Clinico-epidemiologic study of the metabolic syndrome and lifestyle factors associated with the risk of colon adenoma and adenocarcinoma.

BACKGROUND: The numbers of patients with colorectal cancer and associated deaths have been increasing in Japan, probably due to rapid lifestyle changes. Prevention is clearly important and the present study aimed to clarify risk factors and to promote colon cancer screening. METHODS: We investigated lifestyle factors, biochemical data, and pathological features of 727 individuals who underwent colonoscopy. Data were subjected to statistical analysis using SPSS software. RESULTS: Low-grade adenoma was more frequent among the elderly and in men. All of the men and 87.5% of the women with high-grade adenoma or adenocarcinoma were aged≥45 and≥50 years, respectively. In women, a larger waist circumference (=80 cm) increased the odds ratio for colon adenoma or adenocarcinoma (colon tumors) by 1.033 (95% confidence index (CI), 1.001-1.066; p=0.040). Metabolic syndrome significantly increased the odds ratio of colon tumors in men, but not in women. Cigarette smoking, drinking alcohol, and increased physical activity were significant risk factors for colon tumors in men, with odds ratios of 1.001 (95% CI, 1.000-1.002; p=0.001), 1.001 (95% CI, 1.000-1.003; p=0.047), and 1.406 (95% CI 1.038-1.904; p=0.028), respectively. CONCLUSIONS: Colon tumors have a high prevalence in the elderly. A larger waist circumference in women and metabolic syndrome in both men and women elevate the risk of colon tumors. In addition, smoking, drinking, and excessive physical activity are risk factors for adenoma and adenocarcinoma in men. For early detection of colorectal cancer, men older than 45 years and women older than 50 years with these risk factors are recommended to undergo colonoscopy.

[Two cases of gastric cancer expressing Glypican 3, but producing AFP with different lectin affinity].

We encountered 2 cases of AFP-producing gastric cancer. In the first patient, an 82-year-old man was found to have advanced type II advanced carcinoma in the stomach with a massive tumor embolus in the portal vein. In the second case, an 80-year-old man was given a diagnosis of multiple liver metastases of gastric cancer with portal vein thrombosis. Our diagnosis of gastric cancer in both cases was AFP-producing. It was supposed that the elevation of serum level of AFP might be caused by enteroblastic differentiation in the first case and hepatoid differentiation in the second case. Although, in both cases, the biopsy specimens of the gastric neoplasm proved moderately to poorly differentiated adenocarcinoma without hepatoid differentiation, the localization of Glypican 3 in gastric cancer cells was observed using immunostaining with a monoclonal antibody. In both cases, Glypican 3 was a sensitive and useful marker for AFP-producing gastric cancer with or without hepatoid differentiation.

Ursodeoxycholic acid exacerbates peginterferon-induced interstitial pneumonia in a patient with hepatitis C.

Pegylated interferon alpha combined with ribavirin is currently the standard treatment for hepatitis C virus (HCV) infection. Ursodeoxycholic acid (UDCA) is used as a complementary treatment in patients who are non-responders or who develop severe side effects of this combined therapy. UDCA is generally considered to be a relatively safe drug. However, we recently encountered a patient with chronic hepatitis C in whom interferon-induced interstitial pneumonia was exacerbated by UDCA. This patient responded to initial antiviral therapy with non-pegylated interferon alpha-2b and ribavirin, but hepatitis recurred soon after the end of treatment. A second course of antiviral therapy using peginterferon alpha-2b and ribavirin achieved normalization of serum transaminases and HCV-RNA, but also caused interstitial pneumonia. After discontinuing peginterferon, this side effect was ameliorated. On the other hand, hepatitis relapsed four months later. UDCA treatment was started and serum transaminase levels decreased, but exacerbation of interstitial pneumonia occurred with marked elevation of the serum KL-6 level. To our knowledge, this is the first reported case of peginterferon-induced interstitial pneumonia showing exacerbation due to UDCA therapy.

Understanding the hypercarcinogenic state in chronic hepatitis: a clue to the prevention of human hepatocellular carcinoma.

Human hepatocellular carcinomas (HCCs) are preceded by chronic hepatitis and cirrhosis. Despite a clear viral etiology (hepatitis B virus [HBV] and hepatitis C virus [HCV] of human hepatocarcinogenesis, the mechanism is complex and the distinct molecular pathway or molecules that explain this phenomenon are not yet known. Viral hepatitis, "inflammation-mediated" hepatocarcinogenesis, greatly influences the incidence of somatic genetic events in hepatocytes, by increasing the number of target cells or the proliferation of once-hit hepatocytes, eventually leading to HCC. We propose that hepatitis virus can cause HCC by a combination of two mechanisms; (i) cell killing and stimulation of mitosis, leading to an accumulation of events necessary for transformation; and (ii) an increase in chromosomal instability mediated by induced recombinogeneic protein(s) during chronic hepatitis. These conditions may be designated as the "hypercarcinogenic state". Our goal is to change the "hypercarcinogenic state" to the "normo- or hypocarcinogenic" state and to prevent HCC development.

Efficacy of Stronger Neo-Minophagen C compared between two doses administered three times a week on patients with chronic viral hepatitis.

BACKGROUND: A daily injection of glycyrrhizin (Stronger Neo-Minophagen C (SNMC) containing 40 mg glycyrrhizin in a 20 mL ampoule) lowers alanine aminotransferase (ALT) levels in patients with chronic viral hepatitis. METHODS: The therapeutic effects of intermittent administration of SNMC three times a week for 12 weeks were evaluated and compared between two doses (40 and 100 mL) in a randomized clinical trial. RESULTS: Overall, the therapeutic response was better in the 53 patients allocated 100 mL than the 59 who were allocated to have 40 mL SNMC (P = 0.0243). At the completion of SNMC treatment, ALT levels decreased more extensively in the patients on 100 mL than those on 40 mL SNMC (-29 vs-50% in comparison with the baseline value, P = 0.0002). Minor side-effects occurred in both the patients on 100 mL (20%) and those on 40 mL (12%), but they did not require any therapies. CONCLUSIONS: Intermittent SNMC would be efficient in suppressing ALT levels in patients with chronic viral hepatitis in a dose-dependent manner. Taken along with infrequent and very mild side-effects, long-term intermittent SNMC would benefit patients with chronic hepatitis by maintaining their quality of life with easier compliance.

Somatic mutation and SNP in the promoter of dbpA and human hepatocarcinogenesis.

Human DNA-binding protein (dbpA) is a member of a Y-box binding protein family containing a cold shock domain. The increased expression of Y box binding proteins in somatic cells is associated with cell proliferation and transformation. Recently, we isolated a splicing variant of dbpA as a candidate for the cellular recombinogenic protein that leads to genomic instability and inflammation-mediated hepatocarcinogenesis. The expression of dbpA is enhanced in proliferating cells, but the manner in which it regulates transcription is largely unknown. In this study, we analyzed the transcriptional regulatory region of dbpA, and searched for the mutation in this region by a direct sequence method. In 3 of 55 human hepatocellular carcinoma (HCC) cases, we identified one nucleotide replacement (T right curved arrow G transversion) in nucleotide position -6 of the promoter region. Among 3 cases showing this transversion, one HCC case was due to a somatic mutation and the other two were due to single nucleotide polymorphism (SNP). By luciferase assay, we showed that the transcriptional activity of the promoter region with the transversion was significantly higher than that of the wild-type. Using the Southwestern blotting, we also confirmed the existence of a cellular proteins (about 25 and 50 kDa) that specifically bind to the sequence with this transversion. Our results suggested the biological significance of the transversion of dbpA's promoter region as one of the factors accelerating hepatocarcinogenesis.

Molecular aspects of human hepatocarcinogenesis mediated by inflammation: from hypercarcinogenic state to normo- or hypocarcinogenic state.

In spite of great efforts in the research relating to human hepatocarcinogenesis, its mechanism on the molecular level is yet to be determined. Chronic viral hepatitis may increase the chances of genetic events in hepatocytes of the host, by increasing the number of target cells or through proliferation of initiated hepatocytes, toward the eventual development of hepatocellular carcinoma. These conditions are referred to comprehensively as the 'hypercarcinogenic state'. Our goal, then, should be directed to the reversion of the 'hypercarcinogenic state' to the 'normo- or hypocarcinogenic state' so as to hopefully prevent or at least postpone the development of hepatocellular carcinoma.