[Viral hepatitis and liver cirrhosis].
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Adult↗
Biomedical subjects
Haruhiko Yoshida
Publications and source records attributed to Haruhiko Yoshida.
The evaluation of putative virulence factors of Helicobacter pylori for gastroduodenal disease by use of a short-term Mongolian gerbil infection model.
Few virulence determinants of Helicobacter pylori have been tested in vivo. We conducted this study to establish an animal model for their screening. Six-week-old male Mongolian gerbils were inoculated with wild-type H. pylori (TN2) or its isogenic mutant with deletion of cagE (TN2DeltacagE), total cag pathogenicity island (TN2DeltacagPAI), HP0499 (TN2DeltaHP499), or HP0638 (TN2DeltaHP638) (n=5 each). The animals were killed 3 weeks later, and the density of bacteria and the degree of inflammation in the stomach were compared. Infection was established in all animals except those inoculated with TN2DeltaHP638. TN2 and TN2DeltaHP499, but not TN2DeltacagE and TN2Deltacag PAI, induced intense inflammation, although the densities of bacteria were similar. The Mongolian gerbil model was useful for the screening of virulence determinants in vivo, which confirmed the importance of cag PAI while questioning that of HP0499.
Animals↗
Progression from chronic hepatitis to hepatocellular carcinoma: natural course and treatments.
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Carcinoma, Hepatocellular↗
Relationship between nuclear factor-kappaB activation and virulence factors of Helicobacter pylori in Japanese clinical isolates.
BACKGROUND: Several factors have been proposed as a possible virulence determinant of Helicobacter pylori infection. The aim of the present study was to evaluate these candidates in nuclear factor (NF)-kappaBeta activation, which is a critical regulator of genes involved in inflammatory reactions. METHODS: We determined the status of cagE, iceA, HP0441 (a virB4 homolog), the s1 signal sequence of vacA and babA2 by polymerase chain reaction, all of which are candidate virulence determinants, in 107 H. pylori strains isolated from Japanese patients. Nuclear factor-kappaBeta activation was evaluated by the luciferase reporter assay. The gastric mucosa of the hosts was examined histologically. RESULTS: The cagE gene was positive in 102 (95.3%) strains, iceA1 was positive in 71 (66.4%) strains, HP0441 was positive in 68 (63.6%) strains, vacA s1 was positive in 105 (98.1%) strains and babA2 was positive in 103 (96.3%) strains. Nuclear factor-kappaBeta was activated by all cagE-positive strains, but was not activated by any of the cagE-negative strains. The status of iceA or HP0441 was not associated with NF-kappaBeta activation. Neutrophil infiltration in gastric mucosa was significantly more severe in patients infected with cagE-positive strains than in patients infected with negative strains. No association was found between the degree of neutrophil infiltration and the status of HP0441 or iceA. Due to very high positivity of vacA s1 and babA2 in Japanese strains, their roles remain to be investigated. CONCLUSIONS: The cag pathogenicity island (PAI) status, as determined by cagE polymerase chain reaction, but not the status of iceA or HP0441, is closely associated with NF-kappaBeta activation and the degree of gastric mucosal inflammation in the hosts.
Adult↗
Interferon therapy prolonged life expectancy among chronic hepatitis C patients.
BACKGROUND & AIMS: The effects of interferon therapy in chronic hepatitis C patients on survival are unclear. Our objective was to analyze survival among a large cohort of chronic hepatitis C patients. METHODS: We used a retrospective cohort study design in the setting of 7 university hospitals and 1 regional core hospital in Japan. Our study included 2889 patients with histological-proven chronic hepatitis C: 2430 patients received interferon therapy, and 459 patients were untreated. For intervention, the median dose and duration of interferon administration was 480 million units and 137 days, respectively. For measurements, survival status was confirmed by medical records or direct questionnaires. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality among the Japanese general population and by risk ratio calculated by proportional hazards regression. RESULTS: Thirty of 459 untreated patients, 7 of 817 virologic sustained responders, and 49 of 1613 nonresponders died in 5.4-years follow-up. Fifty-eight (67%) of 86 patient deaths were due to liver diseases (39 to hepatocellular carcinoma). Compared with the general population, overall mortality was high among untreated patients (SMR: 1.9; CI: 1.3-2.8) but not among interferon-treated patients (SMR: 0.9; CI: 0.7-1.1). The risk of death was reduced, compared with untreated patients, among interferon-treated patients (risk ratio for overall death: 0.367; CI: 0.236-0.596; for liver-related death: 0.284; CI: 0.164-0.494) and among sustained responders (risk ratios: 0.148; CI: 0.064-0.343 and 0.050; CI: 0.012-0.216). The risk of liver-unrelated deaths remained unchanged. CONCLUSIONS: Interferon therapy improved survival of chronic hepatitis C patients by preventing liver-related deaths.
Adult↗
Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation.
BACKGROUND & AIMS: Infection with Helicobacter pylori possessing the cag pathogenicity island (PAI) is associated with severe gastritis and gastric cancer. CagA protein, one of the products of cag PAI, is translocated into epithelial cells, where cytoskeletal rearrangements occur as a result of CagA tyrosine (Tyr) phosphorylation. Here we identify a new role for CagA protein as an activator of host cell signaling. METHODS: We transfected CagA into epithelial cells and analyzed its effect on transcription by reporter assays. The mechanism of reporter activation was assessed by electrophoretic mobility shift assays (EMSA) and immunoblots. Responsible regions of CagA for reporter activation were determined by truncation and mutagenesis of cagA gene. RESULTS: In HeLa cells, expression of CagA increased serum response element (SRE)-driven and serum response factor (SRF)-driven transcription by 40-fold and 3.3-fold, respectively, but did not affect nuclear factor kappaB- or AP-1-driven transcription. CagA-mediated SRE activation was also observed in gastric cell lines. Immunoblotting and EMSA revealed that transfection of CagA enhanced phosphorylation of and DNA binding by Elk1. Furthermore, involvement of Ras and MEK in CagA-mediated Elk1 phosphorylation was observed. SRE activation was dependent on several regions within the C-terminal portion of CagA (CagA(873-1002)), and independent of Tyr phosphorylation. CONCLUSIONS: The C-terminal portion of CagA enhances SRE-driven transcription by activating an upstream signaling cascade without requiring CagA Tyr phosphorylation. This result suggests that translocated CagA regulates 2 distinct cellular responses: phosphorylation-dependent cytoskeletal rearrangement and phosphorylation-independent transcriptional activation.
Amino Acid Sequence↗
Polyurethane-covered metal stent for management of distal malignant biliary obstruction.
BACKGROUND: The efficacy of polyurethane-covered metal expandable stents for treatment of neoplastic distal biliary obstruction was analyzed. METHODS: Twenty-one patients with unresectable malignant tumors involving the mid to distal bile duct who were seen with obstructive jaundice were consecutively enrolled. Eighteen patients underwent endoscopic implantation of a polyurethane-covered metal stent and 3 patients underwent transhepatic insertion because of duodenal obstruction. The stent patency, complications, and patient survival were analyzed. RESULTS: Effective biliary decompression was achieved in all patients. Adverse events were minor: mild pancreatitis (1) and cholecystitis (2) occurred within 7 days of stent insertion. Mean survival and stent patency were 233 days and 206 days, respectively. Stent occlusion occurred in 3 patients (14%) after a mean of 188 days. Tumor ingrowth through the stent mesh was not observed. However, 2 stents were occluded by tumor overgrowth and 1 by compacted alimentary debris. CONCLUSIONS: A polyurethane membrane may prevent tumor ingrowth and reduce the occlusion rate for expandable metal stents implanted in patients with malignant obstruction of the distal bile duct.
Adult↗
Relationship between age and site of colorectal cancer based on colonoscopy findings.
BACKGROUND: Colorectal cancer occurs more frequently in older people. Because the population of aged persons is increasing, a better understanding of the characteristics of colorectal cancer with respect to age would be useful. The purpose of this study was to determine whether there is any relationship between the site of colorectal adenoma and adenocarcinoma in the colon and age. METHODS: Colonoscopy was performed (September 1995 to December 1998) on 2942 consecutive patients (1907 men, 1035 women; mean age 61 years, range 11 to 95 years) with no history of colorectal adenoma, adenocarcinoma, or inflammatory bowel disease. The occurrence of colorectal neoplasia, histologically proven as adenoma or adenocarcinoma, was analyzed for a possible association between site in the colon and patient age. RESULTS: Adenocarcinoma was found in 191 patients (196 lesions). The proportion of patients with right-sided colonic adenocarcinoma increased with patient age: < 50 years, 15% (2/13); 50 to 59 years, 21% (8/39); 60 to 69 years, 32% (18/57); 70 to 79 years, 42% (25/49); > or =80 years, 57% (16/28). The proportion of patients with right-sided adenoma did not significantly differ among age groups: < 50 years, 40% (98/246); 50 to 59 years, 41% (280/678); 60 to 69 years, 46% (459/1001); 70 to 79 years, 53% (270/508); and > or =80 years, 57% (87/152). CONCLUSION: The frequency of right-sided colon cancer increases with patient age. Hence, colonoscopy may be indicated in the elderly for colorectal cancer screening. Over half of colon carcinomas may be missed if sigmoidoscopy alone is used for screening.
Adenocarcinoma↗
[Triple therapy with faropenem, proton pump inhibitor (PPI), and amoxicillin for clarithromycin-resistant H. pylori eradication].
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2-Pyridinylmethylsulfinylbenzimidazoles↗
Expression of minichromosome maintenance-2 in human malignant fibrous histiocytomas: Correlations with Ki-67 and P53 expression, and apoptosis.
This study examined the clinicopathological significance of minichromosome maintenance-2 (MCM2) expression in 38 human malignant fibrous histiocytomas (MFHs) and 36 benign fibrohistiocytic tumors (BFHTs) immunohistochemically, and in 9 human sarcoma or carcinoma cell lines, as well as 7 surgical specimens by Western blotting. MCM2 was detected in all the cell lines and surgical specimens as a single band at 120 kDa, while P53 expression was variable. Nuclear expression of MCM2 was noted in tumor but not mitotic cells of all the MFHs and 26 (72.2%) of the BFHTs, the labeling indices (LIs) being 62.0% in the 28 ordinary types, 38.5% in the 10 myxoid types, and 11.2% in the BFHTs with significant difference. Moreover, the LI was significantly higher for MCM2 than that for Ki-67 in the MFHs of both types (p<0.05). No correlation was noted between the MCM2-LI and P53 expression or apoptotic indices, which were significantly higher in the MFHs than BFHTs (p<0.01). These results indicate that MCM2 would correlate with cell proliferation rather than apoptosis in MFHs, and the expression is ubiquitous in proliferating cells, regardless of the expression of P53. Thus, MCM2 might be a reliable marker of proliferating cells in human MFH.
Apoptosis↗
[HCV-related hepatocellular carcinoma].
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Carcinoma, Hepatocellular↗
Risk factors for esophageal variceal bleeding in patients with hepatocellular carcinoma.
BACKGROUND/AIMS: To evaluate the risk factors for esophageal variceal bleeding in patients with hepatocellular carcinoma. METHODOLOGY: 103 patients with esophageal varices and hepatocellular carcinoma without previous history of varices bleeding or treatment of varices were followed up and the risk factors for variceal bleeding were evaluated by Cox proportional hazards regression. RESULTS: During an average of 650 days' follow-up, 17 patients (17%) suffered from variceal bleeding, showing an annual incidence rate of 9.3%. Another 8 patients (8%) underwent endoscopic variceal ligation for the aggravation of esophageal varices. Multivariate analysis showed that the red color sign of varices and the size of tumor (> or = 33 mm) were independently associated with an increased risk of variceal bleeding (Risk Ratio = 20.33, P < 0.0001 and Risk Ratio = 2.64, P = 0.0231, respectively). CONCLUSIONS: The large size of tumor, as well as the red color sign of varices, was a significant risk factor for variceal bleeding in patients with hepatocellular carcinoma.
Aged↗
Factors affecting the prognosis of patients with hepatocellular carcinoma invading the portal vein--a retrospective analysis using 952 consecutive HCC patients.
BACKGROUND/AIMS: Hepatocellular carcinoma with portal venous invasion has a very poor prognosis. The aim of this study is to clarify the factors contributing to the survival of hepatocellular carcinoma patients with portal venous invasion. METHODOLOGY: Out of 952 patients with hepatocellular carcinoma admitted to Tokyo University hospital and its affiliated hospitals from 1987 to 1999, 53 patients developed portal venous invasion until December 2000. The main portal vein was invaded in 33 patients, and the first branch was invaded in the 20 patients. The factors contributing to the prognosis of hepatocellular carcinoma patients with portal venous invasion were determined by univariate and multivariate analyses using 19 clinicopathological parameters. RESULTS: Overall survival rates of the 53 patients at 6 months, and 1 and 2 years were 40%, 18%, and 12%, respectively. Univariate analysis indicated that the serum albumin level, Child classification, number of tumor foci, portal venous invasion-targeted irradiation, and percutaneous tumor ablation of the parenchymal main tumor were significant. Multivariate analysis showed that percutaneous tumor ablation (P = 0.033; risk ratio = 0.28) was the most important factor contributing to a favorable prognosis followed by number of tumor foci (P = 0.048; risk ratio = 0.41). CONCLUSIONS: This study showed the significance of treatment for the parenchymal main tumor in addition to portal venous invasion in patients with hepatocellular carcinoma involving portal venous invasion. Therefore, the efficacy of combined therapy using portal venous invasion-targeted irradiation and percutaneous tumor ablation for the parenchymal main tumor on survival of hepatocellular carcinoma patients with portal venous invasion is suggested.
Aged↗
A selective cyclooxygenase-2 inhibitor, NS-398, inhibits cell growth by cell cycle arrest in a human malignant fibrous histiocytoma cell line.
BACKGROUND: NS-398, a selective cyclooxygenase-2 (COX-2) inhibitor, has been shown to suppress cell proliferation and induce apoptosis in a variety of human cancer cell lines in vitro, except for sarcoma cell lines. The aim of this study was to examine the effect of NS-398 on two human malignant fibrous histiocytoma (MFH) cell lines: MFH-ino and MFH-ToE. MATERIALS AND METHODS: We investigated the effect of NS-398 at various concentrations on the growth of MFH cell lines using cell proliferation assay, cell cycle analysis and EIA assay of PGE2 production. RESULTS: Western blot analysis revealed COX-2 protein expression in both MFH cell lines. NS-398 at 10 or 100 microM resulted in inhibition of the cell proliferation in a dose- and time-dependent manner. NS-398 at 100 microM also induced G0/G1 arrest accompanied by up-regulation of P21WAF1 in MFH-ino cells in a time-dependent manner until 72 hours. NS-398 slightly increased the number of cells in the G2/M-phase and decreased the number in the G0/G1-phase in MFH-ToE cells lacking p53 gene function. Moreover, NS-398 down-regulated PGE2 production in the MFH-ToE cells in a time-dependent manner, but not in the MFH-ino cells. CONCLUSION: Our results indicate that NS-398 inhibits the cell growth and induces G0/G1 arrest in MFH-ino cells accompanied with up-regulation of P21WAF1.
Cell Cycle↗
Three-dimensional power Doppler ultrasonography for hepatocellular carcinoma: a comparison with angiography?
BACKGROUND/AIMS: To assess clinical usefulness of three-dimensional power Doppler ultrasonography for the diagnosis of hepatocellular carcinoma. METHODOLOGY: Fifty-two hepatocellular carcinoma nodules (median 31mm in diameter, range 8 to 94), histologically proven afterwards, in 33 patients were examined by three-dimensional power Doppler ultrasonography (ATL-HDI 5000 with a 5-MHz convex transducer) for tumor vascularity. We classified tumor Doppler signals into four types; Type 1: spotty signals in the tumor, Type 2: signals surrounding the tumor, Type 3: Type 3 with visualized penetrating arteries, Type 4: Type 3 with visualized drainage vein. Types 2-4 were considered specific to hepatocellular carcinoma, and compared with findings on digital subtraction angiography. RESULTS: Definite diagnosis of hepatocellular carcinoma was obtained in 29 of 52 nodules (56%) with three-dimensional ultrasonography (5 with Type 2, 19 with Type 3, and 5 with Type 4) while all nodules revealed tumor stain on angiography. 23 nodules showed only Type 1 signals, which were not specific to hepatocellular carcinoma. These nodules included small nodules less than 2cm in diameter, located more than 5cm from body surface, and those in the subphrenic portion of the left lobe. CONCLUSIONS: Three-dimensional power Doppler ultrasonography provides definite diagnosis of hepatocellular carcinoma in a real-time, non-invasive manner under certain conditions.
Aged↗
Factors predisposing to poorly differentiated hepatocellular carcinoma and its recurrence.
BACKGROUND/AIMS: We investigated the clinical factors predisposing moderately or poorly differentiated hepatocellular carcinoma and analyzed which clinical and histological factors are associated with poorly differentiated hepatocellular carcinoma (HCC) recurrence. METHODOLOGY: Percutaneous fine-needle biopsy was taken from the liver tumor of 191 consecutive patients between January 1994 and September 1996. The histological degree of differentiation of hepatocellular carcinoma at the first time of initial treatment and at the time of second recurrence was classified according to the criteria of Edmondson and Steiner. RESULTS: At the time of the first therapy, 86 patients, 81, 24, and 0 patients had liver tumors classified as Edmondson (Ed), 1, 2, 3, and 4, respectively. The prognosis of patients with Ed-3/4 HCC was worse than and the tumor sizes were larger than that of Ed-1/2 HCC patients. Of the 167 patients classified as Ed-1/2 at the time of first therapy, HCC recurred in 95 of the patients during the mean follow-up period of 3.4 years. Multivariate analysis revealed that only tumor size (P=0.035) and TACE therapy (P=0.0009) were independently significant factors in predicting future Ed-3/4 or multiple HCC recurrence. CONCLUSIONS: Tumor size and TACE therapy were clinical predisposing factors for Ed-3/4 or multiple HCC recurrences.
Adult↗
Age-related comparison of the profiles of patients with hepatocellular carcinoma.
BACKGROUND/AIMS: It is not known whether the putative etiologic factors and clinical and pathological features of hepatocellular carcinoma differ between young adults and older patients. Therefore this study aims to evaluate whether the clinicopathological features in young patients with HCC significantly differ from those of elderly patients. METHODOLOGY: A total of 1014 consecutive patients with HCC were divided into two groups based on age. Among them, 73 patients younger than 50 years of age comprised the first group and 941 patients 50 years and older made up the second. Clinical, laboratory, and pathological characteristics were compared between the two age groups. RESULTS: The male: female ratio and the incidence of positive hepatitis B surface antigen were significantly higher in young patients than in elderly patients. Tumor size, pathological grading of the tumor, and the severity of liver disease did not differ between the two groups. Especially in those patients demonstrating positive antibody to hepatitis C virus, alanine aminotransferase was higher in the younger, and platelet count was lower. Younger patients also had a higher ratio of alcohol consumption compared to elderly patients. CONCLUSIONS: There were age-related differences in the clinicopathological characteristics of HCC patients. Concerning hepatocarcinogenesis, male and HBsAg positive patients were at high risk in young. Of the HCV-related HCC patients, heavy drinking may accelerate the progression from chronic hepatitis to cirrhosis and HCC.
Adult↗