%) patients with grade 2 or 3 improved to grade 1. Multivariate analysis identified the HCC occurrence after achievement of SVR (hazard ratio [HR]: 3.08, P < 0.0138), male sex (HR: 3.45, P = 0.0143), hemoglobin level of <11.5 g/dL (HR: 4.19, P = 0.0157), the presence of a portosystemic shunt (HR: 3.07, P = 0.0349), and alanine aminotransferase levels <45 U/L (HR: 2.67, P = 0.0425) as factors inhibiting improvement to grade 1. However, old age was not an inhibitory factor. CONCLUSION: Our results demonstrate that hepatic reserve could be improved even in elderly patients over a long course of time.

PNPLA3 and HLA-DQB1 polymorphisms are associated with hepatocellular carcinoma after hepatitis C virus eradication.

BACKGROUND: Even though both interferon (IFN)-based and direct-acting antiviral (DAA) therapies against hepatitis C virus (HCV) reduce the risk of hepatocellular carcinoma (HCC), post-sustained virological response (SVR) patients remain at elevated risk of HCC. METHODS: A total of 4620 patients who achieved SVR were enrolled in this retrospective cohort study. After excluding patients who had a history of HCC or developed HCC within 1 year and whose follow-up period was less than 1 year and who were positive for HBsAg, we investigated the association between clinical characteristics and HCC development after SVR in the remaining 3771 patients. RESULTS: Median observation period was 41 months. We confirmed known risk factors. In addition, we found that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. Finally, we propose an estimation model for the incidence of HCC after SVR. Based on gender, FIB-4 index, AFP, and PNPLA3 polymorphism, about 18% of all patients were classified as having high risk, with a cumulative incidence rate (CIR) at 5 years of 16.5%. Another 17% were classified as having moderate risk with a CIR of 7.6%. The remaining 65% showed a CIR of 0.5%. The effect of PNPLA3 polymorphism might be more pronounced in patients with lower body mass index (BMI) and without diabetes mellitus compared to those with higher BMI and diabetes mellitus. CONCLUSIONS: We demonstrated that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. These findings might be useful to inform risk stratification for HCC surveillance after SVR.

Bile duct adenoma: imaging features and radiologic-pathologic correlation.

PURPOSE: This study aimed to reveal characteristic imaging features of bile duct adenoma (BDA) by radiologic-pathologic correlation. MATERIALS AND METHODS: We retrospectively analyzed pathological and imaging findings of seven patients with BDA. RESULTS: The median maximum diameter of BDA was 5.5 mm. Six lesions had hemispheric morphology. Seven lesions were located in the liver subcapsular region, and proliferation of bile ductules without atypia and fibrous stroma was observed. Two lesions had different microscopic findings. In both lesions, proliferation of bile ductules without atypia was observed in the margin. In one lesion, the percentage of fibrosis and hyalinization was higher at the center than at the margin. In the other lesion, inflammatory cell infiltration was observed in the center. On contrast-enhanced imaging, BDAs showed hypervascularity in the early phase and prolonged enhancement in the delayed phase. On contrast-enhanced multidetector computed tomography during hepatic arteriography, two lesions showed ring-like enhancement in the first phase and prolonged enhancement in the second phase. These were the different histopathologic features of BDAs between the margin and center. CONCLUSION: Bile duct adenoma can be characterized as a small semicircular lesion located in the liver subcapsular region, which show hypervascularity in the early phase with prolonged enhancement.

Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease.

Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson-stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0-3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis-4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0-3, suggesting a heterogeneity in disease severity within NAFLD-related cirrhosis. (Hepatology Communications 2018;2:58-68).

The prognosis of hepatitis B inactive carriers in Japan: a multicenter prospective study.

BACKGROUND: Hepatitis B e antigen (HBeAg)-negative inactive carriers, the majority of hepatitis B virus (HBV) carriers, are considered to have a good prognosis. The definition of the inactive HBV carrier state has been based on HBV DNA and alanine aminotransferase (ALT) levels. Here we conducted a prospective study involving 18 hospitals to clarify the prognosis of HBeAg-negative inactive carriers. METHODS: Three hundred eighty-eight HBeAg-negative inactive carriers at the baseline were observed prospectively from January 2011 to November 2015. We evaluated the primary end point, defined as the development of cirrhosis, hepatocellular carcinoma (HCC), or liver-related death. Also, we analyzed the factors associated with inactive carrier dropout and markedly increased levels of ALT or HBV DNA or both during the follow-up period. RESULTS: At the baseline, the mean age was 57.5 ± 13.1 years and 42 % of patients were male. No individual developed cirrhosis, HCC, or liver-related death during the follow-up period (1035 ± 252 days). Loss of inactive carrier status was seen in 75 patients (19.3 %). Factors associated with failure to meet the inactive carrier criteria in the multivariate analysis were the levels of ALT (hazard ratio 1.13, 95 % confidence interval 1.07-1.19, p < 0.001), HBV DNA (hazard ratio 2.70, 95 % confidence interval 1.63-4.49, p < 0.001), and γ-glutamyl transpeptidase (hazard ratio 1.01, 95 % confidence interval 1.00-1.02, p = 0.003) at the baseline. CONCLUSIONS: Most inactive carriers in Japan had a good prognosis. However, despite the short observation period, some patients had loss of IC status. The long-term prognosis of inactive carriers remains unclear; therefore, careful follow-up of inactive carriers is needed.

Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease.

BACKGROUND: Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study were (1) to measure serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis. METHODS: Serum WFA(+)-M2BP values were retrospectively evaluated in 289 patients with NAFLD who had undergone liver biopsy. Histological findings were evaluated by three blinded, experienced liver-specific pathologists. RESULTS: For stages 0 (n = 35), 1 (n = 113), 2 (n = 49), 3 (n = 41), and 4 (n = 51) of liver fibrosis, the serum WFA(+)-M2BP cutoff indexes were 0.57, 0.70, 1.02, 1.57, and 2.96, respectively. Multivariate regression analysis showed that serum WFA(+)-M2BP values were associated with the stage of fibrosis (≥stage 2). The areas under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum WFA(+)-M2BP were 0.876, 85.9, and 74.6%, respectively, for severe fibrosis (≥stage 3) and were 0.879, 74.6, and 87.0%, respectively, for cirrhosis. When compared with six non-invasive conventional markers, serum WFA(+)-M2BP had the greatest AUROC for diagnosing severe fibrosis and cirrhosis. CONCLUSIONS: Serum WFA(+)-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.

New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia.

Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09 ∶ 01 (P = 1.36 × 10(-6); OR= 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02 ∶ 01 (P = 5.22 × 10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02 ∶ 01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55 × 10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.

Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-κB/mitogen-activated protein kinase.

Heat shock factor 1 (HSF1), a major transactivator of stress responses, has been implicated in carcinogenesis in various organs. However, little is known about the biological functions of HSF1 in the development of hepatocellular carcinoma (HCC). To clarify the functional role of HSF1 in HCC, we established HSF1-knockdown (HSF1 KD) KYN2 HCC cells by stably expressing either small hairpin RNA (shRNA) against HSF1 (i.e. HSF1 KD) or control shRNA (HSF1 control). Tumorigenicity was significantly reduced in orthotopic mice with HSF1 KD cells compared with those with HSF1 control cells. Reduced tumorigenesis in HSF1 KD cells appeared attributable to increased apoptosis and decreased proliferation. Tumor necrosis factor-α-induced apoptosis was increased in HSF1 KD cells and HSF1(-/-) mouse hepatocytes compared with controls. Decreased expression of IκB kinase γ, a positive regulator of nuclear factor-κB, was also observed in HSF1 KD cells and HSF1(-/-) mouse hepatocytes. Furthermore, expression of bcl-2-associated athanogene domain 3 (BAG3) was dramatically reduced in HSF1 KD cells and HSF1(-/-) mouse hepatocytes. We also found that epidermal growth factor-stimulated mitogen-activated protein kinase signaling was impaired in HSF1 KD cells. Clinicopathological analysis demonstrated frequent overexpression of HSF1 in human HCCs. Significant correlations between HSF1 and BAG3 protein levels and prognosis were also observed. In summary, these results identify a mechanistic link between HSF1 and liver tumorigenesis and may provide as a potential molecular target for the development of anti-HCC therapies.

A serum "sweet-doughnut" protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis.

Although liver fibrosis reflects disease severity in chronic hepatitis patients, there has been no simple and accurate system to evaluate the therapeutic effect based on fibrosis. We developed a glycan-based immunoassay, FastLec-Hepa, to fill this unmet need. FastLec-Hepa automatically detects unique fibrosis-related glyco-alteration in serum hyperglycosylated Mac-2 binding protein within 20 min. The serum FastLec-Hepa counts increased with advancing fibrosis and illustrated significant differences in medians between all fibrosis stages. FastLec-Hepa is sufficiently sensitive and quantitative to evaluate the effects of PEG-interferon-α/ribavirin therapy in a short post-therapeutic interval. The obtained fibrosis progression is equivalent to -0.30 stages/year in patients with sustained virological response, and 0.01 stages/year in relapse/nonresponders. Furthermore, long-term follow-up of the severely affected patients found hepatocellular carcinoma developed in patients after therapy whose FastLec-Hepa counts remained above a designated cutoff value. FastLec-Hepa is the only assay currently available for clinically beneficial therapy evaluation through quantitation of disease severity.

Chronic hepatitis B in patients coinfected with human immunodeficiency virus in Japan: a retrospective multicenter analysis.

A nationwide survey in Japan revealed that about 6 % of human immunodeficiency virus (HIV)-positive patients are coinfected with hepatitis B virus (HBV). To further analyze the features of liver disease in HIV/HBV-coinfected patients, we analyzed 252 patients from six hospitals in the HIV/AIDS (acquired immunodeficiency syndrome) Network of Japan. The mean age was 39.5 years, and the proportion of male patients was very high (243 of 252; 96 %). The main transmission route was male homosexual contact (186 of 252; 74 %), followed by heterosexual contact. The HBV genotype was determined in 77 patients. Among them, genotype A HBV was the most frequent (58 of 77; 75 %) and was detected almost exclusively in homosexual patients. Acute hepatitis B was documented in 21 patients (8 %). Three of the 252 HIV/HBV-coinfected patients developed advanced liver disease with the complication of ascites, hepatic encephalopathy, or hepatocellular carcinoma. A comparison between patients not treated and those treated with antiretroviral drugs including anti-HBV drugs revealed that the baseline liver function was worse in treated patients. However, the serum albumin levels and platelet counts in both groups increased after treatment and were similar. Liver disease-associated death was not observed. Here, we characterize the clinical features of liver disease in HIV/HBV-coinfected patients in Japan for the first time. The findings suggest that antiretroviral therapy with anti-HBV drugs may retard the progression of a liver disease and prevent liver disease-associated death in such patients.

Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean.

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85-90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with P(meta) = 1.89×10⁻¹² for rs3077 and P(meta) = 9.69×10⁻¹° for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (P(meta) = 4.40×10⁻¹9 for rs3077 and P(meta) = 1.28×10⁻¹5 for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.

No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations.

BACKGROUND: A recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV-derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations. RESULTS: We did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR = 1.09, 95 % CI = 0.82-1.43; replication 2: OR = 0.79, 95 % CI = 0.54-1.15), in the Korean cohort (replication 3: OR = 0.95, 95 % CI = 0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR = 1.17, 95 % CI = 0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P = 0.97. CONCLUSIONS: None of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations.

LecT-Hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients.

UNLABELLED: Assessment of liver fibrosis in patients with chronic hepatitis C (CHC) is critical for predicting disease progression and determining future antiviral therapy. LecT-Hepa, a new glyco-marker derived from fibrosis-related glyco-alteration of serum alpha 1-acid glycoprotein, was used to differentiate cirrhosis from chronic hepatitis in a single-center study. Herein, we aimed to validate this new glyco-marker for estimating liver fibrosis in a multicenter study. Overall, 183 CHC patients were recruited from 5 liver centers. The parameters Aspergillus oryzae lectin (AOL) / Dature stramonium lectin (DSA) and Maackia amurensis lectin (MAL)/DSA were measured using a bedside clinical chemistry analyzer in order to calculate LecT-Hepa levels. The data were compared with those of seven other noninvasive biochemical markers and tests (hyaluronic acid, tissue inhibitor of metalloproteases-1, platelet count, aspartate aminotransferase-to-platelet ratio index [APRI], Forns index, Fib-4 index, and Zeng's score) for assessing liver fibrosis using the receiver-operating characteristic curve. LecT-Hepa correlated well with the fibrosis stage as determined by liver biopsy. The area under the curve (AUC), sensitivity, and specificity of LecT-Hepa were 0.802, 59.6%, and 89.9%, respectively, for significant fibrosis; 0.882, 83.3%, and 80.0%, respectively, for severe fibrosis; and 0.929, 84.6%, and 88.5%, respectively, for cirrhosis. AUC scores of LecT-Hepa at each fibrosis stage were greater than those of the seven aforementioned noninvasive tests and markers. CONCLUSION: The efficacy of LecT-Hepa, a glyco-marker developed using glycoproteomics, for estimating liver fibrosis was demonstrated in a multicenter study. LecT-Hepa given by a combination of the two glyco-parameters is a reliable method for determining the fibrosis stage and is a potential substitute for liver biopsy.

Relationship between diffusion-weighted magnetic resonance imaging and histological tumor grading of hepatocellular carcinoma.

BACKGROUND: Intrahepatic and extrahepatic recurrence remains a significant problem for hepatocellular carcinoma (HCC). The aim of this study was to determine the usefulness of diffusion-weighted magnetic resonance imaging (DWI) for histological tumor grading and preoperative prediction of early HCC recurrence within 6 months of operation. METHODS: A total of 44 patients who had undergone hepatic resection for HCC (50 nodules) were reviewed retrospectively. DWI was performed within 30 days before hepatectomy, and apparent diffusion coefficients (ADCs) were measured using 2 methods: mean ADC and minimum-spot ADC. Relationships between ADCs and histological differentiation and between ADCs and early recurrence of HCC were analyzed. RESULTS: Mean ADC was significantly lower in poorly differentiated HCC (n=18, 1.07±0.15×10(-3) mm2/s) than in moderately differentiated HCC (n=29, 1.29±0.21×10(-3) mm2/s; P<.05). Minimum-spot ADC was significantly lower in poorly differentiated HCC (n=18, 0.69±0.19×10(-3) mm2/s) than in well-differentiated HCC (n=3, 1.15±0.10×10(-3) mm2; P<.01) or in moderately differentiated HCC (n=29, 0.98±0.18×10(-3) mm2/s; P<.0001). Of 34 patients who were able to be observed for >6 months after resection, 9 showed early recurrence. Minimum-spot ADC was significantly lower in patients with early recurrence (n=9, 0.64±0.24×10(-3) mm2/s) than in patients without early recurrence (n=25, 0.88±0.19×10(-3) mm2/s; P<.05). On multivariate analysis, minimum-spot ADC was a significant risk factor for early recurrence (P<.05). CONCLUSION: Quantitative measurement of ADC of HCC with magnetic resonance diffusion weighted imaging is a promising functional imaging tool in the prediction of histological grade and early recurrence before treatment.

[Comprehensive strategy for extermination of hepatocellular carcinoma--prevention, diagnosis and treatment].

In this symposium, we explained etiology, prevention and treatment for hepatocellular carcinoma (HCC). It has been revealed that the carcinogenesis in hepatocellular carcinoma is almost caused by the infection of hepatitis virus B and/or C. Therefore, the carcinogenesis in hepatocellular carcinoma is able to be prevented. Even if the carcinogenesis in hepatocellular carcinoma occurs, the diagnosis and treatment in the worldwide level; radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), hepatectomy, and liver transplantation will be offered to patients with HCC in Japan. We hope that this symposium would help the attendance to understand the prevention and treatment for HCC.

Efficacy of therapy for advanced hepatocellular carcinoma: intra-arterial 5-fluorouracil and subcutaneous interferon with image-guided radiation.

BACKGROUND AND AIM: To evaluate the efficacy of intra-arterial 5-fluorouracil (5-FU) and subcutaneous interferon (IFN) combined with image-guided radiation therapy (IGRT) in advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). METHODS: Twenty HCC patients with PVTT were treated with 5-FU and IFN combined with image-guided radiation therapy (IGRT) (IGRT group), and as controls, 20 patients with PVTT were treated with 5-FU and IFN alone (non-IGRT group). Overall survival (OS) time, response rates, time to progression (TTP) and safety were compared across groups. RESULTS: Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) of PVTT were 5%, 55%, 40% and 0% in the IGRT group and 0%, 30%, 35% and 35%, in the non-IGRT group, respectively. CR, PR, SD, and PD of the whole tumor were 0%, 35%, 45% and 20% in the IGRT group and 0%, 30%, 35% and 35%, in the non-IGRT group, respectively. Overall median survival was significantly longer in the IGRT group (12.0 months 95% confidence interval [CI], 9.3-17.6 months) than in the non-IGRT group (9.1 months [95% CI, 5.5-11.1 months]) (P = 0.041). TTP was significantly longer in the IGRT group (6.9 months [95% CI, 5.6-10.2 months]) than in the non-IGRT group (4.0 months [95% CI, 3.3-6.4 months]) (P = 0.034). CONCLUSIONS: The response rates, median OS time and TTP in patients with advanced HCC with PVTT who received this novel combination therapy of intra-arterial 5-FU and subcutaneous IFN with IGRT are encouraging, and this combination therapy warrants further investigation.

The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma.

BACKGROUND: Prediction and prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) recurrence is an important clinical issue. We investigated whether HBV DNA level and antiviral therapy are associated with HCC recurrence. METHODS: This retrospective study involved 103 patients who underwent hepatic resection or radiofrequency ablation for initial HCC. Patients were divided into four groups. Thirty had high serum HBV DNA levels (>4 log(10) copies/mL) and had not received antiviral therapy (high virus group; HVG). Thirty-four had low HBV DNA levels (< or =4 log(10) copies/mL) and had not received antiviral therapy (low virus group; LVG). Twenty received antiviral therapy after HCC developed (therapeutic group A, TG-A). Nineteen received antiviral therapy before HCC developed (therapeutic group B, TG-B). RESULTS: Cumulative HCC recurrence rates at 3 years in the HVG, LVG, TG-B, and TG-A were 71.1%, 42.2%, 42.3%, and 52.0%, respectively. Recurrence rates differed significantly between the HVG and LVG (P = 0.016) and between the HVG and TG-B (P = 0.008). Recurrence rate in the TG-A was marginally lower than in the HVG (P = 0.10). On multivariate analysis, high serum hepatitis B virus DNA levels (hazard ratio: HR 2.67; 95% CI 1.31-5.47; P = 0.007) and absence of antiviral therapy (HR 2.57; 95% CI 1.34-4.94; P = 0.005) were independent risk factors for hepatocellular carcinoma recurrence. CONCLUSION: HBV DNA level and antiviral therapy are associated with HCC recurrence. For patients with high HBV DNA levels, antiviral therapy before the development of HCC is important for prevention of recurrence.

Chronic hepatitis C in patients co-infected with human immunodeficiency virus in Japan: a retrospective multicenter analysis.

AIM: A nationwide survey in Japan revealed that nearly one-fifth of human immunodeficiency virus (HIV)-positive patients are co-infected with hepatitis C virus (HCV). We conducted a study to further analyze the features of liver disease in HIV-HCV co-infected patients. METHODS: We analyzed 297 patients from eight hospitals belonging to the HIV/AIDS Network of Japan. RESULTS: HCV genotypes 1, 2, 3, 4 and mixed genotypes were detected in 55.2, 13.7, 18.9, 0.9 and 11.3% of patients, respectively, in contrast to the fact that only genotypes 1 and 2 are detected in HCV mono-infected patients in Japan. This is compatible with the transmission of HCV through imported blood products contaminated by HCV. Sixteen of 297 HIV-HCV co-infected patients had advanced liver disease accompanied by ascites, hepatic encephalopathy or hepatocellular carcinoma. The average age of such patients was 41.1 +/- 14.0 years, which was much younger than that of HCV mono-infected patients with the same complications. The progression speed of liver disease estimated from the changes in the levels of serum albumin, bilirubin, or platelet was slower in patients who achieved sustained virological response with interferon treatment than in those who did not receive it. The overall sustained virological response rate to interferon treatment was 43.3%. CONCLUSIONS: Our findings suggest that liver disease is more advanced in HIV-HCV co-infected patients than in HCV mono-infected patients, and interferon treatment may retard the progression of liver disease in such patients.