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Background/objectives: Eating a variety of foods has been recommended in the dietary guidelines of many developed nations, as well as global dietary guidelines. We investigated the potential effect of dietary diversity on the risk of total mortality and major causes of mortality in a large-scale cohort study involving the Japanese population., Subjects/methods: From 1995 to 2012, 79,904 participants (37,240 men and 42,664 women) aged 45 to 74 years, without histories of ischemic heart disease, stroke, or cancer were followed-up for a median of 14.9 years. We used 133 food and beverage items listed on a 5-year follow-up food frequency questionnaire, and the daily frequency of consumption for each item (excluding five alcoholic beverages) was counted. Multivariable-adjusted Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to compare the highest and lowest quintiles., Results: An inverse association was identified between total dietary diversity and mortality rates in women (highest quintile HR: 0.81; 95% CI: 0.71, 0.92; p for trend = 0.002) but the same trend was not observed in men (highest quintile HR: 0.96; 95% CI: 0.87, 1.10; p for trend = 0.266). In addition, fruit diversity was associated with lower mortality rates in men (highest quintile HR: 0.87; 95% CI: 0.79, 0.95; p for trend = 0.006), whereas soy diversity was associated with lower mortality rates in women (highest quintile HR: 0.89; 95% CI: 0.79, 1.00; p for trend = 0.004). With regard to men, meat and fish diversity were associated with higher mortality rates (highest quintiles of meat and fish diversity HR: 1.15 [95% CI: 1.06, 1.25] and 1.12 [95% CI: 1.02, 1.22], respectively)., Conclusions: These findings indicate that consuming a greater diversity of total foods and increasing the diversity of fruit and soy consumed have considerable public health implications.

Background & Aims: Many studies have suggested that fish intake is associated with protection from risk of atherosclerotic diseases; however, this association with aortic diseases has not been elucidated worldwide. We hypothesized that fish intake is inversely associated with mortality from aortic diseases (aortic dissection and aneurysm)., Methods: The study was conducted as a pooled analysis of original data from a maximum of 8 cohort studies, comprising a total of 366,048 community-based men and women who had no history of cardiovascular disease or cancer. In each cohort, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality from aortic dissection, aneurysm and total aortic disease according to the frequency of fish intake and estimated summary HRs derived from each study., Results: Nonlinear inverse associations were found between fish intake and total aortic disease. Compared with persons who ate fish 1-2 times/week, persons who seldom ate fish had higher mortality from total aortic disease (multivariable-adjusted pooled HR = 1.93; 95% CI, 1.13-3.31). Higher mortality was not seen in those who ate fish 1-2 times/month. A similar pattern was observed for aortic dissection. Regarding aortic aneurysm, both persons who seldom ate fish and those who ate fish 1-2 times/month had higher mortality (HR = 1.99; 95% CI, 0.90-4.40 and HR = 1.86; 95% CI, 0.87-3.98, respectively)., Conclusions: Persons who seldom ate fish had higher mortality from aortic dissection, aneurysm, and total aortic diseases., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Experimental and epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, but evidence is inconclusive. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations that minimize risk are unknown. Current Institute of Medicine (IOM) vitamin D guidance is based solely on bone health., Methods: We pooled participant-level data from 17 cohorts, comprising 5706 colorectal cancer case participants and 7107 control participants with a wide range of circulating 25(OH)D concentrations. For 30.1% of participants, 25(OH)D was newly measured. Previously measured 25(OH)D was calibrated to the same assay to permit estimating risk by absolute concentrations. Study-specific relative risks (RRs) for prediagnostic season-standardized 25(OH)D concentrations were calculated using conditional logistic regression and pooled using random effects models., Results: Compared with the lower range of sufficiency for bone health (50-<62.5 nmol/L), deficient 25(OH)D (<30 nmol/L) was associated with 31% higher colorectal cancer risk (RR = 1.31, 95% confidence interval [CI] = 1.05 to 1.62); 25(OH)D above sufficiency (75-<87.5 and 87.5-<100 nmol/L) was associated with 19% (RR = 0.81, 95% CI = 0.67 to 0.99) and 27% (RR = 0.73, 95% CI = 0.59 to 0.91) lower risk, respectively. At 25(OH)D of 100 nmol/L or greater, risk did not continue to decline and was not statistically significantly reduced (RR = 0.91, 95% CI = 0.67 to 1.24, 3.5% of control participants). Associations were minimally affected when adjusting for body mass index, physical activity, or other risk factors. For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women (RR = 0.81, 95% CI = 0.75 to 0.87) and 7% lower in men (RR = 0.93, 95% CI = 0.86 to 1.00) (two-sided Pheterogeneity by sex = .008). Associations were inverse in all subgroups, including colorectal subsite, geographic region, and season of blood collection., Conclusions: Higher circulating 25(OH)D was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men. Optimal 25(OH)D concentrations for colorectal cancer risk reduction, 75-100 nmol/L, appear higher than current IOM recommendations., (Published by Oxford University Press 2018.)

Background: To update the findings of relative risk associated with smoking for all-cause mortality and that for lung cancer by considering longitudinal changes in smoking status during follow-up., Methods: Data from the JPHC study of 98,747 middle-aged Japanese adults, which started in 1990-1993, were analyzed. The information on smoking status was obtained from three questionnaire surveys (baseline, the 5th year, and the 10th year after the start of follow-up). A Poisson regression model was used to investigate the impact of smoking on mortality from all causes and lung cancer using two approaches. Model 1 used information only from baseline, while model 2 used the updated smoking status from all three surveys., Results: During the 15-year follow-up, 10,702 all-cause deaths (including 870 lung cancer cases) were identified. We compared the results obtained from two models. The relative risks associated with former smokers versus never smokers were 1.42 (95% confidence interval [CI], 1.31-1.54) among men and 1.46 (95% CI, 1.23-1.73) among women for all-cause mortality and 2.98 (95% CI, 2.09-4.24) among men and 1.83 (95% CI, 0.92-3.64) among women for lung cancer mortality, as determined using model 2. All of these were higher than the relative risks obtained from model 1. In addition, former smokers who had quit smoking due to disease during follow-up had a higher mortality risk than continuous smokers did in this study., Conclusions: The relative risks of all-cause mortality and mortality due to lung cancer among former smokers be higher than previously documented based on updated smoking status data from repeated surveys.

Prior studies on red and processed meat consumption with breast cancer risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the relation of red meat and processed meat consumption with breast cancer incidence. We searched in MEDLINE and EMBASE databases through January 2018 for prospective studies that reported the association between red meat and processed meat consumption with incident breast cancer. The multivariable-adjusted relative risk (RR) was combined comparing the highest with the lowest category of red meat (unprocessed) and processed meat consumption using a random-effect meta-analysis. We identified 13 cohort, 3 nested case-control and two clinical trial studies. Comparing the highest to the lowest category, red meat (unprocessed) consumption was associated with a 6% higher breast cancer risk (pooled RR,1.06; 95% confidence intervals (95%CI):0.99-1.14; I 2 = 56.3%), and processed meat consumption was associated with a 9% higher breast cancer risk (pooled RR, 1.09; 95%CI, 1.03-1.16; I 2 = 44.4%). In addition, we identified two nested case-control studies evaluating the association between red meat and breast cancer stratified by N-acetyltransferase 2 acetylator genotype. We did not observe any association among those with either fast (per 25 g/day pooled odds ratio (OR), 1.18; 95%CI, 0.93-1.50) or slow N-acetyltransferase 2 acetylators (per 25 g/day pooled OR, 0.99; 95%CI, 0.91-1.08). In the prospective observational studies, high processed meat consumption was associated with increased breast cancer risk., (© 2018 UICC.)

Blood levels of inflammation-related markers may reveal molecular pathways contributing to carcinogenesis. To date, prospective associations with colorectal cancer (CRC) risk have been based on few studies with limited sets of analytes. We conducted a case-cohort study within the Japan Public Health Center-based Prospective Study Cohort II, comparing 457 incident CRC cases during median 18 years follow-up with a random subcohort of 774 individuals. Baseline plasma levels of 62 cytokines, soluble receptors, acute-phase proteins, and growth factor markers were measured using Luminex bead-based assays. We estimated hazard ratios (HRs) associating each marker with CRC risk by Cox proportional hazards models adjusted for potential confounders. Subanalyses compared cases by years after blood draw (<5 vs. ≥5) and anatomical subsite (colon vs. rectum). Linear trends in quantiles of four C-C motif ligand (CCL) chemokines, one C-X-C motif ligand (CXCL) chemokine, and a soluble receptor were nominally associated with CRC risk based on p trend < 0.05, but none met false discovery rate corrected statistical significance. HRs for the 4th vs. 1st quartile were: 1.69 for CCL2/MCP1, 1.61 for soluble tumor necrosis factor receptor 2, 1.39 for CCL15/MIP1D, 1.35 for CCL27/CTACK, 0.70 for CXCL6/GCP2 and 0.61 for CCL3/MIP1A. Among cases diagnosed 5+ years after enrollment, CCL2/MCP1, CCL3/MIP1A and CXCL6/GCP2 retained nominal statistical significance. There were no significant differences in associations between colon and rectum. Our findings implicate chemokine alterations in colorectal carcinogenesis, but require replication for confirmation. Noninvasive chemokine assays may have potential application in colorectal cancer screening and etiologic research., (© 2018 UICC.)

The association between plasma C-peptide concentration and prostate cancer is unclear. Inconsistency of results from previous studies motivates this study. Using the Japan Public Health Center-based Prospective study, 201 prostate cancer cases and 402 controls were matched by age, public health center area, residence, date and time of blood collection, and fasting duration before blood collection. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated by conditional logistic regression models. Out of 201 cases, 144 were localized and 48 were advanced. The overall association between median plasma C-peptide concentration and prostate cancer was not significant (OR for the highest tertile=0.81, 95% CI: 0.43-1.56, P-trend=0.54). Although stratification of prostate cancer by stage indicated different effects of plasma C-peptide on localized and advanced cases, there was no association between plasma C-peptide concentration and advanced prostate cancer (OR=2.82, 95% CI: 0.30-26.36 for the highest category, P-trend=0.37) and localized cases (OR=0.49, 95% CI: 0.23-1.04 for the highest category, P-trend=0.06) for patients fasting at the time of blood collection. The association between plasma C-peptide concentration and prostate cancer risk differed by cancer stage. Differentiation of localized and advanced prostate cancer cases is crucial when investigating the association between plasma C-peptide concentration and the risk of prostate cancer.

The aim of this study was to evaluate the associations between menstrual and reproductive factors and thyroid cancer risk among Japanese women. A total 54 776 women aged 40-69 years completed a self-administered questionnaire, which included menstrual and reproductive history. During 1990-2012, 187 newly diagnosed cases of thyroid cancer were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for menstrual and reproductive factors and incidence of thyroid cancer were estimated using Cox proportional hazards regression. Postmenopausal women who had natural menopause were at reduced risk of thyroid cancer than premenopausal women in the age-area-adjusted model (HR: 0.62 per 1 year increase, 95% CI: 0.39-0.99), but this association was slightly attenuated and no longer statistically significant in the multivariable-adjusted model. On analysis by menopausal status, an inverse association between age at menarche and risk of thyroid cancer was observed for premenopausal women (HR: 0.83 per 1 year increase, 95% CI: 0.70-0.98, P trend=0.03), but not for postmenopausal women. The risk of thyroid cancer increased with surgical menopause compared with natural menopause (HR: 2.34, 95% CI: 1.43-3.84). Although increasing age at menopause and duration of fertility were associated with an increased risk of thyroid cancer, this association was not observed among postmenopausal women. This study confirmed that early age at menarche for premenopausal women and surgical menopause and late age at natural menopause for postmenopausal women were associated with the development of thyroid cancer. Our results support the hypothesis that exposure to estrogens increases the risk of thyroid cancer.

Purpose: The development of prostate cancer may be impacted by environmental factors, including diet. The aim of this study was to evaluate the association between dietary patterns and risk of prostate cancer in a large prospective cohort study among Japanese men., Methods: A total of 43,469 men who participated in the Japan Public Health Center-based Prospective Study were followed from 1995 to 1998 to the end of 2012, during which 1,156 cases of prostate cancer were newly identified. Dietary intake was assessed using a validated food frequency questionnaire in the 5-year follow-up survey., Results: Three major dietary patterns were derived using exploratory factors analysis: prudent, westernized, and traditional dietary patterns. The westernized dietary pattern was associated with a higher risk of total prostate cancer (HR: 1.22; 95% CI 1.00-1.49; p trend = 0.021), localized cancer (HR: 1.24; 95% CI 0.97-1.57; p trend = 0.045), and advanced cancer (HR: 1.23; 95% CI 0.82-1.84; p trend = 0.233). The prudent dietary pattern was associated with a lower risk of total and localized prostate cancer, with respective multivariable HRs for the highest and lowest quintiles of 0.71 (95% CI 0.50-1.02; p trend = 0.037) and 0.63 (95% CI 0.38-1.03; p trend = 0.048) among subjects detected by subjective symptoms. No association was found between the traditional dietary pattern and prostate cancer risk among our subjects., Conclusion: Our results suggest that a western-style diet may lead to a higher risk of prostate cancer in the total population, whereas the prudent diet contributes to a lower risk among subjects detected by subjective symptoms.

A comprehensive evidence-based cancer prevention recommendation for Japanese was developed. We evaluated the magnitude of the associations of lifestyle factors and infection with cancer through a systematic review of the literature, meta-analysis of published data, and pooled analysis of cohort studies in Japan. Then, we judged the strength of evidence based on the consistency of the associations between exposure and cancer and biological plausibility. Important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: 'Cancer Prevention Recommendation for Japanese'. The recommendation addresses six important domains related to exposure and cancer, including smoking, alcohol drinking, diet, physical activity, body weight and infection. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination.

Background: A high body mass index (BMI) has been proposed as an important risk factor for pancreatic cancer. However, this association of BMI with pancreatic cancer risk has not been confirmed in Asian populations., Methods: We evaluated the association between BMI (either at baseline or during early adulthood) and pancreatic cancer risk by conducting a pooled analysis of nine population-based prospective cohort studies in Japan with more than 340,000 subjects. Summary hazard ratios (HRs) were estimated by pooling study-specific HRs for unified BMI categories with a random-effects model., Results: Among Japanese men, being obese at baseline was associated with a higher risk of pancreatic cancer incidence (≥30 kg/m 2 compared with 23 to <25 kg/m 2 , adjusted HR 1.71; 95% confidence interval [CI], 1.03-2.86). A J-shaped association between BMI during early adulthood and pancreatic cancer incidence was seen in men. In contrast, we observed no clear association among women, although there may be a positive linear association between BMI at baseline and the risk of pancreatic cancer (per 1 kg/m 2 , adjusted HR 1.02; 95% CI, 1.00-1.05)., Conclusions: Pooling of data from cohort studies with a considerable number of Japanese subjects revealed a significant positive association between obesity and pancreatic cancer risk among men. This information indicates that strategies that effectively prevent obesity among men might lead to a reduced burden of pancreatic cancer, especially in Asian populations.

Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer incidence in Western countries. However, few epidemiological studies have assessed the association between anthropometric factors, such as BMI, height, or weight, and thyroid cancer incidence in Asian populations. Using the population-based Japan Public Health Center-based prospective study database, we investigated the relationship between anthropometric factors and thyroid cancer incidence. Data on anthropometric factors were collected through a self-administered questionnaire at baseline. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards model, and the exposure level was categorized into quintiles. A total of 49,062 men and 53,661 women enrolled between 1990 and 1994 were included in our analyses, and 191 cases (37 in men and 154 in women) of thyroid cancer were identified, with 1,695,702 person-years of follow-up until 2010. Compared with the male group with height ≤160 cm, HRs of the male groups with height 165-168 cm and ≥169 cm were 3.92 (95% CI; 1.33-11.55, P = 0.013) and 4.24 (95% CI; 1.32-13.61, P = 0.015), respectively, and the HR per 5-cm increase in height was 1.12 (95% CI 1.06-1.18, P < 0.001). In contrast, the association between anthropometric features and the risk of thyroid cancer did not significantly differ among women. In this population, an increase in risk for increased height was observed in men, but no associations between anthropometric indexes and thyroid cancer risk were observed in women., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Many epidemiological studies have indicated a positive association between coffee intake and lung cancer risk, but such findings were suggested to be confounded by smoking. Furthermore, only a few of these studies have been conducted in Asia. Here, we investigated the association between coffee intake and lung cancer risk in one of the largest prospective cohort studies in Japan., Methods: We investigated the association of coffee drinking and subsequent incidence of lung cancer among 41,727 men and 45,352 women in the Japan Public Health Center-based Prospective Study using Cox proportional hazards regression, with adjustment for potential confounders and by strata of smoking status. Coffee and other dietary intakes were assessed once at baseline with a food frequency questionnaire (FFQ)., Results: During 1,481,887 person-years of follow-up between 1990 and 2011, a total of 1,668 lung cancer cases were identified. In a multivariate regression model, coffee consumption was not associated with risk of lung cancer (HR 1.16; 95% CI, 0.82-1.63; P trend = 0.285 for men and HR 1.49; 95% CI, 0.79-2.83; P trend = 0.942 for women). However, there was a significant increase in the risk for small cell carcinoma (HR 3.52; 95% CI, 1.49-8.28; P trend < 0.001)., Conclusion: Our prospective study suggests that habitual consumption of coffee is not associated with an increased risk of lung cancer incidence, despite observing a significant increase in the risk for small cell carcinoma.

Background: We examined the associations of alcohol consumption and liver holidays with all-cause mortality and with mortality due to cancer, heart disease, cerebrovascular disease, respiratory disease, and injury using a large-scale prospective study in Japan., Methods: We followed 102,849 Japanese who were aged between 40 and 69 years at baseline for 18.2 years on average, during which 15,203 deaths were reported. Associations between alcohol intake and mortality risk were assessed using a Cox proportional hazards model, with analysis by the number of liver holidays (in which a person abstains from drinking for several days a week)., Results: A J-shaped association was observed between alcohol intake and total mortality in men (nondrinkers: reference; occasional drinkers: hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.68-0.80; 1-149 g/week: HR 0.76; 95% CI, 0.71-0.81; 150-299 g/week: HR 0.75; 95% CI, 0.70-0.80; 300-449 g/week: HR 0.84; 95% CI, 0.78-0.91; 450-599 g/week: HR 0.92; 95% CI, 0.83-1.01; and ≥600 g/week: HR 1.19; 95% CI, 1.07-1.32) and in women (nondrinkers: reference; occasional: HR 0.75; 95% CI, 0.70-0.82; 1-149 g/week: HR 0.80; 95% CI, 0.73-0.88; 150-299 g/week: HR 0.91; 95% CI, 0.74-1.13; 300-449 g/week: HR 1.04; 95% CI, 0.73-1.48; and ≥450 g/week: HR 1.59; 95% CI, 1.07-2.38). In current drinkers, alcohol consumption was associated with a linear, positive increase in mortality risk from all causes, cancer, and cerebrovascular disease in both men and women, but not heart disease in men. Taking of liver holidays was associated with a lower risk of cancer and cerebrovascular disease mortality in men., Conclusions: Alcohol intake showed J-shaped associations with the risk of total mortality and three leading causes of death. However, heavy drinking increases the risk of mortality, which highlights the necessity of drinking in moderation coupled with liver holidays.

Although the impact of tobacco consumption on the occurrence of lung cancer is well-established, risk estimation could be improved by risk prediction models that consider various smoking habits, such as quantity, duration, and time since quitting. We constructed a risk prediction model using a population of 59 161 individuals from the Japan Public Health Center (JPHC) Study Cohort II. A parametric survival model was used to assess the impact of age, gender, and smoking-related factors (cumulative smoking intensity measured in pack-years, age at initiation, and time since cessation). Ten-year cumulative probability of lung cancer occurrence estimates were calculated with consideration of the competing risk of death from other causes. Finally, the model was externally validated using 47 501 individuals from JPHC Study Cohort I. A total of 1210 cases of lung cancer occurred during 986 408 person-years of follow-up. We found a dose-dependent effect of tobacco consumption with hazard ratios for current smokers ranging from 3.78 (2.00-7.16) for cumulative consumption ≤15 pack-years to 15.80 (9.67-25.79) for >75 pack-years. Risk decreased with time since cessation. Ten-year cumulative probability of lung cancer occurrence estimates ranged from 0.04% to 11.14% in men and 0.07% to 6.55% in women. The model showed good predictive performance regarding discrimination (cross-validated c-index = 0.793) and calibration (cross-validated χ 2 = 6.60; P-value = .58). The model still showed good discrimination in the external validation population (c-index = 0.772). In conclusion, we developed a prediction model to estimate the probability of developing lung cancer based on age, gender, and tobacco consumption. This model appears useful in encouraging high-risk individuals to quit smoking and undergo increased surveillance., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The effects of cigarette smoking and alcohol drinking on the incidence of oral cavity and pharyngeal cancer (OCPC) in the Asian population have been poorly understood. To assess the effects of cigarette smoking, alcohol drinking, and facial flushing response on incidence of OCPC, a total of 95 525 middle-aged and older eligible individuals were followed in a large-scale population-based cohort study in Japan from 1990 to 2010. In this study, the person-years of observation were 698 006 in men and 846 813 in women, and a total of 222 cases (men=160, women=62) of OCPC were newly diagnosed during the study period. A multivariate Cox proportional-hazards model was used to assess the incidence risk of OCPC and subsites by cigarette smoking and alcohol drinking. The result showed that cigarette smoking and regular alcohol drinking were associated significantly with the incidence of OCPC in men. Compared with nonsmokers and nondrinkers, current male smokers showed a hazard ratio (HR) of 2.37 [95% confidence interval (CI)=1.51-3.70] and regular male drinkers showed an HR of 1.82 (95% CI=1.20-2.76). Cigarette smoking also increased the risk of OCPC among male heavy alcohol drinkers (HR=4.05, 95% CI=2.31-7.11). However, there was no significant association between facial flushing response and OCPC. In conclusion, cigarette smoking and alcohol drinking are independent risk factors for OCPC and its subsites in the male Japanese population.

Background: Although East Asia is one of the largest tobacco-epidemic regions in the world, only a few prospective studies from Asia have investigated the impact of smoking and cessation of smoking on cancer. We aimed to assess the effect of cessation of smoking on the risk of cancer using eight population-based cohort studies in Japan., Methods: We analyzed pooled data from eight population-based prospective cohort studies in Japan with more than 320,000 participants to assess the effect of smoking cessation on the risk of total cancers and smoking-related cancers., Results: After adjustment for potential confounders, cancer risks in men with >21years of smoking cessation before baseline were found to decrease to the same level as never smokers for total cancer (never smokers: reference; former smokers with ≥21 years since smoking cessation: HR, 1.01; 95%CI: 0.91, 1.11). Even men who are heavy smokers (more than 20 pack-years) reported a reduced risk of total cancer (never smokers: reference; former smokers with ≥21 years since smoking cessation: HR, 1.06; 95%CI: 0.92, 1.23). In women, the risk of total cancer did not differ from that of never smokers after 11 years of smoking cessation before baseline (never smokers: reference; former smokers with ≥11 years since smoking cessation: HR, 0.96; 95%CI: 0.74, 1.23)., Conclusions: Our study suggests that longer duration of smoking cessation may attenuate the risk of cancer in both men and women, and that even heavy smokers (more than 20 pack-years) were found to benefit from quitting smoking., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The influence of body mass index (BMI) change during adulthood on the development of oesophageal squamous-cell carcinoma (ESCC) is unknown., Methods: Based on the Japan Public Health Center-based Prospective Study, we enrolled 103 238 participants from 1990 to 1994. Anthropometric data at age 20 years, baseline, and 5- and/or 10-year follow-up surveys were collected by questionnaire. The effect of BMI change between age 20 years and baseline on ESCC risk was estimated by Cox proportional hazards regression models. The updated BMI was taken into account by fitting a simple linear regression model for each individual, where the slope was incorporated into regressions as a time-varying variable., Results: After excluding the first 5 years of observation, we identified 342 newly diagnosed ESCC cases. An increase in BMI during adulthood was linked with a decreased risk of ESCC development, with each 1% increase per 5 years corresponding to a 15% decrease in ESCC risk (95% confidence interval 9-21%). Identical estimates were obtained from time-dependent models. The importance of BMI change was not modified by gender, smoking, or alcohol drinking but confined to participants assessed as non-overweight at baseline., Conclusions: An increase in BMI during adulthood is associated with a lower risk of developing ESCC among non-overweight subjects.

Objective: To estimate cumulative incidence and mortality risk for gastric cancer by risk category., Methods: Risk was classified into four types according to the presence/absence of Helicobacter pylori infection and chronic atrophic gastritis: in order of lowest to highest risk, Group A: H. pylori(-) and atrophic gastritis(-); Group B: H. pylori(+) and atrophic gastritis(-); Group C:H. pylori(+) and atrophic gastritis(+); and, Group D: H. pylori(-) and atrophic gastritis(+). We used vital statistics for the crude all-cause and crude gastric cancer mortality rates in 2011 and data from population-based cancer registries (the Monitoring of Cancer Incidence in Japan) for gastric cancer incidence in 2011. For relative risk and prevalence, we used the results of a meta-analysis integrating previous studies and data from the Japan Public Health Center-based Prospective Study for the Next Generation, respectively (baseline survey 2011-16). We calculated the crude incidence and mortality rates and estimated the cumulative risk using a life-table method., Results: The estimated lifetime cumulative incidence risk was 11.4% for men and 5.7% for women. The estimated risk for Groups A, B, C and D was 2.4%, 10.8%, 26.7% and 35.5% for men, and 1.2%, 5.5%, 13.5% and 18.0% for women, respectively. Similarly, the estimated lifetime cumulative mortality risk was 3.9% for men and 1.8% for women. The estimated risk of mortality for Groups A, B, C and D was 0.8%, 3.6%, 9.0% and 12.0% for men, and 0.4%, 1.7%, 4.2% and 5.7% for women, respectively., Conclusions: Our results may be useful for designing individually tailored prevention programs., (© The Author 2017. Published by Oxford University Press.)

Evidence regarding stress as a risk factor for cancer onset is inconsistent. In this study, based on the Japan Public Health Center-based Prospective Study, we enrolled 101,708 participants aged 40-69 years from 1990-1994. The self-reported perceived stress level was collected at baseline and updated through 5-year follow-up. The association between perceived stress and cancer risk was measured by Cox proportional hazards regression model, adjusted for all known confounders. During follow-up (mean = 17.8 years), we identified 17,161 cancer cases. We found no association between baseline perceived stress level and cancer incidence. However, by taking account of the dynamic changes in perceived stress, time-varying analyses revealed a slightly (4-6%) increased overall cancer risk for subjects under elevated perceived stress levels compared to the 'low stress level' group. Analyses concerning long-term perceived stress level showed that individuals with constantly high perceived stress level had an 11% (95% confidence interval 1-22%) excess risk for cancer compared to subjects with persistently low stress levels. This association was confined to men (20% excess risk), and was particularly strong among smokers, alcohol drinkers, obese subjects, and subjects without family history of cancer. Therefore, we concluded high perceived stress level might contribute to excess overall cancer incidence among men.

We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case-control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Online dietary assessment tools offer advantages over printed questionnaires, such as the automatic and direct data storage of answers, and have the potential to become valuable research methods. We developed an online survey system (web-FFQ) for the existing printed FFQ used in the JPHC-NEXT protocol, the platform of a large-scale genetic cohort study. Here, we examined the validity of ranking individuals according to dietary intake using this web-FFQ and its usability compared with the printed questionnaire (print-FFQ) for combined usage., Methods: We included 237 men and women aged 40-74 years from five areas specified in the JPHC-NEXT protocol. From 2012 to 2013, participants were asked to provide 12-day weighed food records (12d-WFR) as the reference intake and to respond to the print- and web-FFQs. Spearman's correlation coefficients (CCs) between estimates using the web-FFQ and 12d-WFR were calculated. Cross-classification of intakes was compared with those using the print-FFQ., Results: Most participants (83%) answered that completing the web-FFQ was comparable to or easier than completing the printed questionnaire. The median value of CCs across energy and 53 nutrients for men and women was 0.47 (range, 0.10-0.86) and 0.46 (range, 0.16-0.69), respectively. CCs for individual nutrient intakes were closely similar to those based on the print-FFQ, irrespective of response location. Cross-classification by quintile of intake based on two FFQs was reasonably accurate for many nutrients and food groups., Conclusion: This online survey system is a reasonably valid measure for ranking individuals by intake for many nutrients, like the printed FFQ. Mixing of two FFQs for exposure assessments in epidemiological studies appears acceptable., (Copyright © 2017. Production and hosting by Elsevier B.V.)

An association between female reproductive factors, exogenous hormone use, and pancreatic cancer risk has long been suggested in laboratory settings, but epidemiological findings remain mixed and inconclusive. Studies carried out on Asian populations are also limited. In this study, 45 617 women aged 40-69 years were followed for an average of 18.4 years in the Japan Public Health Center-based prospective cohort and 211 pancreatic cases were identified as of 31 December 2011. We applied multivariate-adjusted Cox proportional hazards regression models using age as a time-scale to assess the association between female reproductive factors (menstrual status, menarche age, menopause age, number of births, age at first birth, total years of fertility, history of breastfeeding) and exogenous hormone use with the incidence of pancreatic cancer through hazard ratios and confidence intervals. No significant associations were found between our examined female reproductive factors and pancreatic cancer incidence. The use of exogenous hormones was found to be associated with an increased risk of pancreatic cancer in a multivariate-adjusted model (hazard ratio: 1.47; 95%; confidence interval: 1.00-2.14) in the Japanese female population. Our results suggest that exogenous hormones may play a role in the formation of pancreatic cancer, and further prospective studies are warranted for clarification.

Smoking and alcohol are important modifiable risk factors for human cancers. However, few epidemiological studies have investigated their association with the risk of myelodysplastic syndromes (MDS). Here, we investigated the association of smoking and alcohol consumption and the risk of MDS in a large-scale population-based cohort study in Japan. We included 95 510 Japanese subjects (45 451 men and 50 059 women; age 40-69 years at baseline) and identified 70 MDS cases (50 men and 20 women) during 18·3 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox regression model adjusted for potential confounders. Smoking was marginally associated with an increased risk of MDS among men, with a HR for current smokers relative to never smokers of 2·11 (95% CI: 0·91-4·89). In contrast, alcohol consumption was associated with a dose-dependent decrease in the risk of MDS among men (nondrinkers: reference, occasional drinkers: HR = 0·48, 0·16-1·41; 0-299 g/week: HR = 0·37, 0·19-0·73; ≥300 g/week: HR = 0·49, 0·22-1·08, P for trend = 0·010). This study showed that alcohol has a significant protective effect on the risk of MDS. In addition, this study might indicate that smoking increases the risk of MDS among Japanese population, as it does in Western populations., (© 2017 John Wiley & Sons Ltd.)

Background: Randomized controlled studies have investigated the short-term effect of soy product intake on blood pressure (BP) in normotensive people. To our knowledge, no prospective studies exist on the effect of habitual intake of fermented soy products, separate from total soy products, on BP in the general population. Objective: We examined the association between the habitual intake of soy products, including fermented soy products, and the development of high BP during a 5-y period among participants in a population-based prospective cohort study in Japan. Methods: The study included normotensive participants aged 40-69 y at baseline (926 men and 3239 women) who completed 2 questionnaires and whose BP was measured at the baseline survey between 1993 and 1994 and the 5-y follow-up in the Japan Public Health Center-Based Prospective Study Cohort II. The intake of soy products was assessed with a food-frequency questionnaire. High BP was defined as systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥85 mm Hg, or antihypertensive medication use. ORs and 95% CIs of high BP by frequency of soy products (miso, natto, and tofu) consumption, intake of total and fermented soy products, and intake of isoflavones from total and fermented soy products were estimated with the use of multiple logistic regression analysis. Results: Multivariable-adjusted ORs of high BP for the highest compared with the lowest tertile of total and fermented soy product intake were 1.03 (95% CI: 0.84, 1.25; P -trend = 0.786) and 0.72 (95% CI: 0.56, 0.92; P -trend = 0.009), respectively. The frequency of nonfermented soy product (tofu) intake was not associated with the development of high BP ( P -trend = 0.597). Conclusions: The intake of fermented soy products, but not total or nonfermented soy products, was inversely associated with developing high BP in men and women with normal BP., Competing Interests: Author disclosures: MN, TS, SS, HC, NM, MM, NS, M Iwasaki, TY, M Inoue, YK, KY, HI, and ST, no conflicts of interest., (© 2017 American Society for Nutrition.)

Background: The aim of this study was to investigate the association of coffee and green tea consumption and the risk of malignant lymphoma and multiple myeloma in a large-scale population-based cohort study in Japan. Methods: In this analysis, a total of 95,807 Japanese subjects (45,937 men and 49,870 women; ages 40-69 years at baseline) of the Japan Public Health Center-based Prospective Study who completed a questionnaire about their coffee and green tea consumption were followed up until December 31, 2012, for an average of 18 years. HRs and 95% confidence intervals were estimated using a Cox regression model adjusted for potential confounders as a measure of association between the risk of malignant lymphoma and multiple myeloma associated with coffee and green tea consumption at baseline. Results: During the follow-up period, a total of 411 malignant lymphoma cases and 138 multiple myeloma cases were identified. Overall, our findings showed no significant association between coffee or green tea consumption and the risk of malignant lymphoma or multiple myeloma for both sexes. Conclusions: In this study, we observed no significant association between coffee or green tea consumption and the risk of malignant lymphoma or multiple myeloma. Impact: Our results do not support an association between coffee or green tea consumption and the risk of malignant lymphoma or multiple myeloma. Cancer Epidemiol Biomarkers Prev; 26(8); 1352-6. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Cigarette smoking has been reported to be associated with an increased risk of leukemia. Most epidemiological evidence on the association between cigarette smoking and leukemia risk is from studies conducted in Western populations, however, and evidence from Asian populations is scarce., Methods: We conducted a large-scale population-based cohort study of 96,992 Japanese subjects (46,493 men and 50,499 women; age 40-69 years at baseline) with an average 18.3 years of follow-up, during which we identified 90 cases of acute myeloid leukemia (AML), 19 of acute lymphoblastic leukemia (ALL), and 28 of chronic myeloid leukemia (CML). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a Cox regression model adjusted for potential confounders., Results: When we adjusted for age, sex, and study area, our findings showed no significant association or increasing dose-response relationship between risk of AML and cigarette smoking overall. However, after further adjustment for body mass index and occupation, current smokers with more than 30 pack-years of cigarette smoking had a significantly increased risk of AML compared to never smokers among men (HR 2.21; 95% CI, 1.01-4.83). This increased risk was not clear among women., Conclusions: Our results suggest that cigarette smoking increases the risk of AML in Japanese men. The associations of smoking with AML among women, and with CML and ALL among men and women, should be assessed in future studies., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Reproductive/menstrual factors may be involved in the etiology of gallbladder cancer (GBC) and bile duct cancer (BDC). However, the results from previous epidemiological studies have been inconsistent. We investigated the association of reproductive/menstrual factors with the risk for GBC and BDC in a population-based prospective cohort study in Japan. Data on reproductive/menstrual factors were collected through a self-administered questionnaire at baseline. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model. A total of 55 786 women enrolled between 1990 and 1994 were included in the analysis, and 115 GBC and 113 BDC cases were identified, with 944 861 person-years follow-up until 2010. For GBC, irregular and longer cycles were moderately associated with an increased risk [HR=2.12 (95% CI: 1.30-3.47) and HR=1.76 (95% CI: 1.08-2.89), respectively]. This effect tended to be greater in premenopausal than in postmenopausal women. Furthermore, older age at first pregnancy tended to be associated with an increased risk [HR=1.84 (95% CI: 1.03-3.29), P-trend=0.036], whereas increased duration of fertility tended to be associated with a decreased risk [HR=0.59 (95% CI: 0.35-1.01), P-trend=0.055] of GBC. No clear association with BDC was observed. This finding suggests that women with irregular or longer cycles may have an increased risk for GBC and female hormones may play an important role in the etiology of GBC.

Background: Although open-ended dietary assessment methods, such as weighed food records (WFRs), are generally considered to be comparable, differences between procedures may influence outcome when WFRs are conducted independently. In this paper, we assess the procedures of WFRs in two studies to describe their dietary assessment procedures and compare the subsequent outcomes., Methods: WFRs of 12 days (3 days for four seasons) were conducted as reference methods for intake data, in accordance with the study protocol, among a subsample of participants of two large cohort studies. We compared the WFR procedures descriptively. We also compared some dietary intake variables, such as the frequency of foods and dishes and contributing foods, to determine whether there were differences in the portion size distribution and intra- and inter-individual variation in nutrient intakes caused by the difference in procedures., Results: General procedures of the dietary records were conducted in accordance with the National Health and Nutrition Survey and were the same for both studies. Differences were seen in 1) selection of multiple days (non-consecutive days versus consecutive days); and 2) survey sheet recording method (individual versus family participation). However, the foods contributing to intake of energy and selected nutrients, the portion size distribution, and intra- and inter-individual variation in nutrient intakes were similar between the two studies., Conclusion: Our comparison of WFR procedures in two independent studies revealed several differences. Notwithstanding these procedural differences, however, the subsequent outcomes were similar., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Diet-induced metabolic acidosis has been linked to cardiometabolic abnormalities including hypertension and type 2 diabetes. However, there are limited data on its association with other chronic diseases and mortality. Objective: The present study aimed to examine the association between dietary acid load and total and cause-specific mortality. Design: This study was a large-scale, population-based, prospective cohort study in Japan involving 42,736 men and 49,742 women, aged 45-75 y, who had no history of cancer, stroke, ischemic heart disease (IHD), or chronic liver disease at baseline. Dietary intake was assessed by using a validated 147-item food-frequency questionnaire. Potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores were derived from nutrient intake. Death and cause of death were identified by using the residential registry and death certificates. Cox proportional hazards regression was used to estimate HRs and 95% CIs for total and cause-specific mortality with adjustment for potential confounding variables. Results: During a median follow-up of 16.9 y, 12,993 total deaths occurred. A higher PRAL score was associated with higher total mortality: the multivariable-adjusted HR for total mortality for the highest compared with the lowest quartiles of PRAL scores was 1.13 (95% CI: 1.07, 1.18; P -trend < 0.001). This score was positively associated with mortality from cardiovascular disease (CVD) and particularly from IHD; the HRs (95% CIs) for the highest compared with the lowest quartile of PRAL score were 1.16 (1.06, 1.28) and 1.16 (1.02, 1.33) for CVD and IHD mortality, respectively. There was no association between PRAL score and cancer mortality. Similar associations were observed between NEAP score and total and cause-specific mortality. Conclusion: A high dietary acid load score was associated with a higher risk of total mortality and mortality from CVD, particularly from IHD, in Japanese adults., (© 2017 American Society for Nutrition.)

Purpose: Epidemiological studies have suggested a protective effect of dietary fiber intake on breast cancer risk while the results have been inconsistent. Our study aimed to investigate the association between dietary fiber intake and breast cancer risk and to explore whether this association is modified by reproductive factors and hormone receptor status of the tumor., Methods: A total of 44,444 women aged 45 to 74 years from the Japan Public Health Center-based Prospective Study were included in analyses. Dietary intake assessment was performed using a validated 138-item food frequency questionnaire (FFQ). Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer incidence were calculated by multivariate Cox proportional hazards regression models., Results: During 624,423 person-years of follow-up period, 681 breast cancer cases were identified. After adjusting for major confounders for breast cancer risk, inverse trends were observed but statistically non-significant. Extremely high intake of fiber was associated with decreased risk of breast cancer but this should be interpreted with caution due to limited statistical power. In stratified analyses by menopausal and hormone receptor status, null associations were observed except for ER-PR- status., Conclusions: Our findings suggest that extreme high fiber intake may be associated with decreased risk of breast cancer but the level of dietary fiber intake among Japanese population might not be sufficient to examine the association between dietary fiber intake and breast cancer risk.

Background: Cruciferous vegetables, a rich source of isothiocyanates, have been reported to lower the risk of several types of cancer, including lung cancer. However, evidence from prospective observations of populations with a relatively high intake of cruciferous vegetables is sparse. Objective: We investigated the association between cruciferous vegetable intake and lung cancer risk in a large-scale population-based prospective study in Japan. Methods: We studied 82,330 participants (38,663 men; 43,667 women) aged 45-74 y without a past history of cancer. Participants were asked to respond to a validated questionnaire that included 138 food items. The association between cruciferous vegetable intake and lung cancer incidence was assessed with the use of Cox proportional hazard regression analysis to estimate HRs and 95% CIs (with adjustments for potential confounding factors). Results: After 14.9 y of follow-up, a total of 1499 participants (1087 men; 412 women) were diagnosed with lung cancer. After deleting early-diagnosed cancer and adjusting for confounding factors, we observed a nonsignificant inverse trend between cruciferous vegetable intake and lung cancer risk in men in the highest compared with the lowest quartiles (multivariate HR: 0.85; 95% CI: 0.69, 1.06; P -trend = 0.13). Stratified analysis by smoking status revealed a significant inverse association between cruciferous vegetable intake and lung cancer risk among those who were never smokers and those who were past smokers after deleting lung cancer cases in the first 3 y of follow-up [multivariate HR for never smokers: 0.49 (95% CI: 0.27, 0.87; P -trend = 0.04); multivariate HR for past smokers: 0.59 (95% CI: 0.35, 0.99; P -trend = 0.10)]. No association was noted in men who were current smokers and women who were never smokers. Conclusion: This study suggests that cruciferous vegetable intake may be associated with a reduction in lung cancer risk among men who are currently nonsmokers., Competing Interests: 2: Author disclosures: M Inoue is a beneficiary of a financial contribution from the AXA Research Fund. N Mori, T Shimazu, S Sasazuki, M Nozue, M Mutoh, N Sawada, M Iwasaki, T Yamaji, R Takachi, A Sunami, J Ishihara, T Sobue, and S Tsugane, no conflicts of interest., (© 2017 American Society for Nutrition.)

Objective: A meta-analysis showed an inverse association of a prudent/healthy dietary pattern with all-cause mortality and no association of a western/unhealthy dietary pattern. However, the association of distinctive dietary patterns of Japanese population with mortality remains unclear. We prospectively investigated the association between dietary patterns and all-cause, cancer, and cardiovascular disease mortality among Japanese adults., Methods: Participants were 36,737 men and 44,983 women aged 45-74 years who participated in the second survey of the Japan Public Health Center-based Prospective Study (1995-1998) and who had no history of serious disease. Dietary patterns were derived from principal component analysis of the consumption of 134 food and beverage items ascertained by a food frequency questionnaire. Hazard ratios of death from the second survey to December 2012 were estimated using cox proportional hazard regression analysis., Results: A prudent dietary pattern, which was characterized by high intake of vegetables, fruit, soy products, potatoes, seaweed, mushrooms, and fish, was significantly associated with decreased risk of all-cause and cardiovascular disease mortality. The multivariable-adjusted hazard ratios (95% confidence intervals) of all-cause and cardiovascular disease mortality for the highest versus lowest quartile of the prudent dietary pattern score were 0.82 (0.77 to 0.86) and 0.72 (0.64 to 0.79), respectively (P for trend <0.001 in both). A Westernized dietary pattern, characterized by high intake of meat, processed meat, bread, and dairy products, was also inversely associated with risk of all-cause, cancer, and cardiovascular disease mortality. A traditional Japanese dietary pattern was not associated with these risks., Conclusions: The prudent and Westernized dietary patterns were associated with a decreased risk of all-cause and cardiovascular disease mortality in Japanese adults.

Background: A series of recent reports from large-scale cohort studies involving more than 100,000 subjects reported no or only very small inverse associations between fruit and vegetable intake and overall cancer incidence, despite having sufficient power to do so. To date, however, no such data have been reported for Asian populations., Objective: To provide some indication of the net impact of fruit and vegetable consumption on overall cancer prevention, we examined these associations in a pooled analysis of large-scale cohort studies in Japanese populations., Methods: We analyzed original data from four cohort studies that measured fruit and vegetable 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 2,318,927 person-years of follow-up for a total of 191,519 subjects, 17,681 cases of overall cancers were identified. Consumption of fruit or vegetables was not associated with decreased risk of overall cancers: corresponding HRs for the highest versus lowest quartiles of intake for men and women were 1.03 (95% CI, 0.97-1.10; trend p = 1.00) and 1.03 (95% CI, 0.95-1.11; trend p = 0.97), respectively, for fruit and 1.07 (95% CI, 1.01-1.14; trend p = 0.18) and 0.98 (95% CI, 0.91-1.06; trend p = 0.99), respectively, for vegetables, even in analyses stratified by smoking status and alcohol drinking., Conclusions: The results of this pooled analysis do not support inverse associations of fruit and vegetable consumption with overall cancers in the Japanese population., (Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Chronic Helicobacter pylori infection plays a central role in the development of gastric cancer as shown by biological and epidemiological studies. The H. pylori antibody and serum pepsinogen (PG) tests have been anticipated to predict gastric cancer development., Methods: We determined the predictive sensitivity and specificity of gastric cancer development using these tests. Receiver operating characteristic analysis was performed, and areas under the curve were estimated. The predictive sensitivity and specificity of gastric cancer development were compared among single tests and combined methods using serum pepsinogen and H. pylori antibody tests., Results: From a large-scale population-based cohort of over 100,000 subjects followed between 1990 and 2004, 497 gastric cancer subjects and 497 matched healthy controls were chosen. The predictive sensitivity and specificity were low in all single tests and combination methods. The highest predictive sensitivity and specificity were obtained for the serum PG I/II ratio. The optimal PG I/II cut-off values were 2.5 and 3.0. At a PG I/II cut-off value of 3.0, the sensitivity was 86.9% and the specificity was 39.8%. Even if three biomarkers were combined, the sensitivity was 97.2% and the specificity was 21.1% when the cut-off values were 3.0 for PG I/II, 70 ng/mL for PG I, and 10.0 U/mL for H. pylori antibody., Conclusions: The predictive accuracy of gastric cancer development was low with the serum pepsinogen and H. pylori antibody tests even if these tests were combined. To adopt these biomarkers for gastric cancer screening, a high specificity is required. When these tests are adopted for gastric cancer screening, they should be carefully interpreted with a clear understanding of their limitations.

Vegetable and fruit consumption may have a protective effect against several types of cancers. However, the effect on biliary cancers is unclear. We investigated the association of vegetable/fruit consumption with the risks of gallbladder cancer (GBC), intrahepatic bile duct cancer (IHBDC) and extrahepatic bile duct cancer (EHBDC) in a population-based prospective cohort study in Japan. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model, and the exposure level was categorized into quartiles, with the lowest group used as the reference. A total of 80,371 people aged 45 to 74 years were enrolled between 1995 and 1999, and followed up for 1,158,632 person-years until 2012, during which 133 GBC, 99 IHBDC, and 161 EHBDC cases were identified. Increased consumption of total vegetable and fruit was significantly associated with a decreased risk of EHBDC (HR = 0.49; 95% CI: 0.29-0.81 for the highest group; p trend = 0.005). From the analysis of relevant nutrients, significantly decreased risk of EHBDC was associated with folate and insoluble fiber (HR = 0.48, 0.53; 95% CI: 0.28-0.85, 0.31-0.88 for the highest group; p trend = 0.010, 0.023; respectively), and a significant trend of decreased EHBDC risk associated with vitamin C was observed (p trend = 0.029). No decreased risk of GBC and IHBDC was found. Our findings suggest that increased vegetable/fruit consumption may decrease a risk of EHBDC, and folate, vitamin C, and insoluble fiber might be key contributors to the observed protective effect., (© 2016 UICC.)

Epidemiological findings on the association between fruit and vegetable consumption and gastric cancer risk remain inconsistent. The present analysis included 810 prospectively ascertained non-cardia gastric cancer cases and 1,160 matched controls from the Helicobacter pylori Biomarker Cohort Consortium, which collected blood samples, demographic, lifestyle, and dietary data at baseline. Conditional logistic regression adjusting for total energy intake, smoking, and H. pylori status, was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer risk across cohort- and sex-specific quartiles of fruit and vegetable intake. Increasing fruit intake was associated with decreasing risk of non-cardia gastric cancer (OR = 0.71, 95% CI: 0.52-0.95, p trend = 0.02). Compared to low-fruit consumers infected with CagA-positive H. pylori, high-fruit consumers without evidence of H. pylori antibodies had the lowest odds for gastric cancer incidence (OR = 0.12, 95% CI: 0.06-0.25), whereby the inverse association with high-fruit consumption was attenuated among individuals infected with CagA-positive H. pylori (OR = 0.82, 95% CI: 0.66-1.03). To note, the small number of H. pylori negative individuals does influence this finding. We observed a weaker, nondose-response suggestion of an inverse association of vegetable intake with non-cardia gastric cancer risk. High fruit intake may play a role in decreasing risk of non-cardia gastric cancer in Asia., (© 2016 UICC.)

Background/objectives: Although vitamin D has been experimentally reported to inhibit tumorigenesis, cell growth and prostate cancer invasion, epidemiologic data regarding prostate cancer risk are inconsistent, and some studies have suggested positive but nonsignificant associations. Further, the impact of vitamin D on prostate cancer between Western and Japanese populations may differ due to different plasma vitamin D levels., Subjects/methods: We performed a nested case-control study within the Japan Public Health Center-based Prospective (JPHC) Study in 14,203 men (40-69 years) who answered a self-administered questionnaire at baseline (1990-1994) and gave blood samples, and were followed until 2005. We identified 201 prostate cancers which are newly diagnosed during follow-up (mean 12.8 years). We selected two matched controls for each case from the cohort. We used a conditional logistic regression model to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer with respect to levels of 25-hydroxy vitamin D (25(OH)D) in plasma., Results: We did not observe statistically significant association between 25(OH)D level and total prostate cancer (multivariate OR=1.13 (95%CI=0.66-1.94, P trend =0.94) for the highest versus lowest tertile) However, 25(OH) levels were slightly positively associated with advanced cancer. The results remained substantially unchanged after stratification by intake of fish or calcium intake., Conclusions: 25(OH)D level showed no association with overall prostate cancer among Japanese men in this large cohort.

Few prospective studies have investigated the etiology of brain tumor, especially among Asian populations. Both coffee and green tea are popular beverages, but their relation with brain tumor risk, particularly with glioma, has been inconsistent in epidemiological studies. In this study, we evaluated the association between coffee and greed tea intake and brain tumor risk in a Japanese population. We evaluated a cohort of 106,324 subjects (50,438 men and 55,886 women) in the Japan Public Health Center-Based Prospective Study (JPHC Study). Subjects were followed from 1990 for Cohort I and 1993 for Cohort II until December 31, 2012. One hundred and fifty-seven (70 men and 87 women) newly diagnosed cases of brain tumor were identified during the study period. Hazard ratio (HR) and 95% confidence intervals (95%CIs) for the association between coffee or green tea consumption and brain tumor risk were assessed using a Cox proportional hazards regression model. We found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR = 0.47, 95%CI = 0.22-0.98) and in women (≥3 cups/day; HR = 0.24, 95%CI = 0.06-0.99), although the number of cases in the highest category was small. Furthermore, glioma risk tended to decrease with higher coffee consumption (≥3 cups/day; HR = 0.54, 95%CI = 0.16-1.80). No association was seen between green tea and brain tumor risk. In conclusion, our study suggested that coffee consumption might reduce the risk of brain tumor, including that of glioma, in the Japanese population., (© 2016 UICC.)

The association between alcohol intake and colorectal cancer (CRC) may vary secondary to single nucleotide polymorphisms (SNPs) in two pathways related to alcohol intake. 375 cases of CRC were identified among 38 373 Japan Public Health Center-based prospective Study (JPHC Study) participants who had returned a baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. For each case, two controls were selected on matching variables. Logistic regression models were used to determine matched Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between alcohol consumption, genetic polymorphisms of enzymes in the alcohol- and folate metabolic pathways (e.g. methylenetetrahydrofolate reductase (MTHFR) rs1801133) and CRC risk. Compared to never/occasional alcohol intake, moderate to heavy alcohol intake was associated with CRC (OR = 2.12, 95% CI, 1.34-3.36). When compared to the CC genotype, the MTHFR rs1801133 CT/TT genotype was inversely associated with CRC (OR = 0.72, 95% CI, 0.54-0.97). Never/occasional consumers of alcohol with the MTHFR rs1801133 CT/TT genotype were also at a reduced risk of CRC compared to never/occasional drinkers with the CC genotype (OR = 0.68, 95% CI, 0.47-0.98) (P for interaction = 0.27). The results indicate that the folate pathway is likely to be involved in alcohol-related CRC development.