A prospective study of interferon therapy modified by pre‐treatment viral load in cirrhotic patients

Abstract: Background/Aims: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. Methods: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with “low” viral load (≤10^5.8 copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with “high” viral load (≤10^6.3 copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1404 MU). Results: HCV‐RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with “low” viral load, in contrast to 14% in patients with “high” viral load. Sustained virological response was found in 40% of patients with “low” viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with “high” viral load. Viral eradication was found in approximately 50% of patients having a low virus load (≤10^4.3 copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. Conclusions: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12‐month course of intensive IFN therapy. This result indicates that there is a certain cut‐off level of HCV RNA load which can not be eradicated.     

Declining trend in the in-hospital case-fatality rate from acute myocardial infarction in Miyagi Prefecture from 1980 to 1999.

The case-fatality rate from acute myocardial infarction (AMI) appears to have been declining in recent decades, so the present study reviewed the trend in in-hospital case-fatalities from AMI in Miyagi Prefecture, Japan, 1980-1999. The causes of death and the effects of gender and age on the trend were also analyzed. From the AMI registration database of the Miyagi Study Group for AMI, 12,961 cases of AMI were analyzed. The 30-day in-hospital case-fatality was calculated from the data for 1980-1999: data for causes of death were available for 1980-1997, and the data concerning primary percutaneous transluminal coronary angioplasty (PTCA) for AMI were available for 1997-1999. The in-hospital case-fatality rate declined from 17.0% in the early 80s to 7.3% in the late 90s (approximately 57% reduction). The in-hospital case-fatality rate was higher in female patients. Rhythm failure substantially decreased in the late 1980s. Pump failure is decreasing, but is still the biggest problem. The in-hospital case-fatality rate was significantly lower in patients received PTCA. The declining trend in the in-hospital case-fatality rate suggests the benefits of current therapeutic procedures, including primary PTCA, for AMI. Pump failure is an important target for further decreasing the trend.     

Interleukin-8 Production in Primary Cultures of Human Gastric Epithelial Cells Induced by Helicobacter pylori

Interleukin-8 (IL-8) production by the gastricmucosa is increased in Helicobacter pylori infection.Previous studies indicated that H. pylori induces IL-8synthesis in cancer cell lines, and the ability of H. pylori to stimulate IL-8 production issupposed to be associated with cag A and other cagpathogenicity island genes, including pic B gene. In thepresent study, we investigated the induction of IL-8 in primary cultures of normal human gastricepithelial cells to elucidate the IL-8 induction by wildtype strains and by the pic B knockout strain. Humangastric epithelial cells were obtained from surgically resected specimens from four patients. Three H.pylori strains (TN2F4; type 1 clinical isolate, TN2F4m1;isogenic pic B mutant of TN2F4, Tx30a; type 2 strain)were cocultured with the normal gastric epithelial cells or the transformed MKN-28. IL-8 levels inculture medium were determined by enzyme immunoassay.Human gastric epithelial cells produced IL-8 at a 10 -50times higher level than MKN-28 did when cocultured with TN2F4. The mutant TN2F4m1 induced IL-8 atsignificantly lower levels than the parent strain. Cellsfrom four patients behaved similarly on IL-8 production.The results of the present study demonstrated the induction of IL-8 in normal gastricepithelial cells, suggesting that pic B gene product mayplay an essential role in vivo.     

Polymorphisms of matrix metalloproteinase-7 and chymase are associated with susceptibility to and progression of gastric cancer in Japan

Background  Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most macromolecules making up the extracellular matrix. MMPs are involved in not only the gastric mucosal inflammatory response but also the pathogenesis of Helicobacter pylori-associated diseases. In the renin-angiotensin system, chymase (CMA) is related to gastric carcinogenesis and angiogenesis in H. pylori-infected patients. We aimed to clarify the association of MMP-7-181 and CMA/B polymorphisms with susceptibility to gastric cancer and cancer progression in H. pylori-infected patients. Methods  We assessed the MMP-7-181 and CMA/B polymorphisms in H. pylori-positive patients with gastric cancer (n = 160), gastric ulcer (n = 157), duodenal ulcer (n = 121), and H. pylori-positive gastritis alone as controls (n = 156). Results  For gastric cancer risk, the age-and sex-adjusted odds ratio (OR) of the MMP-7-181 G allele carrier relative to the A/A genotype was significantly increased [OR, 2.32; 95% confidence interval (CI), 1.24–4.35], especially in patients with noncardia cancer (OR, 2.31; 95% CI, 1.22–4.36) and those with clinical stage III or IV cancer (OR, 3.66; 95% CI, 1.54–8.73). Carriage of the CMA/B A allele was significantly associated with gastric cancer development (OR, 1.73; 95% CI, 1.10–2.71). Simultaneous carriage of both the MMP-7-181 G allele and the CMA/B A allele dramatically increased the gastric cancer risk (OR, 8.18; 95% CI, 2.79–23.93). Conclusions  In Japan, carriage of the MMP-7-181 G allele and of the CMA/B A allele were each associated with an increased risk for H. pylori-related noncardia gastric cancer development. MMP-7-181 and CMA/B genotyping tests might be useful tools for screening for individuals with higher gastric cancer risk.     

Impaired left ventricular rapid filling during exercise in patients with hypertrophic cardiomyopathy

The influence of exercise on left ventricular diastolic filling was evaluated in 14 patients with hypertrophic cardiomyopathy (HCM) and 14 normal controls (NC) by dynamic exercise echocardiography. Using X-Y digitizer and computer, normalized peak rate of change of the left ventricular dimension during systole (pVs) and the rapid filling phase (pVd) were determined from the left ventricular echocardiograms at rest and during exercise when heart rate reached 100 beats/min. At rest and during exercise, pVs was significantly higher in HCM (3.2 +/- 0.4/s at rest, 4.3 +/- 1.4/s during exercise) than in NC (2.4 +/- 0.5/s at rest, 3.0 +/- 0.4s during exercise) (p less than 0.001, p less than 0.001, respectively), but pVd in HCM (4.2 +/- 1.0/s at rest, 5.8 +/- 1.0/s during exercise) was not significantly different from that in NC (4.1 +/- 1.0/s at rest, 6.0 +/- 0.7/s during exercise). The ratio of pVd to pVs (pVd/pVs) in HCM did not show significant increment during exercise (1.35 +/- 0.38 to 1.43 +/- 0.35), though that ratio in NC was significantly increased by exercise (1.67 +/- 0.22/s to 1.97 +/- 0.19/s, p less than 0.001). There was no correlation between pVd and the degree of left ventricular hypertrophy. These results suggest that diastolic reserve to exercise is depressed in HCM and that other factors besides left ventricular hypertrophy may account for diastolic abnormality.     

What is the risk factor for metachronous colorectal carcinoma?

PURPOSE: The purpose of this study was to determine the risk factors for developing metachronous colorectal carcinoma and to determine an adequate postoperative colonoscopic surveillance. METHODS: Two hundred eighty-four patients, examined by routine colonoscopy after resection for colorectal carcinoma, were reviewed. Clinical and pathologic factors were assessed by multiple logistic regression analysis. RESULTS: One hundred eighty-three patients with synchronous adenoma or carcinoma at the initial operation had a significantly higher incidence of both metachronous adenoma and carcinoma than the 101 patients without a synchronous lesion. Other clinical factors including age, gender, tumor stage, tumor site, and tumor grade were not significant for an increased incidence of metachronous carcinoma. The presence of synchronous lesions proved to be the only risk factor (relative risk, 3.293;P=0.0155) for developing metachronous carcinoma. Metachronous carcinoma was detected in 30 patients (10.6 percent) and completely removed from all patients. Mucosal carcinoma was found in 25 patients (8.8 percent) and invasive carcinoma in 5 patients (1.8 percent). All five invasive carcinomas were detected in asymptomatic patients having synchronous lesion. Four patients required a second operation for metachronous carcinoma more than 13 months following the first. CONCLUSION: The risk factor for developing metachronous carcinoma is the presence of synchronous adenoma or carcinoma at the initial operation. To detect metachronous carcinoma at a curable stage, annual colonoscopic surveillance should be performed for highrisk patients.Read at the meeting of the Japanese Society of Gastroenterological Surgery, Osaka, Japan, February 22 to 23, 1996.