The activity of interferon (IFN) is not elucidated from the viewpoint of cancer prevention in chronic hepatitis C patients en masse. The hepatocellular carcinogenesis rate was analyzed statistically in 1,643 patients with chronic hepatitis C: 1,191 patients with IFN therapy and 452 without IFN therapy. Hepatocellular carcinogenesis rates in the treated and untreated groups were 2.1% and 4.8% at the end of the 5th year, and 7.6% and 12.4% at the 10th year, respectively (P ‫؍‬ .0036). Multivariate analysis showed that IFN slightly decreased the risk of carcinogenesis by 33%, compared with that of untreated patients (P ‫؍‬ .14), adjusting for the confounding effects of age, fibrotic stage, gender, and ␥-glutamyl transpeptidase (GGTP) value. Until recently, hepatitis C virus (HCV) has been reported to be a causative agent of hepatocellular carcinoma (HCC) aside from hepatitis B virus. [1][2][3][4] In two cohort studies from Tokyo 5 and Osaka 6 of Japanese patients with cirrhosis, the cumulative appearance rates of HCC at 3, 5, 10, and 15 years were respectively, 12.5%, 19.4%, 44.3%, and 58.2%. HCC occurred more frequently (75.2% at 15 years) in those patients with only HCV antibodies at enrollment than in those with only hepatitis B surface antigen (27.2%). According to our estimation of the carcinogenesis rates in untreated patients with chronic hepatitis C, 7 5-year, 10-year, and 15-year rates were 4.8%, 13.6%, and 26.0%, respectively. Because life expectancy of patients with HCV-related cirrhosis is largely influenced by development of HCC in the clinical course, and because an effective and truly curative therapy for HCC still remains limited at best, primary prevention of HCC in patients with chronic liver disease is of great importance.Interferon (IFN) is effective in eliminating HCV and in reducing serum alanine transaminase (ALT) in some patients with chronic hepatitis C. [8][9][10][11] The response to IFN therapy is related to factors including HCV subtype, serum concentration of HCV, IFN treatment schedule, and liver histology. 11-14 A Japanese trial of IFN for patients with HCV-related cirrhosis showed that IFN therapy decreased the HCC appearance rate through the disappearance of HCV RNA. 15 However, there has been no report about the anticarcinogenic activity of IFN in patients with chronic hepatitis type C, comparing a large number of untreated patients. To elucidate whether IFN suppresses the carcinogenesis rate in patients with chronic hepatitis C, we studied a total of 1,191 patients with IFN therapy compared with 452 patients without treatment, adjusting background features using multivariate analysis. One of the principal aims of our study was therefore to show a role of IFN in cancer prevention in chronic hepatitis type C en masse: To what extent could IFN decrease the carcinogenesis rate from chronic hepatitis C in society? The other aim was to assess a possible mechanism, if any, of cancer prevention by IFN. PATIENTS AND METHODSStudy Population. A total of 1,643 patients with chronic hepatitis ...

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Treatment of hepatitis B virus (HBV) with lamivudine is effective in suppressing virus replication and results in reduced inflammatory activity. However, the emergence of lamivudine-resistant mutant virus, with amino acid substitution in the YMDD motif of DNA polymerase, has been reported. We report the emergence and takeover of YMDD mutant and re-takeover by wild type during and after long-term lamivudine therapy. YMDD mutants were detected in five patients who showed DNA breakthrough (HBV DNA becoming detectable after a period of DNA negativity), which occurred after 9 to 14 months of lamivudine therapy. Four of five mutants had amino acid sequence YIDD, and the remaining mutant had YVDD. Patients with high HBV-DNA titer and/or hepatitis B e antigen tended to develop breakthrough (P ‫؍‬ .038). Using a sensitive and specific polymerase chain reaction (PCR)-based method developed in this study, the emergence of YMDD mutants was detected 1 to 4 months before DNA breakthrough, but not detected in any of the pretreatment sera. The mutants were predominant at breakthrough, but were replaced by wild-type virus 3 to 4 months after cessation of therapy in the two patients who discontinued therapy. One of these patients had a relapse of hepatitis. Mutant continued to replicate in the remaining three patients who continued to receive treatment, and relapse occurred in only one of these patients. Our results suggest that the replication of YMDD mutant viruses is less than wild type and is re-overtaken by wild type after cessation of therapy. Re-administration of lamivudine, possibly combined with other antiviral therapy, might be useful in some patients experiencing hepatitis with lamivudine-resistant variants. (HEPATOLOGY 1998;27: 1711-1716.)is a potent inhibitor of RNA-dependent DNA polymerase of hepatitis B virus (HBV), as well as human immunodeficiency virus (HIV) reverse transcriptase. [1][2][3][4][5][6][7][8][9][10] The in vivo antiviral activity of lamivudine has been reported in animal studies as well as in humans. [11][12][13][14][15][16][17][18][19][20][21][22] However, the emergence of lamivudineresistant HBV strains was initially noticed in patients who received orthotopic liver transplantation and immunosuppressive therapy. [23][24][25][26][27][28] Such resistant viruses show a characteristic mutation of the 550th amino acid methionine in the YMDD motif of DNA polymerase to isoleucine (YIDD mutant) or valine (YVDD mutant). Honkoop et al. 29 recently showed the emergence of such mutant viruses in 5 of 14 (36%) immunocompetent patients who were treated with lamivudine over 26 weeks. However, in a larger placebo-controlled study in 358 Asian patients with HBV infection treated for 52 weeks, the rate of detection of lamivudine-resistant variants by polymerase chain reaction (PCR) was 19 of 134 (14%) in patients treated with 100 mg daily. 30 To our knowledge, there is no report that describes the presence of mutant viruses in the serum before administration of lamivudine. The low incidence and late emergence of YM...

Bone marrow stromal cells (MSCs) have the capability under specific conditions of differentiating into various cell types such as osteocytes, chondrocytes, and adipocytes. Here we demonstrate a highly efficient and specific induction of cells with neuronal characteristics, without glial differentiation, from both rat and human MSCs using gene transfection with Notch intracellular domain (NICD) and subsequent treatment with bFGF, forskolin, and ciliary neurotrophic factor. MSCs expressed markers related to neural stem cells after transfection with NICD, and subsequent trophic factor administration induced neuronal cells. Some of them showed voltage-gated fast sodium and delayed rectifier potassium currents and action potentials compatible with characteristics of functional neurons. Further treatment of the induced neuronal cells with glial cell line-derived neurotrophic factor (GDNF) increased the proportion of tyrosine hydroxylase-positive and dopamine-producing cells. Transplantation of these GDNF-treated cells showed improvement in apomorphine-induced rotational behavior and adjusting step and paw-reaching tests following intrastriatal implantation in a 6-hydroxy dopamine rat model of Parkinson disease. This study shows that a population of neuronal cells can be specifically generated from MSCs and that induced cells may allow for a neuroreconstructive approach.

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Because hepatocellular carcinoma often recurs after surgical resection or ethanol injection therapy, we conducted a prospective randomized controlled trial of interferon (IFN) in patients with chronic liver disease caused by hepatitis C virus (HCV). Twenty eligible patients with cirrhosis were randomized into two groups: 10 patients treated with 6 million units of natural IFN-␤ twice a week for 36 months and 10 patients without IFN therapy. One patient within the treatment group discontinued interferon therapy after 19 months of treatment because of a mild degree of retinopathy. None of the patients in either group lost HCV-RNA until the end of the observation. Although 7 (70.0%) of 10 patients in the nontreatment group showed tumor recurrence, only 1 (10.0%) of 10 patients with IFN therapy developed tumor recurrence during a median observation period of 25.0 months. Cumulative recurrence rates of the treated and untreated groups were 0% and 62.5% at the end of the first year, and 0% and 100% at the second year, respectively (log-rank test, P ‫؍‬ .0004). In conclusion, intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease. (HEPATOLOGY 2000;32: 228-232.)

Bone marrow stromal cells (MSCs) have the capability under specific conditions of differentiating into various cell types such as osteocytes, chondrocytes, and adipocytes. Here we demonstrate a highly efficient and specific induction of cells with neuronal characteristics, without glial differentiation, from both rat and human MSCs using gene transfection with Notch intracellular domain (NICD) and subsequent treatment with bFGF, forskolin, and ciliary neurotrophic factor. MSCs expressed markers related to neural stem cells after transfection with NICD, and subsequent trophic factor administration induced neuronal cells. Some of them showed voltage-gated fast sodium and delayed rectifier potassium currents and action potentials compatible with characteristics of functional neurons. Further treatment of the induced neuronal cells with glial cell line-derived neurotrophic factor (GDNF) increased the proportion of tyrosine hydroxylase-positive and dopamine-producing cells. Transplantation of these GDNF-treated cells showed improvement in apomorphine-induced rotational behavior and adjusting step and paw-reaching tests following intrastriatal implantation in a 6-hydroxy dopamine rat model of Parkinson disease. This study shows that a population of neuronal cells can be specifically generated from MSCs and that induced cells may allow for a neuroreconstructive approach.