Takuji Kishimoto

A community-based, case-control study evaluating mortality reduction from gastric cancer by endoscopic screening in Japan.

Aims Although the incidence of gastric cancer has decreased in the last 3 decades, it remains the second leading cause of cancer death worldwide. In Asian countries, the burden of gastric cancer has remained, and cancer screening is normally expected to reduce gastric cancer death. We conducted a community-based, case-control study to evaluate the reduction of mortality from gastric cancer by endoscopic screening. Methods Case subjects were defined as individuals who had died of gastric cancer between 2003 and 2006 in 4 cities in Tottori Prefecture, and between 2006 and 2010 in Niigata City, Japan. Up to 6 control subjects were matched by sex, birth year (±3 years), and the residence of each corresponding case subject from the population lists in the study areas. Control subjects were required to be disease-free at the time when the corresponding case subjects were diagnosed as having gastric cancer. The odds ratios (ORs) were calculated for those who had participated in endoscopic or radiographic screening before the reference date when the case subjects were diagnosed as having gastric cancer, compared with subjects who had never participated in any screening. Conditional logistic-regression models for matched sets were used to estimate the ORs and 95% confidence intervals (CIs). Results The case subjects consisted of 288 men and 122 women for case subjects, with 2,292 matched control subjects. Compared with those who had never been screened before the date of diagnosis of gastric cancer in the case subjects, the ORs within 36 months from the date of diagnosis were 0.695 (95% CI: 0.489–0.986) for endoscopic screening and 0.865 (95% CI : 0.631–1.185) for radiographic screening. Conclusions The results suggest a 30% reduction in gastric cancer mortality by endoscopic screening compared with no screening within 36 months before the date of diagnosis of gastric cancer.

Metabolic syndrome and incidence of liver and breast cancers in Japan

AIM OF THE STUDY To clarify the relationship between the presence of metabolic syndrome and the incidence of cancer in a general Japanese population. METHODS A retrospective cohort study was conducted among 8329 male and 15,386 female subjects between 1992 and 2000. The analysis used five definitions of metabolic syndrome. The information on the site-specific cancer was obtained from the population-based cancer registry. A Cox proportional hazard model was adapted for the statistical analyses. The average follow-up period was 9.1 years. RESULTS The National Cholesterol Education Program Adult Treatment Panel III 2001 criteria of metabolic syndrome revealed that the hazard ratio of metabolic syndrome for liver cancer was 1.89 (95% confidence interval (CI) 1.11-3.22) for males, and 3.67 (CI 1.78-7.57) for females. The hazard ratio for female breast cancer was 2.87 (CI 1.67-4.94). When the analysis was limited to postmenopausal women (55 years of age or older), the ratio increased to 6.73 (CI 2.93-15.43). The NCEP-ATPIII 2001 criteria were superior to the other four proposed criteria for predicting the incidence of cancer. In the statistical model, which included all components of the metabolic syndrome and the metabolic syndrome (present or absent), high blood glucose was a significant associated factor for all sites and liver cancers, whereas the metabolic syndrome was found to be a significant associated factor for breast cancer. CONCLUSION Metabolic syndrome may play an important role in the incidence of breast cancer. High fasting plasma glucose level is considered to be useful as an associated factor for the incidence of all-sites and liver cancer.

Sensitivity of endoscopic screening for gastric cancer by the incidence method

Although radiographic screening for gastric cancer has been conducted in Japan, it is anticipated that endoscopy will become a new screening method because of its high detection rate. The sensitivities of endoscopic and radiographic screening were calculated by the detection method and the incidence method based on the results of community‐based screening in Japan. There were 56,676 screenings for gastric cancer using endoscopy and radiography from April 2002 to March 2007 in Yonago, Japan. The target age group was from 40 to 79 years. Screen‐detected and interval cancers were investigated based on a screening database linked to the Tottori Cancer Registry. All gastric cancers diagnosed within 1 year after a negative screen were considered interval cancers. Based on the screening history, these were divided into prevalence screening and incidence screening. Prevalence screenings included 7,388 for endoscopic screening and 5,410 for radiographic screening, whereas incidence screenings included 18,021 for endoscopic screening and 11,417 for radiographic screening. The sensitivity of prevalence screening calculated by the incidence method was 0.886 (95% confidence interval [CI] = 0.698–0.976) for endoscopic screening and 0.831 (95% CI = 0.586–0.964) for radiographic screening; however, the difference was not significant (p = 0.626). The sensitivity of incidence screening calculated by the incidence method was 0.954 (95% CI = 0.842–0.994) for endoscopic screening and 0.855 (95% CI = 0.637–0.970) for radiographic screening (p = 0.177). Endoscopic screening for gastric cancer had a higher sensitivity than radiographic screening by the incidence method in both screening rounds. However, further study is needed to evaluate mortality reduction and to estimate overdiagnosis with endoscopic screening for gastric cancer.

Effect of methylmercury (CH3HgCl) injury on nitric oxide synthase (NOS) activity in cultured human umbilical vascular endothelial cells

The effects of methylmercury (CH3HgCl; MeHg) on the production of nitric oxide (NO) and the activity of the enzyme, nitric oxide synthase (NOS), in cultured human umbilical vascular endothelial cells (HUVEC) were examined. To assess the production of NO by HUVEC, platelet aggregation experiments were performed using cuvettes lined with HUVEC. Thrombin (0.05 U/ml)-induced platelet aggregation was inhibited in HUVEC pretreated with indomethacin (1 microM), an inhibitor of the cyclo-oxygenase pathway. The anti-platelet aggregatory effect of HUVEC treated with indomethacin was decreased dose-dependently by 48-h pretreatment with MeHg (0.5-2 microM). The effect of MeHg on the NADPH diaphorase staining of NOS in HUVEC showed dose-dependent cytotoxicity in regard to NOS activity. These findings suggest that MeHg inhibits the production of NO by HUVEC, an action which may be dependent on the cytotoxic effect exerted by MeHg on NOS activity.

Inhibitory effect of methylmercury on migration and tube formation by cultured human vascular endothelial cells

The effect of methylmercury chloride (MeHg) on migration and tube formation by cultured human umbilical vein endothelial cells (HUVECs) was quantitatively analyzed. The distance of endothelial cell outgrowth from the scraped edge of a monolayer was measured. HUVEC outgrowth was inhibited by MeHg (1.0–5.0 μM) treatment in a dose-dependent manner. Tube formation was studied by culturing the cells on gelled basement membrane matrix (Matrigel). Treatment of HUVECs with 0.1–5.0 μM MeHg for 24 h inhibited tube formation dose-dependently. These results suggest that migration and tube formation by HUVECs are susceptible to MeHg cytotoxicity, and that MeHg could be injurious to endothelial cell function, which may be involved in the pathogenesis of arteriosclerosis.

Effect of cadmium (CdCl2) on cell proliferation and production of EDRF (endothelium-derived relaxing factor) by cultured human umbilical arterial endothelial cells

The effect of cadmium chloride (CdCl2) on cell proliferation and EDRF (endothelium-derived relaxing factor) production by cultured human umbilical arterial endothelial cells (HUAECs) was investigated. The viability of HUAECs decreased dose-dependently after the addition of Cd (cadmium chloride). Morphologic examination by phase contrast microscopy revealed severe damaging effects of Cd at higher concentrations. The cytotoxic effect of Cd on DNA synthesis was also concentration-dependent. The effect of Cd on EDRF production by indomethacin-treated HUAECs was assessed by its anti-platelet aggeragory effect. Platelet aggregation studies were carried out in cuvettes lined with HUAECs using an aggregometer. The anti-platelet aggregatory effect was decreased dose-dependently by pretreatment with Cd. These findings suggest that HUAECs are susceptible to concentration-dependent Cd cytotoxicity, and that Cd can inhibit the production of EDRF by HUAECs.

Relation of the Glu298Asp polymorphism of the nitric oxide synthase gene to hypertension and serum cholesterol in Japanese workers

OBJECTIVE To assess whether the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene possibly mediates the relation of blood pressure and serum cholesterol. METHOD Regular health examination in 2003 of 1,694 Japanese workers from the Shimane Prefecture, Japan. RESULTS The frequencies of the Glu/Glu, Glu/Asp, and Asp/Asp genotypes were 85.9%, 13.4%, and 0.7%, respectively. After adjustment for age, sex, BMI, and lifestyle (drinking, smoking, exercise and stress), the odds ratio (OR) of hypertension associated with high (> or = 220 mg/dl or under treatment) total cholesterol was 2.08 (95% Confidence Interval (CI) 1.02-4.24) among carriers of the eNOS 298Asp allele versus 1.18 (95% CI 0.89-1.55, p for interaction=0.50) among non-carriers. Similarly, the ORs of hypertension associated with counseling-need (120-139 mg/dl) and high (> or = 140 mg/dl) levels of LDL cholesterol among carriers of the eNOS 298Asp allele were significantly higher than those among non-carriers, at 2.65 (95% CI 1.16-6.01) versus 1.03 (95% CI 0.77-1.39, p for interaction=0.01), and 2.80 (95% CI 1.33-5.89) versus 0.95 (95% CI 0.71-1.26, p for interaction=0.04), respectively. CONCLUSION These results indicate that the eNOS 298Asp allele, which is weakly associated with hypertension, may increase the risk of hypertension when associated with high serum lipid levels.

The current status of hand washing and glove use among care staff in Japan: its association with the education, knowledge, and attitudes of staff, and infection control by facilities.

ObjectiveHand hygiene is a basic measure to prevent infections. The purpose of this study was to obtain suggestions for the improvement of hand hygiene by evaluating the education, knowledge, and attitudes of care staff at facilities for the elderly in regard to hand washing and glove use, as well as infection control policies by those facilities.MethodsAmong a total of 147 special nursing homes and health service facilities for the elderly in Yamaguchi Prefecture, Japan, questionnaires were sent from October to November 2007 to 56 facilities which had agreed to participate in this survey. Two types of questionnaire, one for the facility manager and the other for care staff, were sent to each facility.ResultsThe questionnaire was responded to by 42 managers (response rate 28.6%) and 1,323 staff members (response rate 26.3%). The rate of compliance with hand hygiene among them was 34.0%. Personal factors promoting hand hygiene were education and attitudes, while facility-related factor was the implementation of hand-washing evaluation.ConclusionSince the hand hygiene compliance rate is low among care staff at facilities for the elderly, it is necessary to take measures to improve hand hygiene. Educational programs for hand hygiene should be developed in view of the conditions of individual facilities.

Polymorphism of Trp64Arg in β3-adrenergic receptor gene and serum LDL-cholesterol concentrations in healthy Japanese

Background Polymorphism of Trp64Arg in the β3-adrenergic receptor (β3-AR) gene may play a critical role in lipid and lipoprotein metabolism by mediating lipolysis and thermogenesis. Since the frequency of Arg alleles of the β3-AR gene is generally low among many populations, studies on the Arg/Arg genotype in relation to lipid and lipoprotein metabolism are required in countries such as Japan which has a relatively high frequency of the Arg allele. Methods We genotyped 275 clinically healthy Japanese (male/female, 134/141, mean 45.7 years) without medication for β3-AR gene polymorphism by polymerase chain reaction–restriction fragment length polymorphism analysis, and investigated the effects of the gene polymorphism on clinical parameters including body mass index (BMI), blood pressure and serum lipid and lipoprotein concentrations. Results The genotype frequencies were: Trp/Trp, 68.0%; Try/Arg, 28.0% and Arg/Arg, 4.0%, with an allele frequency of 0.18 for Arg64. When subjects were divided into three groups according to the genotype, a significant increase of serum LDL-cholesterol (LDL-C) concentration in the Arg/Arg group (3.48 ± 1.59 mmol/L) was observed when compared with those of the Trp/Trp and Arg/Trp groups (3.15 ± 0.80, 3.25 ± 0.92 mmol/L, respectively). Genotype differences did not show any significant effect on other parameters. Spearmans rank correlation demonstrated a significant relationship between LDL-C concentrations and the number of Arg alleles, age and BMI. Multiple regression analysis, using LDL-C concentration as a criterion variable and some factors including β3-AR gene polymorphism as explanatory variables, revealed that the number of Arg alleles was a significant and independent factor for LDL-C concentrations, along with age and BMI. Conclusions These findings suggested a role of the β3-AR gene polymorphism in regulating lipid and lipoprotein metabolism, showing small but significant effects on elevated LDL-C values in subjects with Arg/Arg, but not Trp/Arg and Trp/Trp genotypes.

Survival Analysis of Patients with Interval Cancer Undergoing Gastric Cancer Screening by Endoscopy

Aims Interval cancer is a key factor that influences the effectiveness of a cancer screening program. To evaluate the impact of interval cancer on the effectiveness of endoscopic screening, the survival rates of patients with interval cancer were analyzed. Methods We performed gastric cancer-specific and all-causes survival analyses of patients with screen-detected cancer and patients with interval cancer in the endoscopic screening group and radiographic screening group using the Kaplan-Meier method. Since the screening interval was 1 year, interval cancer was defined as gastric cancer detected within 1 year after a negative result. A Cox proportional hazards model was used to investigate the risk factors associated with gastric cancer-specific and all-causes death. Results A total of 1,493 gastric cancer patients (endoscopic screening group: n = 347; radiographic screening group: n = 166; outpatient group: n = 980) were identified from the Tottori Cancer Registry from 2001 to 2008. The gastric cancer-specific survival rates were higher in the endoscopic screening group than in the radiographic screening group and the outpatients group. In the endoscopic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer and the patients with interval cancer were nearly equal (P = 0.869). In the radiographic screening group, the gastric cancer-specific survival rate of the patients with screen-detected cancer was higher than that of the patients with interval cancer (P = 0.009). For gastric cancer-specific death, the hazard ratio of interval cancer in the endoscopic screening group was 0.216 for gastric cancer death (95%CI: 0.054-0.868) compared with the outpatient group. Conclusion The survival rate and the risk of gastric cancer death among the patients with screen-detected cancer and patients with interval cancer were not significantly different in the annual endoscopic screening. These results suggest the potential of endoscopic screening in reducing mortality from gastric cancer.