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Background: Although accumulating evidence suggests that exposure to organochlorine pesticides and polychlorinated biphenyls (PCBs) may contribute to the development of prostate cancer, few investigations have used biological samples to classify exposure to specific organochlorines. To our knowledge, this is the first prospective study to investigate the association between blood levels of organochlorines and prostate cancer risk., Methods: We conducted a nested case-control study using data from the Japan Public Health Center-based Prospective (JPHC) Study. A total of 14,203 men 40-69 years old who returned the baseline questionnaire and who provided blood samples were followed from 1990 to 2005. Using a mean follow-up period of 12.8 years, we identified 201 participants who were newly diagnosed with prostate cancer. Two matched controls for each case were selected from the cohort. We used a conditional logistic regression model to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer in relation to plasma levels of nine organochlorines: PCBs, dichlorodiphenyltrichloroethane (DDT), hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), trans- and cis-nonachlor, oxychlordane, and mirex., Results: No statistically significant association with total prostate cancer was seen for any plasma organochlorine, although we did observe an insignificant inverse association for plasma HCB and beta-HCH. Total PCB in plasma was also inversely associated with advanced prostate cancer but without statistical significance., Conclusion: Our results suggest that no overall association exists between prostate cancer and organochlorines at the levels measured in our study population.

Magnesium maintains genomic stability and is an essential cofactor for DNA synthesis and repair. Magnesium intake has been reported to be inversely associated with colorectal cancer (CRC) risk in Western populations. This study examined the association between dietary intake of magnesium and CRC risk in Japanese men and women aged 45-74 y. Data from 40,830 men and 46,287 women, at the 5-y follow-up of the Japan Public Health Center-based Prospective Study, who responded to a 138-item FFQ were used in this analysis. A total of 689 and 440 CRC events were observed during the mean follow-up of 7.9 and 8.3 y for men and women, respectively. When adjusted for potential confounders, the hazard ratio and 95% CI in the highest quintile of magnesium intake compared with the lowest quintile in men were 0.65 (95% CI, 0.40-1.03) for CRC (P-trend = 0.04), 0.48 (95% CI, 0.26-0.89) for colon cancer (P-trend = 0.01), and 0.97 (95% CI, 0.47-2.02) for rectal cancer (P-trend = 0.93). Borderline inverse associations were also observed in men who consumed alcohol regularly (P-trend = 0.07) or had a BMI <25 kg/m(2) (P-trend = 0.06). There were similar inverse associations for invasive colon cancer and distal colon cancer. There were no significant associations between magnesium intake and cancer risk in women. Higher dietary intake of magnesium may decrease the risk of CRC in Japanese men.

Gastric carcinogenesis may be under the combined influence of factors related to the host, Helicobacter pylori bacterial virulence and the environment. One possible host-related factor is the inflammatory or immune response. To clarify this point, we investigated the association between plasma levels of C-reactive protein (CRP) and serum amyloid A (SAA) and the subsequent risk of gastric cancer in a population-based nested case-control study. Subjects were observed from 1990 to 2004. Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 494 gastric cancer cases were identified and matched to 494 controls for our analysis. The overall distribution of CRP and SAA was not apparently associated with the development of gastric cancer. However, a statistically significant increased risk was observed when subjects were categorized dichotomously. The adjusted odds ratio (OR) for the development of gastric cancer for the CRP-positive group (CRP > 0.18 mg/dl) compared with the CRP-negative group was 1.90 [95% confidence interval (CI): 1.19-3.02, P = 0.007]. The OR for the SAA-positive group (SAA > 8 mug/ml) compared with the SAA-negative group was 1.93 (95% CI: 1.22-3.07, P = 0.005). In conclusion, our results suggest that those who react strongly to inflammation or who have a high host immune response, as reflected by extremely elevated plasma levels of CRP and SAA, are at a high risk to develop gastric cancer.

Background: Although case-control studies support the idea that soy foods or isoflavone intake is associated with a decreased risk of lung cancer, little evidence is available from prospective cohort studies. Moreover, no prospective study has addressed this association in men., Objective: We investigated the association between isoflavone intake and lung cancer incidence., Design: We conducted a population-based prospective cohort study in 36,177 men and 40,484 women aged 45-74 y with no history of cancer at baseline in 1995-1999. Participants responded to a validated questionnaire, which included 138 food items. We used Cox proportional hazards regression analysis to estimate the hazard ratios (HRs) and 95% CIs of lung cancer incidence according to isoflavone intake, which was estimated by genistein content from soy foods., Results: During 11 y (671,864 person-years) of follow-up, we documented 481 male and 178 female lung cancer cases. In men we found an inverse association between isoflavone intake and risk of lung cancer in never smokers (n = 13,051; multivariate HR in the highest compared with the lowest quartile of isoflavone intake: 0.43; 95% CI: 0.21, 0.90; P for trend = 0.024) but not in current or past smokers. A similar, nonsignificant inverse association was seen in never-smoking women (n = 38,211; HR: 0.67; 95% CI: 0.41, 1.10; P for trend = 0.135). We also tested effect modification by smoking status (P for interaction = 0.085 in men and 0.055 in men and women combined)., Conclusion: In a large-scale, population-based, prospective study in Japan, isoflavone intake was associated with a decreased risk of lung cancer in never smokers.

Background: Although the influence of salt, per se, on the risk of cancer or cardiovascular disease (CVD) might differ from that of salt-preserved foods, few studies have simultaneously examined the effects of sodium and salted foods on the risk of either cancer or CVD., Objective: We simultaneously examined associations between sodium and salted food consumption and the risk of cancer and CVD., Design: During 1995-1998, a validated food-frequency questionnaire was administered to 77,500 men and women aged 45-74 y. During up to 598,763 person-years of follow-up until the end of 2004, 4476 cases of cancer and 2066 cases of CVD were identified., Results: Higher consumption of sodium was associated with a higher risk of CVD but not with the risk of total cancer: multivariate hazard ratios for the highest compared with lowest quintiles of intake were 1.19 (95% CI: 1.01, 1.40; P for trend: 0.06) for CVD and 1.04 (95% CI: 0.93, 1.16; P for trend: 0.63) for total cancer. Higher consumption of salted fish roe was associated with higher risk of total cancer, and higher consumption of cooking and table salt was associated with higher risk of CVD. Similar results were seen for the risk of gastric or colorectal cancer and stroke., Conclusions: Sodium intake as a whole salt equivalent may not increase the risk of cancer but may increase that of CVD. In contrast, salted food intake may increase the risk of cancer. Our findings support the notion that sodium and salted foods have differential influences on the development of cancer and CVD.

Few studies have evaluated the association between alcohol intake and the risk of the lymphoid neoplasms malignant lymphoma (ML) and plasma cell myeloma (PCM) among Asian populations. We conducted a large-scale population-based cohort study of 95,520 Japanese subjects (45,453 men and 50,067 women; age 40-69 years at baseline) with an average 13 years of follow-up, during which a total of 257 cases of ML and 89 of PCM were identified. Hazard ratios and 95% confidence intervals were estimated using a Cox regression model adjusted for potential confounders. Alcohol intake of > or = 300 g/week was associated with a significantly lower risk of lymphoid neoplasms (hazard ratio, 0.60; 95% confidence interval, 0.37-0.98) than occasional drinking at a frequency of <1 day/month, and the trend for alcohol consumption was significant (P = 0.028). A similar trend was observed for the subcategories of ML, PCM, and non-Hodgkin lymphoma (NHL), albeit that the results were significant only for alcohol consumption at > or = 300 g/week in NHL patients, probably due to the small number of subjects in each category. In conclusion, we found that alcohol had an inverse association with the risk of lymphoid neoplasms, particularly the risk of NHL, among a Japanese population.

Although dietary risk factors may differ between localized and advanced prostate cancer, data on associations between the consumption of fruits and vegetables and risk of localized and advanced cancers are limited. We examined associations between fruit and vegetable consumption and risk of prostate cancer in a Japanese population. During 1995-1998, a validated food frequency questionnaire was administered to 43,475 men aged 45-74 yr. During 321,061 person-years of follow-up until the end of 2004, 339 cases of prostate cancer were identified. Consumption of fruits or total vegetables was not associated with a decreased risk of total prostate cancer, with corresponding multivariate hazard ratios of the highest vs. lowest quartiles of 1.09 (95% CI = 0.77-1.53; trend P = 0.39) for fruits and 1.33 (95% CI = 0.93-1.91; trend P = 0.52) for total vegetables. Also, no association was observed for intake of either fruits or vegetables (total or any subtype) with localized or advanced prostate cancer. This prospective cohort study suggests that consumption of fruits or vegetables may not be associated with the risk of either localized or advanced prostate cancer in Japanese men. However, the possibility of confounding by detection bias on the risk of localized cancer could not be totally ruled out.

Introduction: Although many in-vitro and animal studies have demonstrated a protective effect of green tea against breast cancer, findings from epidemiological studies have been inconsistent, and whether high green tea intake reduces the risk of breast cancer remains unclear., Methods: In this Japan Public Health Center-based Prospective Study, 581 cases of breast cancer were newly diagnosed in 53,793 women during 13.6 years' follow-up from the baseline survey in 1990-94. After the 5-year follow-up survey in 1995-98, 350 cases were newly diagnosed in 43,639 women during 9.5 years' follow-up. The baseline questionnaire assessed the frequency of total green tea drinking while the 5-year follow-up questionnaire assessed that of two types of green tea, Sencha and Bancha/Genmaicha, separately., Results: Compared with women who drank less than 1 cup of green tea per week, the adjusted hazard ratio [HR] for women who drank 5 or more cups per day was 1.12 (95% confidence interval [CI] 0.81-1.56; P for trend = 0.60) in the baseline data. Similarly, compared with women who drank less than 1 cup of Sencha or Bancha/Genmaicha per week, adjusted HRs for women who drank 10 or more cups per day were 1.02 (95% CI 0.55-1.89; P for trend = 0.48) for Sencha and 0.86 (0.34-2.17; P for trend = 0.66) for Bancha/Genmaicha. No inverse association was found regardless of hormone receptor-defined subtype or menopausal status., Conclusions: In this population-based prospective cohort study in Japan we found no association between green tea drinking and risk of breast cancer.

Few epidemiologic investigations of visceral adiposity and colorectal neoplasms have attempted the direct quantification of visceral fat. The authors measured visceral fat volume among middle-aged and elderly Japanese men and women who underwent colonoscopy and positron emission tomography/computed tomography for cancer screening in Tokyo, Japan, between February 2004 and February 2005, and examined the association between visceral adiposity and colorectal adenoma in 1,205 eligible subjects. Odds ratios and 95% confidence intervals for colorectal adenoma were estimated by using an unconditional logistic regression model after adjustment for potential confounders. Despite its high correlation with body mass index, visceral fat volume was associated with the prevalence of colorectal adenoma independently of body mass index in both sexes. After further adjustment for body mass index, the odds ratio of colorectal adenoma for the highest compared with the lowest quartile of visceral fat volume was 1.58 (95% confidence interval: 1.11, 2.24) for men and women combined. Conversely, body mass index was unlikely to modify the association between visceral fat volume and colorectal adenoma (P(interaction) = 0.39). These findings add to accumulating evidence that visceral adiposity exerts an important influence on the pathogenesis of colorectal neoplasms. The mechanisms of this potential association between visceral adiposity and colorectal carcinogenesis warrant further investigation.

Background: Previous experimental studies have suggested many possible anti-cancer mechanisms for green tea, but epidemiological evidence for the effect of green tea consumption on gastric cancer risk is conflicting., Objective: To examine the association between green tea consumption and gastric cancer., Methods: We analysed original data from six cohort studies that measured green tea consumption using validated questionnaires at baseline. Hazard ratios (HRs) in the individual studies were calculated, with adjustment for a common set of variables, and combined using a random-effects model., Results: During 2 285 968 person-years of follow-up for a total of 219 080 subjects, 3577 cases of gastric cancer were identified. Compared with those drinking <1 cup/day, no significant risk reduction for gastric cancer was observed with increased green tea consumption in men, even in stratified analyses by smoking status and subsite. In women, however, a significantly decreased risk was observed for those with consumption of > or =5 cups/day (multivariate-adjusted pooled HR = 0.79, 95% confidence interval (CI) = 0.65 to 0.96). This decrease was also significant for the distal subsite (HR = 0.70, 95% CI = 0.50 to 0.96). In contrast, a lack of association for proximal gastric cancer was consistently seen in both men and women., Conclusions: Green tea may decrease the risk of distal gastric cancer in women.

This study investigated the association between glutathione S-transferases (GST) polymorphisms and immunoglobin G (IgG) titer levels in serum against Helicobacter pylori (H. pylori). Out of a total 300 healthy subjects seropositive for H. pylori, we analyzed the relationship between 15 single-nucleotide polymorphisms (SNPs), namely two in GST-mu2 (GST-M2), five in GST-mu3 (GST-M3), four in GST-pi1 (GST-P1) and four in GST-theta2 (GST-T2), and IgG antibody titer levels in serum against cytotoxin-associated gene A (CagA) and the surface antigen of H. pylori (Hp), as well as the levels of pepsinogen I (PGI). Titer levels were classified by tertile. The age-sex adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in the middle and low titer groups were calculated using a polytomous logistic regression model, with the high titer group considered as control. Results for GST-M3 showed a significant association between SNPs, CagA and Hp titers. In addition, the AA genotype (high enzyme activity) from SNP rs7483 (Val224Ile) in GST-M3 showed a significantly low risk for being in the low titer group (OR: 0.48, 95% CI: 0.27-0.86 and OR: 0.46, 95% CI: 0.26-0.83 for CagA and Hp, respectively). Furthermore, the AA genotype from the rs7483 SNP showed significantly (P<0.05) higher PGI levels than did the genotypes harboring a G allele (mean (s.d.)=66.9 (32.0) and 59.1 (30.7) microg ml(-1) for AA and AG+GG, respectively). Our results suggest that GST-M3 polymorphisms are associated with levels of IgG titer in serum against H. pylori. GST-M3 activity is possibly involved in protection against mucosal atrophy caused by H. pylori as the levels of IgG titer and PGI are linked to mucosal status.

We conducted a case-control study in a Japanese population to investigate the association between dietary isoflavone intake and the risk of colorectal adenoma. Participants who underwent magnifying colonoscopy with dye spreading as part of a cancer screening programme responded to a self-administered questionnaire, which included lifestyle information and intake of 145 food items, before the colonoscopy. A total of 721 case and 697 control subjects were enrolled. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. We found a significant inverse association between dietary isoflavone intake and the risk of colorectal adenoma in men and women combined. However, the inverse association was not linear; rather, all quartiles above the first showed a similar decrease in risk, with multivariable-adjusted ORs and 95% CIs compared with the lowest quartile of 0.77 (0.57-1.04), 0.76 (0.56-1.02) and 0.70 (0.51-0.96) in the second, third and highest quartiles, respectively (P for trend=0.03). Of interest, the observed association was more prominent in women than in men. The observed ceiling effect associated with higher isoflavone intake suggests that a lower intake of dietary isoflavone might be associated with an increased risk of colorectal adenoma in Japanese populations.

Background: We clarified the clinical significance of measurement of IgG antibody titers against Helicobacter pylori using data from a nested case-control study from a large-scale cohort study in Japan., Method: Participants included 36,745 subjects from the Japan Health Center-based Prospective Study who responded to the baseline questionnaire and provided a blood sample. Subjects were aged 40-69 years and were followed over 15 years after initial sampling. Controls were matched to 511 gastric cancer patients. Plasma surface antigen (Hp)-IgG titer was measured using ELISA, and mucosal atrophy was determined by measuring pepsinogen I and II levels., Results: Seropositive subjects with low Hp-IgG titer and mucosal atrophy showed a higher risk for gastric cancer than high-titer subjects. Odds ratio (OR) referred to cases with true negative IgG titers and no mucosal atrophy. In moderately atrophic subjects, the low titer OR was 19.0, with a 95% confidence interval (CI) of 7.7-46.9, and 12.5 for high titer, with a 95% CI of 5.2-30.0. In severely atrophic subjects, the low titer OR was almost double that of high-titer subjects (OR = 30.2, 95% CI = 12.4-73.7 and OR = 15.9, 95% CI = 6.3-40.3, respectively). These associations were observed more frequently for differentiated than undifferentiated gastric cancer., Conclusion: Combination assay with Hp-IgG titer and pepsinogens may help identify groups at high risk for gastric cancer. Subjects with low Hp-IgG titer and mucosal atrophy were at extremely high risk for gastric cancer, particularly differentiated cancer. Subjects with this background may require ongoing observation and periodic endoscopic examination for early cancer detection.

The impact of metabolic factors, which are major risk factors for cardiovascular disease, on total cancer risk has not been clarified. We prospectively examined whether metabolic factors and their aggregates predict the subsequent occurrence of total and major sites of cancer in the Japan Public Health Center-based Prospective Study. A total of 27 724 participants (9548 men and 18 176 women) aged 40-69 years participating in a questionnaire and health checkup survey in 1993-1995 were followed for total cancer incidence through 2004. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for metabolic factors and for two criteria of their aggregates (three or more than three factors and two or more than two additional factors in addition to being overweight) with a Cox proportional hazards model to control for potential confounding factors. In both sexes, the presence of metabolic factors in the aggregate did not predict subsequent occurrence of cancer as a whole. By site, a significant increase in risk was observed for male liver cancer [HR = 1.73, CI = 1.03-2.91 (three or more than three factors); HR = 1.99, CI = 1.11-3.58 (two or more than two additional factors in addition to being overweight)], and female pancreatic cancer [HR = 1.99, CI = 1.00-3.96 (two or more than two additional factors in addition to being overweight)]. For other sites, positive associations were observed only for specific metabolic factors, that is, high triglycerides and male colon cancer (HR = 1.71, CI = 1.11-2.62), and obesity and female breast cancer (HR = 1.75, CI = 1.21-2.55). Metabolic factors in the aggregate may have little impact on total cancer risk in the Japanese population, although the association between specific components and specific cancers suggests an etiologic link between them.

We examined the effect of alcohol consumption, cigarette smoking and flushing response on esophageal squamous cell carcinoma (ESCC) in a large-scale population-based cohort study. 44,970 middle-aged and older Japanese men were followed. A total of 215 cases of ESCC were newly diagnosed. Alcohol consumption and cigarette smoking are strongly associated with the incidence of ESCC. Heavy alcohol consumption increased the risk of ESCC especially among heavy smokers with the flushing response (HR = 3.41, 95% CI = 2.10-5.51). Strong effect modification was detected in heavy smokers. Our results suggest that heavy alcohol consumption together with heavy smoking may increase the risk of ESCC particularly in individuals with the flushing response.

Coffee and caffeine consumption are thought to increase the risk of bladder cancer. However, few studies have stratified this risk by smoking status, which is a potential confounder. Here, we investigated the association between coffee, green tea (another major source of caffeine), and caffeine, and bladder cancer incidence in relation to smoking status. We conducted a population-based prospective study in a cohort of Japanese, comprising a total of 49 566 men and 54 874 women aged 40–69 years who reported their coffee and green tea consumption at baseline. During follow-up from 1990 through 2005, 164 men and 42 women were newly diagnosed with bladder cancer. Cigarette smoking was associated with an increased risk of bladder cancer, with a strong dose–response relationship. Coffee was positively associated with bladder cancer risk in men, without statistical significance. When stratified by smoking status, coffee and caffeine consumption were associated with an increased risk of bladder cancer in never- or former-smoking men, with hazard ratios (95% confidence interval) in the highest categories of coffee (one or more cups per day) and caffeine consumption compared with the lowest of 2.24 (95% CI = 1.21–4.16) and 2.05 (95% CI = 1.15–3.66), respectively. In conclusion, cigarette smoking was confirmed as a risk factor for bladder cancer. Coffee and caffeine may be associated with an increased bladder cancer risk in never or former smokers among Japanese men.

Objectives: To promote prevention strategies aimed at reducing the incidence of cancer or cardiovascular disease (CVD), we present a method to project the probability that a subject with given lifestyle risk factors will survive free from either of cancer or CVD., Methods: Projection models were developed from data from a cohort study conducted in Japan. During 1990-2003, 96,592 subjects were followed and 5797 cancer and 2591 CVD cases and 2395 deaths were identified. Smoking, alcohol intake and body mass index (BMI) were used as common risk factors in projection models., Results: According to the projection of individualized probability, avoidance of smoking, excess alcohol intake and high BMI increased 10-year disease-free survival probability from 81.4% to 92.9% and from 88.0% to 94.3% in 50- to 54-year-old men and women, respectively. In terms of population average risk, smoking cessation and avoidance of excess alcohol exerted a large impact, while decreasing BMI had a small impact due to the small at-risk population., Conclusions: Current smoking, excess alcohol intake and obesity were suggested as common risk factors for cancer and CVD. Considering the distribution of risk factors in the Japanese population, smoking prevention/cessation and reduction of excess alcohol intake would prevent a large number of incident cases.

Genomic DNA hypomethylation has been associated with colorectal carcinogenesis. Methionine synthase A2756G (MTR A2756G) is a common nonsynonymous polymorphism in the gene that encodes methionine synthase, a key enzyme in the pathway leading to DNA methylation. Several studies, but not all, have reported relatively lower plasma homocysteine among individuals with the AG or GG genotype. Meanwhile, higher plasma homocysteine was associated with genomic DNA hypomethylation in healthy volunteers. We therefore hypothesized that minor allele carriers possess a decreased risk of colorectal adenoma, and examined this hypothesis in a case-control study of colorectal adenoma in Japan involving 723 cases and 670 controls. An unconditional logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (95% CI) for colorectal adenoma after adjustment for potential confounders. Despite the lack of an overall association, we observed a significant interaction between MTR A2756G and alcohol intake (P for interaction = 0.007). Compared with never drinkers with the AA genotype, never drinkers with the AG or GG genotype exhibited a significantly decreased risk (OR, 0.56; 95% CI, 0.34-0.90) whereas heavy drinkers with the same genotypes showed a substantially increased risk (OR, 1.90; 95% CI, 1.04-3.46). In addition, a marginally significant interaction was observed with folate intake (P for interaction = 0.07). The G allele may confer protection against colorectal adenoma in the presence of a considerably good folate status. Our findings add to increasing evidence that DNA methylation plays an important role even at an early stage of colorectal carcinogenesis.

Purpose: The incidence of prostate cancer is much lower in Japanese than Western populations. Given the preventive effects of isoflavones on carcinogenesis in the prostate in many nonhuman studies and the high consumption of isoflavones in Japanese, this low incidence may be partly due to the effects of soy., Patients and Methods: We conducted a nested case-control study within the Japan Public Health Center-based Prospective Study. A total of 14,203 men aged 40 to 69 years who had returned the baseline questionnaire and provided blood samples were observed from 1990 to 2005. During a mean of 12.8 years of follow-up, 201 newly diagnosed prostate cancers were identified. Two matched controls for each case were selected from the cohort. Conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% CIs for prostate cancer in relation to plasma levels of isoflavone., Results: Plasma genistein level tended to be inversely associated with the risk of total prostate cancer. Although plasma daidzein showed no association, the highest tertile for plasma equol, a metabolite of daidzein, was significantly associated with a decreased risk of total prostate cancer (OR = 0.60; 95% CI, 0.36 to 0.99; P(trend) = .04). These inverse associations were strengthened after analysis was confined to localized cases, with ORs in the highest group of plasma genistein and equol compared with the lowest of 0.54 (95% CI, 0.29 to 1.01; P(trend) = .03) and 0.43 (95% CI, 0.22 to 0.82; P(trend) = .02), respectively. Plasma isoflavone levels were not statistically significantly associated with the risk of advanced prostate cancer., Conclusion: Isoflavones may prevent the development of prostate cancer.

Background: Calcium and vitamin D have a potential protective effect against colorectal cancer., Objective: We investigated the association of dietary intake of calcium and vitamin D with the risk of colorectal cancer in a large prospective cohort study of middle-aged Japanese men and women., Design: A total of 74 639 subjects (35 194 men and 39 445 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1999 to the end of 2004, during which time 761 cases of colorectal cancer (464 men, 297 women) were newly identified. Dietary intake of nutrients was calculated with the use of a 138-item self-administered food-frequency questionnaire., Results: After adjusting for potential confounding factors, the multivariate hazard ratio in the highest quintile of dietary calcium intake compared with the lowest was 0.71 (95% CI: 0.52, 0.98) among men. The association appeared to decrease considerably among subjects in the second quintile without a clear further dose-response relation (P for trend: 0.09). No association was seen among women. No statistically significant association with dietary vitamin D intake was seen in either men or women, although men in the highest dietary intake group of both nutrients had a lower risk than did men in the lowest group., Conclusions: These findings indicate a potential decrease in the risk of colorectal cancer with higher dietary intake of calcium among middle-aged Japanese men, who have a relatively low dietary intake of calcium. Although vitamin D and colorectal cancer risk were not associated, potential effect modification between calcium and vitamin D on the risk of colorectal cancer was indicated.

Objective: Although large-scale studies, including meta-analyses, on the association between alcohol consumption and lung cancer have been reported, the risk of lung cancer in extremely high consumption groups (>or=450 g ethanol/week) in both current smokers and nonsmokers remains unclear. Here, we investigated the association between alcohol consumption and lung cancer incidence., Methods: We conducted a population-based prospective cohort study in 46,347 Japanese men aged 40-69 years with no history of cancer at baseline in 1990-1994. We used Cox proportional hazards regression analysis to estimate the hazard ratio (HR) and 95% confidence interval (CI) of lung cancer incidence according to alcohol consumption., Results: During the 14-year follow-up period, we documented 651 cases of lung cancer. We found a positive association between alcohol consumption and lung cancer risk confined to current smokers. Compared with occasional drinkers, the multivariate HRs (95% CI) in the highest category (>or=450 g ethanol/week) were 1.31 (0.89-1.94) among total participants, 0.58 (0.26-1.30) (p for trend = 0.49) among nonsmokers, and 1.69 (1.05-2.72) (p for trend = 0.02) among current smokers., Conclusions: Among this population with a large variation in alcohol consumption, alcohol consumption was not an independent risk factor for lung cancer except for current smokers.

Coffee has been proposed to decrease the circulating insulin and estrogen levels, which are related to the development of endometrial cancer. However, few studies have prospectively assessed the association between coffee consumption and endometrial cancer. We conducted a population-based prospective cohort study in 53,724 Japanese women aged 40-69 years with no history of cancer at baseline in 1990-1994. We used Cox proportional hazards regression analysis to estimate the hazard ratio (HR) and 95% confidence interval (CI) of endometrial cancer incidence in relation to coffee consumption. All reported p values are 2-tailed. During the 15-year follow-up period, we documented 117 cases of endometrial cancer. Coffee consumption was significantly associated with a decreased risk of endometrial cancer. After adjustment for age, study area, body mass index, menopausal status, age at menopause for postmenopausal women, parity, use of exogenous female hormones, smoking status and by consumption of green vegetables, beef, pork and green tea, the multivariate HRs (95% CI) of endometrial cancer in women who drank coffee /=3 cups/day were 1.00, 0.97 (0.56-1.68), 0.61 (0.39-0.97) and 0.38 (0.16-0.91), respectively (p for trend = 0.007). In contrast, green tea consumption was not significantly associated with a reduced risk of endometrial cancer (p for trend = 0.22). The inverse association between coffee consumption and risk of endometrial cancer was consistently observed in subgroup analyses stratified by potential confounders. Coffee consumption may be associated with a decreased risk of endometrial cancer., ((c) 2008 Wiley-Liss, Inc.)

Evidence for an association between reproductive factors, exogenous female hormone use, and colorectal cancer risk from previous epidemiological studies remains controversial and information from nonwestern populations is limited. We analyzed this association in the Japan Public Health Center-based Prospective Study, conducted in 48 511 Japanese women aged 40-69 years who responded to a self-administered questionnaire that included history of reproductive factors, exogenous female hormone use, and other factors. During a mean follow-up of 12 years, a total of 538 colorectal cancer cases were newly identified. Age at menarche, menopausal status, history of exogenous female hormone use, parity, number of births, age at first birth, history of breast feeding, and reproductive period (postmenopausal women only) were not associated with colorectal cancer. When colon and rectal cancer were, however, analyzed separately among all women, multivariate-adjusted hazard ratios (95% confidence intervals) for colon cancer for age at first birth of 23-25, 26-29, 30 years or more in comparison to that at 22 years or less were 0.84 (0.64-1.12), 0.73 (0.53-1.01), and 0.66 (0.41-1.09), respectively (P for trend=0.03). These results were strengthened for colon cancer when analysis was restricted to postmenopausal women (P for trend=0.01), but no association was seen in premenopausal women (P for trend=0.59). In contrast, no statistically significant association was found for rectal cancer. These findings suggest that late age at first birth is associated with a reduced risk of colon cancer in postmenopausal Japanese women.

Epidemiological studies have consistently demonstrated a decrease in the risk of esophageal squamous cell carcinoma (SCC) associated with higher fruit and vegetable intake, although the association has been examined predominantly in case-control studies. Here, we conducted a population-based prospective cohort study among middle-aged Japanese men. Lifestyle characteristics were investigated using a self-administered questionnaire, which included a validated food frequency questionnaire with 138 food and beverage items. We followed a total of 38,790 men aged 45-74 years. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for esophageal SCC, with adjustment for potential confounders. During 297,651 person-years of follow-up, a total of 116 men were newly diagnosed with esophageal SCC. An increase in consumption of total fruit and vegetables by 100 grams per day (g/day) was associated with an 11% decrease in the incidence of esophageal SCC (95% CI: 1-21%). In particular, a higher intake of cruciferous vegetables was associated with a significant decrease in risk (HR per 100 g/day: 0.44; 95% CI: 0.23-0.82). Stratified analyses revealed that the beneficial effect of fruits and vegetables was not able to completely offset the harmful effect of tobacco and alcohol. Our findings provide further evidence for the protective role of fruits and vegetables in the development of esophageal SCC. To effectively reduce the burden of this disease, however, priority should be placed on smoking and drinking cessation. Finally, cruciferous vegetables deserve further investigation as foods possibly effective in the prevention of esophageal SCC.

Background: Although lower education has been associated with poorer health, few studies have examined whether lower education affects mortality, incidence, both or neither of cancer and cardiovascular disease., Methods: The authors conducted a population-based prospective cohort study among 39,228 men and women who were aged 40-59 years and lived in four areas in Japan. Information on education and lifestyle variables were obtained by a self-administered questionnaire in 1990. Follow-up until the end of 2002 (for incidence) or 2003 (for mortality) ascertained 2573 and 1251 incident cases of cancer and cardiovascular disease, respectively, and 2430 deaths (1064 from cancer, 548 from cardiovascular disease and 818 from other causes)., Results: After adjustment for demographic and lifestyle variables, <10 years of education, as compared with >12 years of education, was associated with significantly higher mortality from all causes [hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.05-1.42] and cardiovascular disease (HR = 1.44, 95% CI: 1.01-2.06), but was not associated with higher incidence of cardiovascular disease (HR = 0.96, 95% CI: 0.78-1.18) or higher mortality or incidence of cancer., Conclusion: The findings suggest that lower education is associated with higher mortality from all causes and cardiovascular disease among the Japanese population that is not totally attributable to lifestyle differences or higher cardiovascular disease incidence.

The objective of this study was to develop a computing tool for full-automatic segmentation of body fat distributions on volumetric CT images. We developed an algorithm to automatically identify the body perimeter and the inner contour that separates visceral fat from subcutaneous fat. Diaphragmatic surfaces can be extracted by model-based segmentation to match the bottom surface of the lung in CT images for determination of the upper limitation of the abdomen. The functions for quantitative evaluation of abdominal obesity or obesity-related metabolic syndrome were implemented with a prototype three-dimensional (3D) image processing workstation. The volumetric ratios of visceral fat to total fat and visceral fat to subcutaneous fat for each subject can be calculated. Additionally, color intensity mapping of subcutaneous areas and the visceral fat layer is quite obvious in understanding the risk of abdominal obesity with the 3D surface display. Preliminary results obtained have been useful in medical checkups and have contributed to improved efficiency in checking obesity throughout the whole range of the abdomen with 3D visualization and analysis.

To our knowledge, no prospective study has examined the association between blood levels of organochlorines and breast cancer risk in Asian countries. Here, we tested the hypothesis that higher blood levels of organochlorines are associated with an increased risk of breast cancer in Japanese women. A total of 24,226 women subjects of the Japan Public Health Center-based Prospective Study aged 40 to 69 years who responded to the baseline questionnaire and provided blood in 1990-1995 were followed to December 2002. During 10.7 years follow-up, 144 cases of breast cancer were newly diagnosed. Two matched-controls for each case were selected from the cohort. Plasma levels of p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and beta-hexachlorocyclohexane (beta-HCH) were measured. A conditional logistic regression was used to estimate the odds ratio (OR) of breast cancer according to cholesterol-adjusted organochlorine levels based on 139 matched pairs. We found no statistically significant positive association between plasma organochlorine level and breast cancer risk. Adjusted ORs for p,p'-DDT, HCB, and beta-HCH were less than 1. For p,p'-DDE, adjusted OR for the highest versus lowest quartile was 1.48 (95% confidence interval 0.70-3.13; p for trend=0.25). A stratified analysis by menopausal status showed positive associations for p,p'-DDT and p,p'-DDE in premenopausal but not postmenopausal women, although without statistical significance. Our data do not support the hypothesis that plasma levels of p,p'-DDT, p,p'-DDE, HCB, and beta-HCH are associated with an overall increased risk of breast cancer among Japanese women.

The impact of total physical activity level on cancer risk has not been fully clarified, particularly in non-Western, relatively lean populations. The authors prospectively examined the association between daily total physical activity (using a metabolic equivalents/day score) and subsequent cancer risk in the Japan Public Health Center-based Prospective Study. A total of 79,771 general-population Japanese men and women aged 45-74 years who responded to a questionnaire in 1995-1999 were followed for total cancer incidence (4,334 cases) through 2004. Compared with subjects in the lowest quartile, increased daily physical activity was associated with a significantly decreased risk of cancer in both sexes. In men, hazard ratios for the second, third, and highest quartiles were 1.00 (95% confidence interval (CI): 0.90, 1.11), 0.96 (95% CI: 0.86, 1.07), and 0.87 (95% CI: 0.78, 0.96), respectively (p for trend = 0.005); in women, hazard ratios were 0.93 (95% CI: 0.82, 1.05), 0.84 (95% CI: 0.73, 0.96), and 0.84 (95% CI: 0.73, 0.97), respectively (p for trend = 0.007). The decreased risk was more clearly observed in women than in men, especially among the elderly and those who regularly engaged in leisure-time sports or physical exercise. By site, decreased risks were observed for cancers of the colon, liver, and pancreas in men and for cancer of the stomach in women. Increased daily physical activity may be beneficial in preventing cancer in a relatively lean population.

The incidence of gastric cancer is two-fold to three-fold greater in men than in women. We investigated the reasons for this discrepancy by evaluating the impact of female reproductive factors on gastric cancer risk in the Japan Public Health Center-based Prospective Study. Among the 44,453 women enrolled, 368 cases of gastric cancer were newly diagnosed during follow-up from 1990 to 2004. The influence of female reproductive factors on risk was estimated using a multivariable Cox proportional hazards model after adjustment for potential confounders. Participants were stratified by menopause and gastric cancer status and further subdivided by histological type and anatomic subsite. No statistically significant association between female reproductive factors and gastric cancer risk was seen in general. Compared with those in late menarche (> or =15), however, women in early menarche (< or =12) had a close to 50% decreased risk of stomach cancer (hazard ratio 0.65, 95% confidence interval 0.43-0.98; P trend <0.01). Similar results were obtained in subgroup analyses categorized by histological subtype and anatomic subsite. Although early estrogen exposure may have some protective effect, female reproductive factors may have no substantial influence on gastric cancer development.

Several experimental studies have reported that the anticarcinogenic properties of dietary soy play an important role in preventing colorectal cancer. However, few epidemiologic studies have examined this association in general populations and their findings have been inconsistent. We investigated the association between dietary soy and isoflavone intake and incidence of colorectal cancer in a prospective cohort study of 83,063 Japanese men and women, ages 45 to 74 years. Dietary soy and isoflavone intake was measured through a validated food frequency questionnaire in 1995 and 1998. Throughout 2004, a total of 886 cases of colorectal cancer were newly identified (291 proximal colon, 286 distal colon, and 277 rectum). The hazard ratios and 95% confidence intervals (95% CIs) were estimated by fitting a Cox proportional hazards model. The intake of isoflavones, miso soup, and soy food was not associated with colorectal cancer in either men or women. By colorectal cancer subsite, the risk of proximal colon cancer in men decreased with increasing consumption of isoflavones, miso soup, and soy food. Compared with men in the lowest quartiles of isoflavones, miso soup, and soy food intake, the hazard ratios in the highest quartiles were 0.55 (95% CI, 0.33-0.92), 0.72 (95% CI, 0.43-1.21), and 0.51 (95% CI, 0.30-0.87), respectively. The results showed no association for distal colon and rectal cancer in men or for subsites of colorectal cancer in women. These findings suggest that the intake of isoflavones, miso soup, and soy food has no substantial effect on the risk of colorectal cancer in Japanese men and women.

Purpose: The impact of daily total physical activity level on premature deaths has not been fully clarified in non-Western, relatively lean populations. We prospectively examined the association between daily total physical activity level (METs/day) and subsequent risk of all-cause mortality and mortalities from cancer, heart disease, and cerebrovascular disease., Methods: A total of 83,034 general Japanese citizens ages 45-74 years who responded to the questionnaire in 1995-1999 were followed for any cause of death through December 2005. Mutlivariate-adjusted hazard ratios were calculated with a Cox proportional hazards model controlling for potential confounding factors., Results: During follow-up, a total of 4564 deaths were recorded. Compared with subjects in the lowest quartile, increased daily total physical activity was associated with a significantly decreased risk of all-cause mortality in both sexes (hazard ratios for the second, third, and highest quartiles were: men, 0.79, 0.82, 0.73 and women, 0.75, 0.64, 0.61, respectively). The decreased risk was observed regardless of age, frequency of leisure-time sports or physical exercise, or obesity status, albeit with a degree of risk attenuation among those with a high body mass index. A significantly decreased risk was similarly observed for death from cancer and heart disease in both sexes, and from cerebrovascular disease in women., Conclusion: Greater daily total physical activity level, either from occupation, daily life, or leisure time, may be of benefit in preventing premature death.

Colorectal cancer is an alcohol-related malignancy; however, the association appears to be stronger among Asian populations with a relatively high prevalence of the slow-metabolizing aldehyde dehydrogenase variant. To examine the association between alcohol consumption and colorectal cancer in Japanese, the authors analyzed original data from five cohort studies that measured alcohol intake using validated questionnaires at baseline. Hazard ratios were calculated in the individual studies, with adjustment for a common set of variables, and then combined using a random-effects model. During 2,231,010 person-years of follow-up (ranging variously from 1988 to 2004), 2,802 colorectal cancer cases were identified. In men, multivariate-adjusted pooled hazard ratios for alcohol intakes of 23-45.9 g/day, 46-68.9 g/day, 69-91.9 g/day, and > or =92 g/day, compared with nondrinking, were 1.42 (95% confidence interval (CI): 1.21, 1.66), 1.95 (95% CI: 1.53, 2.49), 2.15 (95% CI: 1.74, 2.64), and 2.96 (95% CI: 2.27, 3.86), respectively (p for trend < 0.001). The association was evident for both the colon and the rectum. A significant positive association was also observed in women. One fourth of colorectal cancer cases in men were attributable to an alcohol intake of > or =23 g/day. An alcohol-colorectal cancer association seems to be more apparent in Japanese than in Western populations. Whether this difference can be ascribed to genetic or environmental factors needs to be clarified.

Objectives: Single nucleotide polymorphisms (SNPs) have potential as markers for identifying genes responsible for common diseases and for personalized medicine. To investigate the association between polymorphisms and gastrointestinal (gastric and colorectal) cancer, we performed a hospital-based case-control study in Japan., Methods: We screened a total of 214 SNPs in 44 candidate genes by using a mass spectrometry-based technique (MassARRAY; Sequenom, Inc., San Diego, CA). In this study, 153 patients and 302 controls for gastric cancer and 121 patients and 245 controls for colorectal cancer were matched with regard to age, sex, and residential area. Genes were selected based on their possible interactions with the environment and lifestyle, and the candidate genes constitute those encoding xenobiotic metabolism enzymes, DNA repair enzymes, and other stress-related proteins. Each polymorphism was tested in controls to ensure its fit with Hardy-Weinberg equilibrium. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression analysis to estimate the association between genetic polymorphisms and the risk of gastric and colorectal cancers., Results: Twenty-one SNPs in nine genes were associated with the risk of gastric cancer (P < 0.05) and 15 SNPs in nine genes were associated with the risk of colorectal cancer (P < 0.05)., Conclusions: The findings of the present study will be the basis for future large-scale association studies of gene-environment factors using the candidate gene approach for the Japanese population.

Background: Although a number of reports regarding the role of reactive oxygen species (ROS) as the first step in cancer induction exist, few studies have investigated how vitamin C influences ROS in human plasma., Aim of the Study: Using the ROS assay system, a method recently established by one of the authors, we aimed to evaluate the effect of vitamin C supplementation on serum ROS among subjects diagnosed with chronic gastritis., Methods: A total of 244 Japanese subjects with atrophic gastritis were randomized to take 5-year supplementation of either 50 mg or 500 mg of vitamin C., Results: The adjusted difference in the changes of total ROS between baseline and after 5-year supplementation was statistically significant between the intervention groups: 2.70 decrease (corresponds to 1.26% decrease) in the high-dose group and 4.16 increase (corresponds to 3.79% increase) in the low-dose group, p for difference = 0.01., Conclusion: Vitamin C was suggested to reduce oxidative stress among subjects with atrophic gastritis.

Fruits and vegetables have been suggested to confer protection against diseases such as cancer through the effects of antioxidants, often represented by carotenoids. We investigated the impact of carotenoids, retinol and tocopherol on gastric cancer development in a large nested case-control study among Japanese with known Helicobacter pylori infection status. A total of 36 745 subjects aged 40-69 in the Japan Public Health Center-based Prospective Study who responded to the baseline questionnaire and provided blood samples in 1990-1995 were followed until 2004. Plasma levels of carotenoids in 511 gastric cancer cases and 511 matched controls were measured by high-performance liquid chromatography. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression models. Plasma level of beta-carotene was inversely associated with the risk of gastric cancer (compared with the lowest quartile: OR = 0.63, 95% CI = 0.31-0.75; OR = 0.48, 95% CI = 0.31-0.75 and OR = 0.46, 95% CI = 0.28-0.75, for quartile 2, 3 and 4, respectively, P(trend) < 0.01). Inverse associations were evident in men for alpha-carotene (P(trend) = 0.04) and beta-carotene (P(trend) < 0.01), but not in women, who had relatively higher plasma levels compared with men. We found no statistically significant association between plasma levels of lutein/zeaxanthin, lycopene, retinol, alpha- or gamma-tocopherol and gastric cancer risk. Our findings suggest that those who have very low plasma levels of alpha-carotene and beta-carotene are at a higher risk of gastric cancer.

Many epidemiologic studies have reported a positive association between dairy products and prostate cancer. Calcium or saturated fatty acid in dairy products has been suspected as the causative agent. To investigate the association between dairy products, calcium, and saturated fatty acid and prostate cancer in Japan, where both the intake of these items and the incidence of prostate cancer are low, we conducted a population-based prospective study in 43,435 Japanese men ages 45 to 74 years. Participants responded to a validated questionnaire that included 138 food items. During 7.5 years of follow-up, 329 men were newly diagnosed with prostate cancer. Dairy products were associated with a dose-dependent increase in the risk of prostate cancer. The relative risks (95% confidence intervals) comparing the highest with the lowest quartiles of total dairy products, milk, and yogurt were 1.63 (1.14-2.32), 1.53 (1.07-2.19), and 1.52 (1.10-2.12), respectively. A statistically significant increase in risk was observed for both calcium and saturated fatty acid, but the associations for these were attenuated after controlling for potential confounding factors. Some specific saturated fatty acids increased the risk of prostate cancer in a dose-dependent manner. Relative risks (95% confidence intervals) on comparison of the highest with the lowest quartiles of myristic acid and palmitic acid were 1.62 (1.15-2.29) and 1.53 (1.07-2.20), respectively. In conclusion, our results suggest that the intake of dairy products may be associated with an increased risk of prostate cancer.

Purpose: Because they have large variations in consumption, Asian countries are suitable settings for studies of the effect of relatively high-dose isoflavone intake on breast cancer risk. Nevertheless, no prospective study from Asia has assessed blood or urine levels as biomarkers of isoflavone intake., Patients and Methods: A total of 24,226 women ages 40 to 69 years in the Japan Public Health Center-based prospective study who responded to the baseline questionnaire and provided blood in 1990 to 1995 were observed to December 2002. During a mean 10.6 years of follow-up, 144 patients newly diagnosed with breast cancer were identified. Two matched controls for each patient were selected from the cohort. Isoflavone levels were assessed by plasma level and food frequency questionnaire, and the odds ratio of breast cancer according to isoflavone level was estimated using a conditional logistic regression model., Results: We found a statistically significant inverse association between plasma genistein and risk of breast cancer, but no association for plasma daidzein. Adjusted odds ratios for the highest versus lowest quartile of plasma level were 0.34 for genistein (95% CI, 0.16 to 0.74; P for trend, .02) and 0.71 for daidzein (95% CI, 0.35 to 1.44; P for trend, .54). Median plasma genistein values in the control group were 31.9 ng/mL for the lowest and 353.9 ng/mL for the highest quartile groups. Regarding dietary intake of isoflavones, nonsignificant inverse associations were observed for both genistein and daidzein., Conclusion: This nested case-control study found an inverse association between plasma genistein and the risk of breast cancer in Japan.

Abundant in vitro and animal studies have shown a protective effect of green tea against various types of cancer, but the evidence from epidemiologic studies is inconclusive. In this nested case-control study, we used plasma biomarkers to directly investigate the effect of tea polyphenols on the risk of gastric cancer. Subjects were followed up from 1990 to 2004. Among 36,745 subjects who answered the baseline questionnaire and provided blood samples, 494 gastric cancer cases matched to 494 controls were used in the analysis. The validated method used high-performance liquid chromatography to analyze baseline plasma samples. For men, a high plasma level of (-)-epigallocatechin was associated with an increased risk of gastric cancer. For women, a high plasma level of (-)-epicatechin-3-gallate (ECG) was associated with a decreased risk of gastric cancer; the adjusted odds ratios (95% confidence intervals) for ECG levels 0.32 to 9.2 and 9.3+ ng/mL were 1.03 (0.41-2.59) and 0.25 (0.08-0.73), respectively, compared with those whose ECG level was under the detection limit (P for trend = 0.02). Cigarette smoking was suggested to play a role as an effect modifier, which explains in part the different patterns observed by gender.

Although smoking is a major cause of lung cancer, the proportion of lung cancer cases among Japanese women who never smoked is high. As the prevalence of smoking in Japan is relatively high in men but low in women, the development of lung cancer in non-smoking Japanese women may be significantly impacted by passive smoking. We conducted a population-based prospective study established in 1990 for Cohort I and in 1993 for Cohort II. The study population was defined as all residents aged 40-69 years at the baseline survey. 28,414 lifelong non-smoking women provided baseline information on exposure to tobacco smoke from their husband, at the workplace and during childhood. Over 13 years of follow-up, 109 women were newly diagnosed with lung cancer, of whom 82 developed adenocarcinoma. Compared with women married to never smokers, hazard ratio (HR) [95% confidence interval (CI)] for all lung cancer incidence in women who lived with a smoking husband was 1.34 (95% CI 0.81-2.21). An association was clearly identified for adenocarcinoma (HR 2.03, 95% CI 1.07-3.86), for which dose-response relationships were seen for both the intensity (p for trend = 0.02) and amount (p for trend = 0.03) of the husband's smoking. Passive smoking at the workplace also increased the risk of lung cancer (HR 1.32, 95% CI 0.85-2.04). Moreover, a higher risk of adenocarcinoma was seen for combined husband and workplace exposure (HR 1.93, 95% CI 0.88-4.23). These findings confirm that passive smoking is a risk factor for lung cancer, especially for adenocarcinoma among Japanese women., ((c) 2007 Wiley-Liss, Inc.)

Objective: There is some evidence that folate may prevent colorectal cancer by stabilizing DNA sufficiently and methylating DNA appropriately. Plasma folate is a good marker to assess folate status in the body, but it has not been adequately examined in prospective epidemiologic studies. We investigated the association between plasma folate and the risk of colorectal cancer in a nested case-control study., Methods: During a 11.5-year follow-up, 375 newly diagnosed colorectal cancers were identified in a cohort of 38,373 adults who had returned their baseline questionnaires and provided blood samples. Two controls for each case were selected from the cohort. The odds ratios (OR) and 95% confidence intervals (CI) of colorectal cancer for plasma folate was estimated using the conditional logistic regression model adjusted for potential confounding factors., Results: Plasma folate was not associated with the risk of colorectal cancer in either men or women, although a small reduction of OR in men was observed in the second (OR, 0.70; 95% CI, 0.37-1.3), the third (OR, 0.72; 95% CI, 0.38-1.3), and the highest quartiles (OR, 0.86; 95% CI, 0.45-1.6) without a dose-response relationship (P for trend 0.88). A similar association was observed in the risk of colon or rectal cancer. No statistical interaction with the risk of colorectal cancer was observed between plasma folate and alcohol consumption., Conclusion: Our results did not support the hypothesis that a folate-rich status may prevent colorectal cancer, though that finding may be due to an insufficient number of folate-deficient subjects in our study population.

Objectives: We examined the association of potential risk factors with the incidence of biliary tract cancer in a large-scale population-based cohort study. Particular focus was placed on a history of cholelithiasis, body mass index (BMI), and their effect modification, and whether risk differs by cancer subsite, namely by gallbladder cancer and extrahepatic bile duct cancer., Design: We investigated 101,868 middle-aged and older Japanese subjects (48,681 men and 53,187 women) during 1,200,386 person-years of follow-up., Results: A total of 235 cases of biliary tract cancer (93 gallbladder cancer and 142 extrahepatic bile duct cancer) were newly diagnosed. Cholelithiasis was associated with an increased risk of biliary tract cancer [HR, 2.53; 95% CI, 1.56-4.12]. This association was similarly observed for both gallbladder [HR, 3.01; 95% CI, 1.56-6.19] and extrahepatic bile duct cancer [HR, 2.12; 95% CI, 1.08-4.18]. Body mass index was associated with an increased risk of extrahepatic bile duct cancer (P for trend = 0.03) and this effect was not modified by a history of cholelithiasis., Conclusions: Cholelithiasis was confirmed to be associated with the risk of biliary tract cancer, both gallbladder and extrahepatic bile duct cancer. Obesity may increase the risk of extrahepatic bile duct cancer only, independent of cholelithiasis.

Few studies have investigated the effects of fruit and vegetables on the risk of both cancer and cardiovascular disease (CVD). The authors examined associations between fruit and vegetable consumption and risk of total cancer and CVD in the same Japanese population. During 1995-1998, a validated food frequency questionnaire was administered in nine areas to 77,891 men and women aged 45-74 years. During as many as 459,320 person-years of follow-up until the end of 2002, 3,230 cancer cases and 1,386 CVD cases were identified. Higher consumption of fruit, but not vegetables, was associated with significantly lower risk of CVD: multivariate hazard ratios for the highest versus lowest quartiles of intake were 0.81 (95% confidence interval (CI): 0.67, 0.97; trend p = 0.01) for fruit and 0.97 (95% CI: 0.82, 1.15; trend p = 0.66) for vegetables. Consumption of fruit or vegetables was not associated with decreased risk of total cancer: corresponding hazard ratios were 1.02 (95% CI: 0.90, 1.14; trend p = 0.95) for fruit and 0.94 (95% CI: 0.84, 1.05; trend p = 0.16) for vegetables. This prospective cohort study demonstrated that, in the Japanese population, consumption of fruit is associated with lower risk of CVD, whereas fruit or vegetables may not be associated with lower risk of total cancer.

The incidence of prostate cancer is much lower in Asian than Western populations. Given that environmental factors such as dietary habits may play a major role in the causation of prostate cancer and the high consumption of green tea in Asian populations, this low incidence may be partly due to the effects of green tea. The JPHC Study (Japan Public Health Center-based Prospective Study) was established in 1990 for cohort I and in 1993 for cohort II. The subjects were 49,920 men aged 40-69 years who completed a questionnaire that included their green tea consumption habit at baseline and were followed until the end of 2004. During this time, 404 men were newly diagnosed with prostate cancer, of whom 114 had advanced cases, 271 were localized, and 19 were of an undetermined stage. Green tea was not associated with localized prostate cancer. However, consumption was associated with a dose-dependent decrease in the risk of advanced prostate cancer. The multivariate relative risk was 0.52 (95% confidence interval: 0.28, 0.96) for men drinking 5 or more cups/day compared with less than 1 cup/day (p(trend) = 0.01). Green tea may be associated with a decreased risk of advanced prostate cancer.

Background: The present study epidemiologically clarified the different roles of Helicobacter pylori (Hp) infection in carcinogenesis between two major histological types of noncardia gastric cancer (ncGC), intestinal (=differentiated) and diffuse (=undifferentiated), by analyzing IgG antibody titer against Hp surface antigen on the data set of a nested case-control study in a large cohort study conducted in Japan., Methods: A total of 36,745 subjects aged 40 to 69 years in the Japan Health Center-based prospective study who responded to the baseline questionnaire and provided blood were followed over 15 years; 350 ncGC cases (differentiated=242, undifferentiated=108) matched to controls were used. Using baseline blood samples, plasma IgG titer was measured using ELISA. The level of IgG titer >10 U (cut-off value) was classified into three grades in groups of equal number: low, middle, and high., Results: IgG titer of Hp was significantly (p<0.01) higher in undifferentiated cases than in differentiated ones. Among the three grades of Hp IgG titer, the high titer was more closely associated with risk of undifferentiated ncGC (odds ratio (OR) for high=7.8, 95% confidence interval (CI)=2.4-24.9 vs. OR for low=6.4, 95% CI=2.1-19.6), while the low titer was a better predictor of differentiated ncGC (OR for high=3.2, 95% CI=1.6-6.4 vs. OR for low=5.9, 95% CI=3.0-11.6, trend p < 0.05). The high titer group had the lowest risk to develop differentiated ncGC with <7 years (OR=3.2, 95% CI=1.3-7.7), whereas the high titer group demonstrated the highest risk for undifferentiated ncGC developing (OR=11.6 95% CI=2.3-59.1)., Conclusion: Our study epidemiologically confirmed that atrophic changes caused by Hp infection determine the development of differentiated-type ncGC, and the inflammation itself induced by Hp infection promotes the development of undifferentiated-type ncGC.

Pancreatic cancer is one of the most aggressive and treatment-refractory malignancies in humans. The most effective means of reducing pancreatic cancer mortality may be primary prevention. Although laboratory studies have demonstrated that green tea possesses anticancer activities, results from epidemiological studies have failed to show a consistent cancer-preventive effect. In addition, there is a lingering concern that coffee mighty increase the risk of pancreatic cancer although the most recent epidemiological studies showed no overall association between coffee and risk. Here, we examined the association between the drinking of green tea or coffee and the risk of pancreatic cancer in a large population-based cohort study in Japan (JPHC study). In total, 102 137 participants were followed for an average of 11 years through to the end of 2003. A total of 233 incident cases of pancreatic cancer were identified among 1 116 945 person-years of follow-up. Overall, the risk of pancreatic cancer was not associated with either green tea or coffee intake in our population, although a reduced risk was apparent among men who drank at least three cups of coffee per day compared with those who did not drink any or only rarely drank coffee. In conclusion, our findings support the idea that green tea or coffee consumption does not have a substantial impact on pancreatic cancer risk in general.

We prospectively examined the association between coffee consumption and the risk of developing colorectal cancer in a large population-based cohort study (the JPHC Study) of Japanese men and women. Data were analyzed from a population-based cohort of 96,162 subjects (46,023 men and 50,139 women). A total of 1,163 incident colorectal cancers were identified during the follow-up period, including 763 cases of colon cancer and 400 of rectal cancer. We observed a significant inverse association between coffee consumption and the risk of developing invasive colon cancer among women. Compared with those who almost never consumed coffee, women who regularly consumed 3 or more cups of coffee per day had a RR of 0.44 (95% CI = 0.19-1.04; p for trend = 0.04) after adjustment for potential confounding factors. However, no significant association was found for rectal cancer in women. In men, no significant decrease was observed in any colorectal cancer site. Further, additional analyses on the association of green tea consumption with colorectal cancer risk found no significant association in men or women. These findings suggest that coffee consumption may lower the risk of colon cancer among Japanese women., ((c) 2007 Wiley-Liss, Inc.)

We investigated the association between plasma 25(OH)D and the subsequent colorectal cancer incidence risk by a nested case-control study in The Japan Public Health Center-based Prospective Study, covering 375 newly diagnosed cases of colorectal cancer from 38 373 study subjects during a 11.5-year follow-up after blood collection. Two controls were matched per case on sex, age, study area, date of blood draw, and fasting time. In a conditional logistic regression model with matched pairs adjusted for smoking, alcohol consumption, body mass index, physical exercise, vitamin supplement use, and family history of colorectal cancer, plasma 25(OH)D was not significantly associated with colorectal cancer in men or in women. However, the lowest category of plasma 25(OH)D was associated with an elevated risk of rectal cancer in both men (odds ratio (OR), 4.6; 95% confidence interval (CI), 1.0-20) and women (OR, 2.7, 95% CI, 0.94-7.6), compared with the combined category of the other quartiles. Our results suggest that a low level of plasma 25(OH)D may increase the risk of rectal cancer.

Background: Helicobacter pylori is a major risk factor for atrophic gastritis and gastric cancer. Various extragastric manifestations of H. pylori infection have also recently been suggested. However, the correlation between H. pylori and colorectal cancer (CRC) is controversial. The aim of this study was to examine the correlation between H. pylori, serum gastrin level, and atrophic gastritis with CRC., Materials and Methods: Subjects were patients with CRC; controls were participants of a health check-up program that was conducted between October 1998 and March 2002 at four hospitals in Nagano Prefecture. For 121 newly diagnosed CRC cases, two controls matched by age (within 3 years), gender, and residence were randomly selected from the program participants. We conducted questionnaires and obtained blood samples from the cases and their controls. Consequently, the CRC cancer pairs consisted of 113 cases and 226 controls., Results: Neither H. pylori infection nor gastrin level nor atrophic gastritis showed any association with a risk for CRC. However, serologically determined atrophic gastritis demonstrated significant elevation in odds ratios (ORs) for rectal cancer (OR = 3.15, 95% confidence interval; 1.19-8.35)., Conclusions: Gastric conditions such as chronic H. pylori infection and atrophic gastritis are unlikely to increase the risk for CRC, although atrophic gastritis may increase the risk of rectal cancer.

Objective: The effects of BMI and physical activity on the risk of pancreatic cancer were investigated in a large population-based cohort study in Japan (JPHC study). In particular, we explored how these effects were influenced by smoking status and a history of diabetes., Methods: In total, 99,670 participants (47,499 men, and 52,171 women) were followed for an average of 11 years through the end of 2003. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated by Cox proportional hazards models., Results: A total of 224 incident cases (128 men, 96 women) of pancreatic cancer were identified. A statistically significant excess risk of pancreatic cancer was associated with current smoking (HR=1.8, CI 1.1-3.0) and a history of diabetes (HR=2.1, CI 1.3-3.5) among men. A similar increase in risk associated with current smoking (HR=2.0, CI 0.9-4.4) and diabetes (HR=1.5, CI 0.7-3.5) was also seen among women. BMI was inversely associated with risk of pancreatic cancer among men, especially among current male smokers or diabetes patients, but no association was found among women. Leisure-time physical activity was not associated with risk in either men or women., Conclusions: Our study confirms the association between cigarette smoking, history of diabetes and increased risk of pancreatic cancer. However, our data suggest that the association between BMI and risk of pancreatic cancer in this Japanese population may be different from that in Western populations.

We investigated the association of dietary intakes of folate, vitamin B-6, vitamin B-12, and methionine with the risk of colorectal cancer in a large prospective cohort study of middle-aged Japanese men and women. A total of 81,184 subjects (38,107 men and 43,077 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1998 to the end of 2002, during which 526 cases of colorectal cancer (335 men, 191 women) were newly identified. Dietary intake of nutrients was calculated using a 138-item self-administered FFQ. We observed a significant inverse association between vitamin B-6 intake and colorectal cancer in men. Compared with the lowest quartile, the multivariate hazard ratio (95% [CI]) in the highest quartile of intake was 0.69 (0.48-0.98) (P(trend) = 0.03). Men who consumed 150 g/wk alcohol or more had twice the risk of colorectal cancer of those who drank less in the lowest quartile of vitamin B-6 intake, but risk due to alcohol intake was not higher in the highest quartile of vitamin B-6 intake. Vitamin B-6 intake and colorectal cancer were not associated in women. Folate and methionine intakes were not associated with colorectal cancer risk in men or women, but colorectal cancer risk tended to increase (P(trend) = 0.05) with increasing intake of vitamin B-12 in men. Our results support previous evidence that low vitamin B-6 intake is associated with an increased risk of colorectal cancer. In particular, a higher intake of vitamin B-6 appears beneficial in men with higher alcohol intake.