The Effect of Prostate-Specific Antigen (PSA) Test on Radiation Risk Estimate for Prostate Cancer Incidence among Atomic-Bomb Survivors.

Following our previous report on the radiation dose-response for prostate cancer incidence rates in the Life Span Study (LSS) cohort of atomic bomb survivors, we reevaluated the radiation-related risk adjusting for differences in baseline cancer incidence rates among three subsets of the LSS cohort defined by the timing of their first participation in biennial health examinations offered to the Adult Health Study (AHS) sub-cohort members and prostate-specific-antigen (PSA) testing status for AHS participants: 1. non-AHS participants, 2. AHS participants before receiving PSA test, and 3. AHS participants after receiving PSA test. We found a 2.9-fold increase in the baseline incidence rates among AHS participants after receiving PSA test. After adjusting for the PSA-testing-status effects on the baseline rates the estimated excess relative risk (ERR) per Gy was 0.54 (95% CI: 0.15, 1.05), which was almost identical to the previously reported unadjusted ERR estimate (0.57, 95% CI: 0.21, 1.00). The current results confirmed that, while the PSA testing among AHS participants increased the baseline incidence rates, it did not impact the radiation risk estimate, strengthening the previously reported dose-response relationship for prostate cancer incidence in the LSS. As the use of PSA tests continue in screening and medical settings, analyses of possible effects of PSA testing should be an important aspect of future epidemiological studies of the association between radiation exposure and prostate cancer.

Tea consumption and risk of bladder cancer in the Bladder Cancer Epidemiology and Nutritional Determinants (BLEND) Study: Pooled analysis of 12 international cohort studies.

BACKGROUND & AIMS: Tea has been shown to be associated with reduced risk of several diseases including cardiovascular diseases, stroke, metabolic syndrome, and obesity. However, the results on the relationship between tea consumption and bladder cancer are conflicting. This research aimed to assess the association between tea consumption and risk of bladder cancer using a pooled analysis of prospective cohort data. METHODS: Individual data from 532,949 participants in 12 cohort studies, were pooled for analyses. Cox regression models stratified by study centre was used to estimate hazard ratios (HR) and corresponding 95% CIs. Fractional polynomial regression models were used to examine the dose-response relationship. RESULTS: A higher level of tea consumption was associated with lower risk of bladder cancer incidence (compared with no tea consumption: HR = 0.87, 95% C.I. = 0.77-0.98 for low consumption; HR = 0.86, 95% C.I. = 0.77-0.96 for moderate consumption; HR = 0.84, 95% C.I. = 0.75-0.95 for high consumption). When stratified by sex and smoking status, this reduced risk was statistically significant among men and current and former smokers. In addition, dose-response analyses showed a lower bladder cancer risk with increment of 100 ml of tea consumption per day (HR-increment = 0.97; 95% CI = 0.96-0.98). A similar inverse association was found among males, current and former smokers while never smokers and females showed non-significant results, suggesting potential sex-dependent effect. CONCLUSIONS: Higher consumption of tea is associated with reduced risk of bladder cancer with potential interaction with sex and smoking status. Further studies are needed to clarify the mechanisms for a protective effect of tea (e.g. inhibition of the survival and proliferation of cancer cells and anti-inflammatory mechanisms) and its interaction with smoking and sex.

Age effects on radiation response: summary of a recent symposium and future perspectives.

One of the principal uncertainties when estimating population risk of late effects from epidemiological data is that few radiation-exposed cohorts have been followed up to extinction. Therefore, the relative risk model has often been used to estimate radiation-associated risk and to extrapolate risk to the end of life. Epidemiological studies provide evidence that children are generally at higher risk of cancer induction than adults for a given radiation dose. However, the strength of evidence varies by cancer site and questions remain about site-specific age at exposure patterns. For solid cancers, there is a large body of evidence that excess relative risk (ERR) diminishes with increasing age at exposure. This pattern of risk is observed in the Life Span Study (LSS) as well as in other radiation-exposed populations for overall solid cancer incidence and mortality and for most site-specific solid cancers. However, there are some disparities by endpoint in the degree of variation of ERR with exposure age, with some sites (e.g., colon, lung) in the LSS incidence data showing no variation, or even increasing ERR with increasing age at exposure. The pattern of variation of excess absolute risk (EAR) with age at exposure is often similar, with EAR for solid cancers or solid cancer mortality decreasing with increasing age at exposure in the LSS. We shall review the human data from the Japanese LSS cohort, and a variety of other epidemiological data sets, including a review of types of medical diagnostic exposures, also some radiobiological animal data, all bearing on the issue of variations of radiation late-effects risk with age at exposure and with attained age. The paper includes a summary of several oral presentations given in a Symposium on "Age effects on radiation response" as part of the 67th Annual Meeting of the Radiation Research Society, held virtually on 3-6 October 2021.

Dietary B group vitamin intake and the bladder cancer risk: a pooled analysis of prospective cohort studies.

PURPOSE: Diet may play an essential role in the aetiology of bladder cancer (BC). The B group complex vitamins involve diverse biological functions that could be influential in cancer prevention. The aim of the present study was to investigate the association between various components of the B group vitamin complex and BC risk. METHODS: Dietary data were pooled from four cohort studies. Food item intake was converted to daily intakes of B group vitamins and pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using Cox-regression models. Dose-response relationships were examined using a nonparametric test for trend. RESULTS: In total, 2915 BC cases and 530,012 non-cases were included in the analyses. The present study showed an increased BC risk for moderate intake of vitamin B1 (HRB1: 1.13, 95% CI: 1.00-1.20). In men, moderate intake of the vitamins B1, B2, energy-related vitamins and high intake of vitamin B1 were associated with an increased BC risk (HR (95% CI): 1.13 (1.02-1.26), 1.14 (1.02-1.26), 1.13 (1.02-1.26; 1.13 (1.02-1.26), respectively). In women, high intake of all vitamins and vitamin combinations, except for the entire complex, showed an inverse association (HR (95% CI): 0.80 (0.67-0.97), 0.83 (0.70-1.00); 0.77 (0.63-0.93), 0.73 (0.61-0.88), 0.82 (0.68-0.99), 0.79 (0.66-0.95), 0.80 (0.66-0.96), 0.74 (0.62-0.89), 0.76 (0.63-0.92), respectively). Dose-response analyses showed an increased BC risk for higher intake of vitamin B1 and B12. CONCLUSION: Our findings highlight the importance of future research on the food sources of B group vitamins in the context of the overall and sex-stratified diet.

The possible impact of passive smoke exposure on radiation-related risk estimates for lung cancer among women: the life span study of atomic bomb survivors.

PURPOSE: Analyses of the Life Span Study cohort of atomic bomb survivors have shown a statistically significant sex difference in the excess risk of incident lung cancer due to radiation exposure, with the radiation-related excess relative risk per gray (ERR/Gy) for women approximately 4 times that for men, after accounting for active smoking. We sought to determine the extent to which this risk difference could be explained by adjustment for passive smoke exposure, which is a known risk factor for lung cancer that was not measured among Life Span Study participants, and which could be particularly influential among female never-smokers. MATERIALS AND METHODS: The Life Span Study includes survivors of the atomic bombings of Hiroshima and Nagasaki and city residents who were not in either city at the time of the bombings, matched to survivors on city, sex, and age. First primary lung cancers were identified from population-based cancer registries between 1958 and 2009. Data on active smoking were obtained from mailed surveys and in-person questionnaires (1965-1991). We calculated passive smoke exposure for female never-smokers by attributing smoking pack-years at various intensities (5-50%) based on smoking patterns among men, stratified by city, birth year, radiation dose, and lung cancer status. Poisson regression models with additive and multiplicative interactions between radiation dose and smoking were used to estimate sex-specific radiation-related excess relative risks for lung cancer. RESULTS: During the study period, 2,446 first primary lung cancers were identified among 105,444 study participants. On average, male smokers started smoking 19.5 cigarettes per day at 21.5 years old. Partially attributing male smoking patterns to female never-smokers-to approximate passive smoke exposure-yielded lower radiation-related ERR/Gy estimates for women under a multiplicative radiation-smoking interaction model, leading to a lower female-to-male ratio of ERR/Gy estimates; however, this difference was evident only at very high passive smoke intensities. Under an additive radiation-smoking interaction model, the results were unchanged. CONCLUSIONS: Our results are consistent with the possibility that failure to account for passive smoke might contribute, in small part, to the higher radiation risk estimates for lung cancer among women compared to men in the Life Span Study.

Vegetable intake and the risk of bladder cancer in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.

BACKGROUND: Although a potential inverse association between vegetable intake and bladder cancer risk has been reported, epidemiological evidence is inconsistent. This research aimed to elucidate the association between vegetable intake and bladder cancer risk by conducting a pooled analysis of data from prospective cohort studies. METHODS: Vegetable intake in relation to bladder cancer risk was examined by pooling individual-level data from 13 cohort studies, comprising 3203 cases among a total of 555,685 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox proportional hazards regression models stratified by cohort for intakes of total vegetable, vegetable subtypes (i.e. non-starchy, starchy, green leafy and cruciferous vegetables) and individual vegetable types. In addition, a diet diversity score was used to assess the association of the varied types of vegetable intake on bladder cancer risk. RESULTS: The association between vegetable intake and bladder cancer risk differed by sex (P-interaction = 0.011) and smoking status (P-interaction = 0.038); therefore, analyses were stratified by sex and smoking status. With adjustment of age, sex, smoking, energy intake, ethnicity and other potential dietary factors, we found that higher intake of total and non-starchy vegetables were inversely associated with the risk of bladder cancer among women (comparing the highest with lowest intake tertile: HR = 0.79, 95% CI = 0.64-0.98, P = 0.037 for trend, HR per 1 SD increment = 0.89, 95% CI = 0.81-0.99; HR = 0.78, 95% CI = 0.63-0.97, P = 0.034 for trend, HR per 1 SD increment = 0.88, 95% CI = 0.79-0.98, respectively). However, no evidence of association was observed among men, and the intake of vegetable was not found to be associated with bladder cancer when stratified by smoking status. Moreover, we found no evidence of association for diet diversity with bladder cancer risk. CONCLUSION: Higher intakes of total and non-starchy vegetable are associated with reduced risk of bladder cancer for women. Further studies are needed to clarify whether these results reflect causal processes and potential underlying mechanisms.

Radiation Risks for the Incidence of Kidney, Bladder and Other Urinary Tract Cancers: 1958-2009.

As part of the recent series of articles to create a comprehensive description of the radiation risks of solid cancer incidence after ionizing radiation exposure, based on the atomic bomb survivors' Life Span Study (LSS), this work focuses on the risks of urinary tract cancer (UTC) and kidney cancer. Analyses covered a 52-year period of follow-up, through 2009, among 105,444 eligible survivors who were alive and cancer free in 1958. This represents an additional 11 years of follow-up since the last comprehensive report, with a total of 3,079,502 person-years. We observed 790 UTC and 218 kidney cancer cases. Adjusted for smoking, there was a strong linear radiation dose response for UTC. The sex-averaged excess relative risk per 1 Gy (ERR/Gy) was 1.4 (95% confidence interval, CI: 0.82 to 2.1). Both males and females showed significantly increased ERRs/Gy with female point estimates at a factor of 3.4 (95% CI: 1.4 to 8.6) greater than male estimates. UTC radiation risks were largely unmodified by age at exposure or attained age. The attributable fraction of UTC to radiation exposure was approximately 18% while that attributed to smoking was 48%. Kidney cancer showed an increased ERR due to smoking (0.56 per 50 pack-years; 95% CI -0.007 to 1.6; P = 0.054), but we did not observe any strong associations of kidney cancer with radiation exposure, although sex-specific dose responses were found to be statistically different.

Risk of Prostate Cancer Incidence among Atomic Bomb Survivors: 1958-2009.

Epidemiological evidence for a radiation effect on prostate cancer risk has been inconsistent and largely indicative of no or little effect. Here we studied prostate cancer incidence among males of the Life Span Study cohort of atomic bomb survivors in a follow-up from 1958 to 2009, eleven years more than was previously reported. During this period there were 851 incident cases of prostate cancer among 41,544 male subjects, doubling the total number of cases in the cohort. More than 50% of the cases were diagnosed among those who were less than 20 years of age at the time of the bombings and who were at, or near, the ages of heightened prostate cancer risks during the last decade of follow-up. In analyses of the radiation dose response using Poisson regression methods, we used a baseline-rate model that allowed for calendar period effects corresponding to the emergence of prostate-specific antigen screening in the general population as well as effects of attained age and birth cohort. The model also allowed for markedly increased baseline rates among the Adult Health Study participants between 2005 and 2009, a period during which a prostate-specific antigen test was included in Adult Health Study biennial health examinations. We found a significant linear dose response with an estimated excess relative risk (ERR) per Gy of 0.57 (95% CI: 0.21, 1.00, P = 0.001). An estimated 40 of the observed cases were attributed to radiation exposure from the bombings. There was a suggestion of the ERR decreasing with increasing age at exposure (P = 0.09). We found no indication of effects of smoking, alcohol consumption and body mass index on the baseline risk of prostate cancer. The observed dose response strengthens the evidence of a radiation effect on the risk of prostate cancer incidence in the atomic bomb survivors.

Radiation Risk of Ovarian Cancer in Atomic Bomb Survivors: 1958-2009.

There is limited evidence concerning the association between radiation exposure and ovarian cancer. We evaluated radiation risk of ovarian cancer between 1958 and 2009 among 62,534 female atomic bomb survivors in the Life Span Study cohort, adding 11 years of follow-up from the previously reported study. Poisson regression methods were used to estimate excess relative risk per Gy (ERR/Gy) for total ovarian cancer and according to tumor type. We assessed the modifying effect of follow-up period and other factors on the radiation risk. We ascertained 288 first primary ovarian cancers including 77 type 1 epithelial cancers, 75 type 2 epithelial cancers, 66 epithelial cancers of undetermined type and 70 other cancers. Radiation dose was positively, although not significantly, associated with risk of total ovarian cancer [ERR/Gy = 0.30, 95% confidence interval (CI): -0.22 to 1.11]. There was a suggestion of heterogeneity in radiation effects (P = 0.08) for type 1 (ERR/Gy = -0.32, 95% CI: <-0.32 to 0.88) and type 2 cancers (ERR/Gy = 1.24, 95% CI: -0.08 to 4.16). There were no significant trends in the ERR with time since exposure or age at exposure. Further follow-up will help characterize more accurately the patterns of radiation risk for total ovarian cancer and its types.

A data mining approach to investigate food groups related to incidence of bladder cancer in the BLadder cancer Epidemiology and Nutritional Determinants International Study.

At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case-control and one nested case-cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.

Coffee consumption and risk of bladder cancer: a pooled analysis of 501,604 participants from 12 cohort studies in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.

Recent epidemiological studies have shown varying associations between coffee consumption and bladder cancer (BC). This research aims to elucidate the association between coffee consumption and BC risk by bringing together worldwide cohort studies on this topic. Coffee consumption in relation to BC risk was examined by pooling individual data from 12 cohort studies, comprising of 2601 cases out of 501,604 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel Weibull regression models. Furthermore, dose-response relationships were examined using generalized least squares regression models. The association between coffee consumption and BC risk showed interaction with sex (P-interaction < 0.001) and smoking (P-interaction = 0.001). Therefore, analyses were stratified by sex and smoking. After adjustment for potential confounders, an increased BC risk was shown for high (> 500 ml/day, equivalent to > 4 cups/day) coffee consumption compared to never consumers among male smokers (current smokers: HR = 1.75, 95% CI 1.27-2.42, P-trend = 0.002; former smokers: HR = 1.44, 95% CI 1.12-1.85, P-trend = 0.001). In addition, dose-response analyses, in male smokers also showed an increased BC risk for coffee consumption of more than 500 ml/day (4 cups/day), with the risk of one cup (125 ml) increment as 1.07 (95% CI 1.06-1.08). This research suggests that positive associations between coffee consumption and BC among male smokers but not never smokers and females. The inconsistent results between sexes and the absence of an association in never smokers indicate that the associations found among male smokers is unlikely to be causal and is possibly caused by residual confounding of smoking.

Radiation risk of incident colorectal cancer by anatomical site among atomic bomb survivors: 1958-2009.

Radiation effects on colorectal cancer rates, adjusted for smoking, alcohol intake and frequency of meat consumption and body mass index (BMI) by anatomical subsite (proximal colon, distal colon and rectum) were examined in a cohort of 105,444 atomic bomb survivors. Poisson regression methods were used to describe radiation-associated excess relative risks (ERR) and excess absolute rates (EAR) for the 1958-2009 period. There were 2,960 first primary colorectal cancers including 894 proximal, 871 distal and 1,046 rectal cancers. Smoking, alcohol intake and BMI were associated with subsite-specific cancer background rates. Significant linear dose-responses were found for total colon (sex-averaged ERR/Gy for 70 years old exposed at age 30 = 0.63, 95% confidence interval [CI]: 0.34; 0.98), proximal [ERR = 0.80, 95% CI: 0.32; 1.44] and distal colon cancers [ERR = 0.50, 95% CI: 0.04; 0.97], but not for rectal cancer [ERR = 0.023, 95% CI: -0.081; 0.13]. The ERRs for proximal and distal colon cancers were not significantly different (p = 0.41). The ERR decreased with attained age for total colon, but not for proximal colon cancer, and with calendar year for distal colon cancer. The ERRs and EARs did not vary by age at exposure, except for decreasing trend in EAR for proximal colon cancer. In conclusion, ionizing radiation is associated with increased risk of proximal and distal colon cancers. The ERR for proximal cancer persists over time, but that for distal colon cancer decreases. There continues to be no indication of radiation effects on rectal cancer incidence in this population.

Radiation-Related Risk of Cancers of the Upper Digestive Tract among Japanese Atomic Bomb Survivors.

As a follow-up to the comprehensive work on solid cancer incidence in the Life Span Study (LSS) cohort of atomic bomb survivors between 1958 and 1998, we report here on updated radiation risk estimates for upper digestive tract cancers. In this study, we added 11 years of follow-up (1958-2009), used improved radiation dose estimates, considered effects of smoking and alcohol consumption and performed dose-response analyses by anatomical sub-site. In examining 52 years'worth of data, we ascertained the occurrence of 394 oral cavity/pharyngeal cancers, 486 esophageal cancers and 5,661 stomach cancers among 105,444 subjects. The radiation risk for oral cavity/pharyngeal cancer, other than salivary gland, was elevated but not significantly so. In contrast, salivary gland cancer exhibited a strong linear dose response with excess relative risk (ERR) of 2.54 per Gy [95% confidence interval (CI): 0.69 to 6.1]. Radiation risk decreased considerably with increasing age at time of exposure (-66% per decade, 95% CI: -88% to -32%). The dose response for esophageal cancer was statistically significant under a simple linear, linear-quadratic and quadratic model. Both linear-quadratic and quadratic models described the data better than a simple linear model and, of the two, the quadratic model showed a marginally better fit based on the Akaike Information Criteria. Sex difference in linear ERRs was not statistically significant; however, when the dose-response shape was allowed to vary by sex, statistically significant curvature was found among males, with no evidence of quadratic departure from linearity among females. The risk for stomach cancer increased significantly with dose and there was little evidence for quadratic departure from linearity among either males or females. The sex-averaged ERR at age 70 was 0.33 per Gy (95% CI: 0.20 to 0.47). The ERR decreased significantly (-1.93 power of attained age, 95% CI: -2.94 to -0.82) with increasing attained age, but not with age at exposure, and was higher in females than males (P = 0.02). Our results are largely consistent with the results of prior LSS analyses. Salivary gland, esophageal and stomach cancers continue to show significant increases in risk with radiation dose. Adjustment for lifestyle factors had almost no impact on the radiation effect estimates. Further follow-up of the LSS cohort is important to clarify the nature of radiation effects for upper digestive tract cancers, especially for oral cavity/pharyngeal and esophageal cancers, for which detailed investigation for dose-response shape could not be conducted due to the small number of cases.

Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958-2009.

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0-9, 10-19 and 20-29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: -0.02, 95% CI: -0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

Type 2 diabetes, obesity, and breast cancer risk among Japanese women of the atomic bomb survivor cohort.

BACKGROUND: Much less is known about diabetes than obesity as a predictor of breast cancer incidence and most previous studies have been conducted in white populations. Therefore, this project within the Radiation Effects Research Foundation's cohort of Japanese atomic bomb survivors aimed to determine the independent contributions of obesity and diabetes to develop breast cancer. METHODS: After excluding women with unknown A-bomb radiation dose, a radiation dose of ≥100 mGy, a pre-existing history of breast cancer, and missing body mass index (BMI), the analysis included 29,818 women. Breast cancer status and deaths until 2009 were identified from cancer registries and vital records. Cox regression with age as the time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BMI and diabetes status as time-varying exposures alone and in combination while adjusting for known confounders. RESULTS: Diabetes prevalence increased from 2.6% to 5.3% and 7.5% from the first to the second and third data collection. During 27.6 ± 12.2 years of follow-up, 703 women had developed breast cancer (mean age of 66.0 ± 12.9 years) and 31 (4.4%) had been diagnosed with diabetes. A diagnosis of diabetes was not significantly associated with breast cancer incidence without (HR 1.12, 95% CI 0.77-1.64) and with BMI (HR 1.01, 95% CI 0.69-1.49) as a covariate. The respective HRs for overweight and obesity were 1.61 (95% CI 1.34-1.93) and 2.04 (95% CI 1.40-2.97). CONCLUSIONS: Among a long-time Japanese cohort, excess body weight but not a diabetes diagnosis was significantly associated with breast cancer risk.

Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies.

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

Association of Diabetes With All-Cause and Cause-Specific Mortality in Asia: A Pooled Analysis of More Than 1 Million Participants.

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations. Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status. Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018. Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age. Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.

Tobacco Smoking and Mortality in Asia: A Pooled Meta-analysis.

Importance: Understanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations. Objectives: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations. Design, Setting, and Participants: This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India. Exposures: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking. Main Outcomes and Measures: Country or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer. Results: Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions. Conclusions and Relevance: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.