Repeated radiofrequency ablation for the distant recurrence in the liver in patients with chronic hepatitis C virus infection achieving long-term survival.

Recurrence of hepatocellular carcinoma (HCC) is frequently observed in patients with hepatitis C virus (HCV) infection and the incidence of HCC recurrence is as high as 20% in these patients even after a complete curative treatment is given for the HCC nodules. We report a 57-year-old female who was referred to our hospital for the treatment of a HCC nodule of 1.8 cm diameter in S5 and having liver cirrhosis of Child-Pugh A classification with HCV infection in April 1999. The HCC nodule showed hypervascularity by computed tomography during hepatic arteriography (CTHA) and was coagulated by microwave under peritoneoscopy. Complete necrosis was confirmed by enhanced-CT scan after microwave coagulation. Thereafter, interferon alfa-2b (3MU, twice weekly) was given but HCV RNA continued to be positive. Thereafter, recurrence of HCC was noted five times in S1, S2, S6; treatment by radiofrequency ablation was given four times; and transarterial chemoembolization was carried out once. Since January 2004, peg-interferon alfa-2a (90 microm/week) has been administered, and no recurrence has been detected until August 2005. She is currently 63 years old, and quite well. Five-year-survival rate in HCC patients treated by radiofrequency ablation is 62.7% in our hospital, however, the recurrence rate is as high as 26.4% per year in the patients with chronic HCV infection. It is a point of controversy when liver transplantation should be recommended in HCC patients with liver cirrhosis of Child-Pugh A classification having chronic HCV infection because of the high incidence of recurrence.

[High-sensitivity C-reactive protein (hs-CRP): a promising biomarker for the screening of non-alcoholic steatohepatitis (NASH)].

Nonalcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) that may progress eventually to cirrhosis. Any clinically useful serum biomarkers have never been reported to distinguish patients with NASH from those with simple steatosis. The serum CRP concentration, formerly used as a marker of acute-phase reaction, has been revealed to be a strong predictor of coronary event after the introduction of the high-sensitivity assay method. Patients with metabolic syndrome also have been reported to have higher high-sensitivity CRP(hs-CRP) concentration. We showed patients with more active form of NASH (grade2-3) have higher concentration of hs-CRP than those with quiescent form of NASH (grade1) or simple steatosis. hs-CRP may be a promising biomarker for screening of NASH, a hepatic manifestation of metabolic syndrome.

Serum KL-6 as a novel tumor marker for hepatocellular carcinoma in hepatitis C virus infected patients.

The up-regulation of MUC1 protein is associated with malignant phenotype of cancer. We investigated the significance of KL-6, one of the MUC1 antigens, as a tumor marker in hepatitis C virus positive hepatocellular carcinoma (HCC). Serum KL-6 was determined in 203 patients with chronic hepatitis (CH), 47 patients with liver cirrhosis (LC) and 78 patients with HCC. KL-6 was higher in HCC compared to non-HCC (p=0.0005) and was higher in patients with multiple HCC nodules compared to a single nodule (p=0.02). There was no correlation between KL-6 and existent tumor markers for HCC such as alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein or des-gamma-carboxyprothrombin. In the prospective analysis, the cumulative incidence of HCC was significantly greater in CH and LC patients with high initial KL-6 (above 400U/ml) compared to the others (p=0.02). Moreover, in the prospective observation of 25 patients whose HCC was completely cured by radiofrequency ablation therapy, the cumulative incidence of distant recurrences was significantly greater in patients with high initial KL-6 compared to the others (p=0.005). These results suggest that serum KL-6 could be a novel tumor marker in the diagnosis and the prediction of prognosis of HCC that may have additive value to the existent markers.

Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C.

BACKGROUND/AIMS: To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. METHODS: Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. RESULTS: Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P < 0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9 x 10(-2)/site/year and 1.3 x 10(-2)/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60 x 10(-2)/site/year and 0.24 x 10(-2)/site/year, P = 0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n = 10) than in non-responders (8.8 x 10(-2)/site/year vs. 0.38 x 10(-2)/site/year, P = 0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. CONCLUSIONS: Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.

Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B.

Breakthrough hepatitis remains the major issue in long-term lamivudine therapy for chronic hepatitis B. However, the emergence of drug-resistant hepatitis B virus (HBV) is not always accompanied by a relapse of hepatitis. To elucidate factors predictive of breakthrough hepatitis, 53 patients with genotype C of HBV on long-term lamivudine therapy were analyzed. HBV reappeared during therapy in 19 patients with a cumulative incidence of 15% at 1 year, 34% at 2 years, and 60% at 3 years. Within this group, breakthrough hepatitis developed in 12 patients (63%). A polymerase gene domain B mutation (rt180M) emerged in 13 patients, and domain C mutations (rt204I, rt204V) were found in 19 patients. The rt180M mutation was associated with breakthrough hepatitis (p < 0.05) with a positive predictive value of 85% and a negative predictive value of 83%. Patients with the rt180M mutation had higher HBV-DNA levels during viral breakthrough compared to patients with rt180wt (p < 0.05). The mutational pattern of rt204 was not associated with breakthrough hepatitis. In conclusion, genotypic assays for the rt180M mutation after viral breakthrough may be useful in predicting the risk of breakthrough hepatitis and in deciding when to initiate alternative or additive nucleoside analogue therapy.

Development of hepatocellular carcinoma after interferon therapy in chronic hepatitis C. Is it possible to reduce the incidence by ribanirin and IFN combination therapy?

OBJECTIVES: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after interferon (IFN) monotherapy in chronic hepatitis C, the risk factors for the development of HCC have not been fully understood. The aim of this study is to investigate the risk factors for the development of HCC after IFN in chronic hepatitis C as well as whether the incidence of HCC will be reduced by ribavirin and IFN combination therapy or not. METHODS: 495 patients with chronic hepatitis C and which received IFN monotherapy were followed and the incidence and risk factors for the development of HCC were examined. On the other hand, in the patients which received ribavirin and IFN combination therapy, the sustained response rate was assessed and the reduction rate of HCC development was predicted. RESULTS: Multivariate analysis by the Cox proportional hazard model revealed that the risk factors for HCC development were age, male gender, severe fibrosis and outcome of IFN therapy. On ribavirin and IFN combination therapy, the sustained response rate reached 17.3% in genotype 1b and 74% in genotypes 2a and 2b infection, thus reducing 20% of the estimated incidence of HCC. CONCLUSION: To reduce the incidence of HCC in chronic hepatitis C, improvement of the sustained response rate is an essential issue, and ribavirin and IFN combination therapy shows to be promising.

Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis.

The aim of this study was to evaluate the effects of the combination therapy with bezafibrate and ursodeoxycholic acid (UDCA) for primary biliary cirrhosis (PBC), compared to UDCA monotherapy. Sixteen patients with compensated PBC were divided randomly into two groups. Group A received treatment with bezafibrate and UDCA for 6 months, while group B received UDCA alone, treatment protocols were then exchanged for another 6 months. The laboratory data was followed every month. The mean levels of alkaline phosphatase (ALP) decreased significantly more in group A than in group B in the first half of the study. Then serum ALP levels were elevated in group A after exchanged the therapy, but fell down in group B. Serum levels of gamma-glutamyl transferase (GGT), immunoglobulin M and triglycerides values were significantly lower in group B than in group A, after changing therapies from monotherapy to combination therapy with bezafibrate and UDCA. The mean levels of ALP, GGT and triglycerides were significantly lower at the end of the combination therapy than those at the end of the monotherapy. The combination therapy with bezafibrate and UDCA significantly improves the laboratory data that specific for PBC in comparison with UDCA monotherapy.

A comparison of the exponential decay slope between PEG-IFN alfa-2b/ribavirin and IFN alfa-2b/ribavirin combination therapy in patients with chronic hepatitis C genotype 1b infection and a high viral load.

OBJECTIVES: A high virological response rate can often be shown to be obtained with PEG-IFN alpha-2b and ribavirin combination therapy in chronic hepatitis C patients. Viral dynamics have been utilized for the evaluation of antiviral effects, especially the exponential second decay slope, which represents the elimination of infected cells. METHODS: Forty-nine patients were randomly assigned to the IFN alpha-2b group (n = 26) or the PEG-IFN alpha-2b group (n = 23). Ribavirin was administered equally to both groups. Measuring the serum concentration of HCVRNA, the exponential viral decay during phase 1 and 2 was calculated. RESULTS: The exponential decay slope in phase 2 during the first 2 weeks was greater in the IFN alpha-2b group than in the PEG-IFN alpha-2b group; however, from weeks 3 to 4, it was greater in the PEG-IFN alpha-2b group than in the IFN alpha-2b group. Interestingly, in the PEG-IFN alpha-2b group, the exponential decay slope was greater from weeks 3 to 4 after initiating combination therapy than during the weeks 1-2 (p < 0.01), despite administration of the same PEG-IFN alpha-2b dose (1.5 microg/kg once weekly). CONCLUSIONS: In PEG-IFN alpha-2b and ribavirin combination therapy, elimination of infected cells may be pronounced following an increase in serum ribavirin concentration in chronic hepatitis C patients with genotype 1b infection and a high viral load.

[A case of advanced gastric cancer acquired long-term response two years or more by treatment with oral anticancer drug TS-1].

A 66-year-old male with massive ascites was diagnosed as advanced gastric scirrhous cancer at Musashino Red Cross Hospital. We detected the adenomatous cancer cells from his ascites, and an X-ray photograph of his stomach showed less capability of expansion in the upper gastrointestinal series. We attempted treatment with oral anticancer drug TS-1 with the patient's consent and achieved a long-term response of two years or more.

Core promoter/pre-core mutations are associated with lamivudine-induced HBeAg loss in chronic hepatitis B with genotype C.

BACKGROUND/AIMS: To clarify the factors associated with the efficacy of lamivudine. METHODS: Variables including basic core promoter (BCP) and pre-core (PreC) mutations were evaluated in 60 chronic hepatitis B e antigen (HBeAg)-positive patients with genotype C. Thirty patients were treated with lamivudine and the remaining 30 patients were age- and sex-matched controls. RESULTS: Severe fibrosis was significantly more frequent in patients with the BCP-mutant/PreC-wild (MW) and BCP-mutant/PreC-mutant (MM) patterns compared to BCP-wild/PreC-wild (WW) pattern (P=0.02). The cumulative rates of HBeAg loss at 6, 12 and 18 months were significantly higher in the lamivudine group (14.2, 36.3, and 60.9%) compared with the control group (17.6, 17.6, and 24.5%, P=0.03), and was especially pronounced in patients with the MW pattern (P=0.04). The rate of lamivudine-related HBeAg loss was significantly lower in patients with the WW pattern (P=0.03). Factors correlating with HBeAg loss were histological fibrosis and activity, hepatitis B virus-DNA levels, BCP/PreC mutation and lamivudine therapy. Multivariate analysis revealed BCP/PreC mutations and fibrosis were independent factors for HBeAg loss. CONCLUSIONS: With specific reference to the genotype C, we found earlier HBeAg loss was expected in patients carrying MM and MW patterns, while the efficacy of lamivudine was limited in patients with the WW pattern.

Assessment of Kupffer cells by ferumoxides-enhanced MR imaging is beneficial for diagnosis of hepatocellular carcinoma: comparison of pathological diagnosis and perfusion patterns assessed by CT hepatic arteriography and CT arterioportography.

To investigate the clinical significance of the radiographic assessment of Kupffer cells and hemodynamics in the diagnosis of hepatocellular nodules, both magnetic resonance (MR) imaging enhanced by ferumoxides and CT hepatic arteriography (CTHA)/CT arterioportography (CTAP) were undertaken for 118 patients with 158 primary nodular hepatocellular lesions. The radiographic findings were analyzed in the context of the pathological diagnosis. Among nodules presumed to be pre- or early HCC by CTHA/CTAP, all 13 hyperintense nodules identified by MR imaging (MRI) were found pathologically to be hepatocellular carcinoma (HCC). In contrast, in 14 hypointense nodules, no advanced (moderately or poorly differentiated) HCC was pathologically identified and none of these progressed to advanced HCC during the follow up period (mean: 24 months). Instead, 78% of these cases were pathologically confirmed as dysplastic nodules. For the 16 lesions undetectable by CTHA/CTAP, four of eight (50%) hypointense nodules turned out to be dysplastic nodules and one hyperintense lesion was HCC. Signal intensity by ferumoxides-enhanced MRI showed a strong correlation with the increase or decrease of Kupffer cells assessed by immunohistochemistry. Assessment of Kupffer cells by ferumoxides-enhanced MRI is beneficial for the accurate diagnosis of primary hepatocellular nodules that are considered borderline or early stage HCC by their hemodynamic profile.

Interferon-stimulated gene expression and hepatitis C viral dynamics during different interferon regimens.

BACKGROUND/AIMS: To address the molecular mechanism for enhanced antiviral efficacy associated with a frequent dosing of interferon (IFN)-beta. METHODS: Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated protein kinase (PKR) mRNA and MxA mRNA levels in peripheral blood mononuclear cells (PBMC) were analyzed serially in 140 patients who were randomly assigned to a twice daily (3 MU bid) or once daily (6 MU qd) administration group. RESULTS: In twice daily group, the rate of HCV decline during the second phase was 2-fold greater than in the once daily group (P=0.04). Peak PKR and MxA gene expression levels in the first phase (observed 4 h after a single administration) were 2-fold higher in the once daily group. However, the expression in the second phase was maintained at a significantly higher level in the twice daily group. Initial and peak expression levels were related to initial viral load. Basal expressions in PBMC were significantly correlated with those in the liver tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001). CONCLUSIONS: Our data suggest that elimination of HCV-infected cells is enhanced by twice daily dosing of IFN-beta, and that this enhanced effect is associated with a higher intracellular expression of PKR and MxA during the second phase.

Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study.

This study examined the incidence, clinical course and its risk factors for major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy. Ninety-nine subjects underwent the psychiatric interviews for diagnosis of major depressive episode according to the DSM-IV criteria before the start of interferon therapy, and once every 4 weeks during both the 24-week treatment period and 12 weeks after the end of therapy. Depressive symptoms were also evaluated using the Hamilton Rating Scale for Depression. Major depression occurred during interferon therapy in 23 patients (23.2%). In 73.9% of them depression occurred within 8 weeks after the start of therapy. Twenty-two patients with depression completed the therapy and 59.1% of them achieved remission by the end of therapy with a mean duration of 11.6 weeks. Although the other 40.9% were not in remission at the end of therapy, they achieved remission within 12 weeks thereafter. The only risk factor for depression was advanced age. Depression occurs frequently among patients with hepatitis type C undergoing interferon-alpha therapy. Such patients require careful observation, and psychiatrists should be sufficiently aware of this significant psychiatric complication of interferon therapy.

A case of primary leiomyoma of the liver in a patient without evidence of immunosuppression.

A 31-year-old Japanese male was admitted to our hospital for investigation of an asymptomatic nodular lesion of the liver detected by abdominal ultrasonography (US) during a routine medical examination. Computed tomography (CT) revealed a single, hypovascular mass 35 mm in diameter, within the left lobe of the liver. The tumor demonstrated hypointensity on T1-weighted, and hyperintensity on T2-weighted magnetic resonance (MR) imaging. Hematological and biochemical investigations were normal. There were no abnormalities of the gastrointestinal or urinary tracts. A left lateral segmentectomy of the liver was performed. Pathological examination of the nodule revealed a primary leiomyoma of the liver, with positive immunohistochemical staining for vimentin and desmin antigens. Primary leiomyoma of the liver is rare, with the majority of cases associated with immunodeficiency disorders. This patient had no evidence of any underlying disease. Primary leiomyoma of the liver should be considered when a nodular lesion is found in a patient without evidence of viral hepatitis.