Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. METHODS: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). RESULTS: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. CONCLUSIONS: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.

Cigarette smoking and postmenopausal breast cancer risk in a prospective cohort.

BACKGROUND: The relationship between cigarette smoking and breast cancer risk has been inconsistent, potentially due to modification by other factors or confounding. METHODS: We examined smoking and breast cancer risk in a prospective cohort of 186 150 female AARP (formerly American Association of Retired Persons) members, ages 50-71 years, who joined the study in 1995-96 by responding to a questionnaire. Through 2006, 7481 breast cancers were diagnosed. Multivariable-adjusted hazard ratios (HRs) were estimated, overall and stratified by breast cancer risk factors, using Cox proportional hazards regression. Multiplicative interactions were evaluated using the likelihood ratio test. RESULTS: Increased breast cancer risk was associated with current (HR 1.19, 95% confidence interval (CI) 1.10-1.28) and former (HR 1.07, CI 1.01-1.13) smoking. The current smoking association was stronger among women without (HR 1.24, CI 1.15-1.35) as compared to those with a family history of breast cancer (HR 0.94, CI 0.78-1.13) (P-interaction=0.03). The current smoking association was also stronger among those with later (≥ 15 years: HR 1.52, CI 1.20-1.94) as compared with earlier (≥12 years: HR 1.14, CI 1.03-1.27; 13-14 years: HR 1.18, CI 1.05-1.32) ages at menarche (P-interaction=0.03). CONCLUSIONS: Risk was elevated in smokers, particularly in those without a family history or late menarche. Research into smoking's effects on the genome and breast development may clarify these relationships.

Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study.

BACKGROUND: Nutrients in the one-carbon metabolism pathway may be involved in carcinogenesis. Few cohort studies have investigated the intakes of folate and related nutrients in relation to gastric and esophageal cancer. METHODS: We prospectively examined the association between self-reported intakes of folate, methionine, vitamin B6, and vitamin B12 and gastric and esophageal cancer in 492,293 men and women. RESULTS: We observed an elevated risk of esophageal squamous cell carcinoma with low intake of folate (relative risk (95% confidence interval): Q1 vs Q3, 1.91 (1.17, 3.10)), but no association with high intake. Folate intake was not associated with esophageal adenocarcinoma, gastric cardia adenocarcinoma, or non-cardia gastric adenocarcinoma. The intakes of methionine, vitamin B6, and vitamin B12 were not associated with esophageal and gastric cancer. CONCLUSION: Low intake of folate was associated with increased risk of esophageal squamous cell carcinoma.

Cigarette smoking, alcohol intake, and risk of glioma in the NIH-AARP Diet and Health Study.

BACKGROUND: Although cigarette smoking and alcohol drinking increase the risk of several cancers and certain components of cigarette smoke and alcohol can penetrate the blood-brain barrier, it remains unclear whether these exposures influence the risk of glioma. METHODS: We examined the associations between cigarette smoking, alcohol intake, and risk of glioma in the National Institutes of Health-AARP Diet and Health Study, a prospective study of 477,095 US men and women ages 50-71 years at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using models with age as the time metric and adjusted for sex, race/ethnicity, education, and marital status. RESULTS: During a median 10.5 person-years of follow-up, 492 men and 212 women were diagnosed with first primary glioma. Among men, current, heavier smoking was associated with a reduced risk of glioma compared with never smoking, but this was based on only nine cases. No associations were observed between smoking behaviours and glioma risk in women. Greater alcohol consumption was associated with a decreased risk of glioma, particularly among men (>2 drinks per day vs <1 drink per week: HR=0.67, 95% CI=0.51-0.90). CONCLUSION: Smoking and alcohol drinking do not appear to increase the risk of glioma.

A prospective investigation of fish, meat and cooking-related carcinogens with endometrial cancer incidence.

BACKGROUND: There are limited prospective studies of fish and meat intakes with risk of endometrial cancer and findings are inconsistent. METHODS: We studied associations between fish and meat intakes and endometrial cancer incidence in the large, prospective National Institutes of Health-AARP Diet and Health Study. Intakes of meat mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and benzo(a)pyrene (BaP) were also calculated. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We observed no associations with endometrial cancer risk comparing the highest to lowest intake quintiles of red (HR=0.91, 95% CI 0.77-1.08), white (0.98, 0.83-1.17), processed meats (1.02, 0.86-1.21) and fish (1.10, 95% CI 0.93-1.29). We also found no associations between meat mutagen intakes and endometrial cancer. CONCLUSION: Our findings do not support an association between meat or fish intakes or meat mutagens and endometrial cancer.

Flavonoid intake and risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study Cohort.

BACKGROUND: Limited epidemiological studies show inverse associations between dietary flavonoid intake and pancreatic cancer risk, but results are inconsistent and are based on few cases. We examined the association between intake of flavonoids and pancreatic cancer risk in the large, prospective National Institutes of Health-AARP Diet and Health Study Cohort. METHODS: During follow-up through 2006 (median follow-up 10.6 years), 2379 pancreatic cancer cases were identified. We used Cox proportional hazards modelling to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We found no association between total flavonoid intake (Q5 vs Q1 HR=1.09, 95% CI: 0.96-1.24) or any flavonoid subtypes and pancreatic cancer risk. Significant interactions were not observed by age, sex, smoking status, BMI or diabetes. CONCLUSION: Our results do not support the hypothesis that flavonoids have a protective role in pancreatic cancer carcinogenesis.

Dietary intake of nitrate and nitrite and risk of renal cell carcinoma in the NIH-AARP Diet and Health Study.

BACKGROUND: Nitrate and nitrite are present in many foods and are precursors of N-nitroso compounds, known animal carcinogens and potential human carcinogens. We prospectively investigated the association between nitrate and nitrite intake from dietary sources and risk of renal cell carcinoma (RCC) overall and clear cell and papillary histological subtypes in the NIH-AARP Diet and Health Study. METHODS: Nitrate and nitrite intakes were estimated from a 124-item food frequency questionnaire. Over a mean follow-up of 9 years, we identified 1816 RCC cases (n=498, clear cell; n=115, papillary cell) among 491 841 participants. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Individuals in the highest quintile of nitrite intake from animal sources compared with those in the lowest quintile, had an increased risk of total RCC and clear cell subtype (HR=1.28, 95% CI, 1.10-1.49 and HR=1.68, 95% CI, 1.25-2.27, respectively). Nitrite from processed meats and other animal sources were associated with increased clear cell adenocarcinoma risk (HR=1.33, 95% CI, 1.01-1.76 and HR=1.78, 95% CI, 1.34-2.36, respectively). We found no association for nitrite intake from plant sources or nitrate intake overall. CONCLUSION: Our findings suggest that nitrite from animal sources may increase the risk of RCC, particularly clear cell adenocarcinomas.

Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study.

BACKGROUND: Women using unopposed estrogens during menopause are at increased risk of ovarian cancer. It is uncertain whether oestrogen plus progestin therapy exerts similar effects. METHODS: We evaluated menopausal hormone use and incident ovarian cancer (n=426) in 92601 post-menopausal women enrolled in the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study. Participants were administered questionnaires in 1996-1997 and followed through 2006. Hazard rate ratios (RR) and 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: Increased risks were associated with long duration (10+ years) use of unopposed oestrogen (RR 2.15, 95% CI: 1.30-3.57 among women with a hysterectomy) and oestrogen plus progestin (RR 1.68, 95% CI: 1.13-2.49 among women with intact uteri) therapy. Similar risks were associated with progestins that were used sequentially (<15 days progestin per month) (RR 1.60, 95% CI: 1.10-2.33) or continuously (>25 days progestin per month) (RR 1.43, 95% CI: 1.032-2.01; P-value for heterogeneity=0.63). CONCLUSION: Our findings suggest that long duration use of both unopposed estrogens and oestrogen plus progestins are associated with increased risks of ovarian cancer, and that risk associated with oestrogen plus progestin use does not vary by regimen (sequential or continuous).

Dietary fat intake and risk of ovarian cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Fat intake has been postulated to increase risk of ovarian cancer, but previous studies have reported inconsistent results. METHODS: The NIH-AARP Diet and Health Study, a large prospective cohort, assessed diet using a food frequency questionnaire at baseline in 1995-1996. During an average of 9 years of follow-up, 695 ovarian cancer cases were ascertained through the state cancer registry database. The relative risks (RRs) and 95% confidence interval (CI) were estimated using a Cox proportional hazard model. RESULTS: Women in the highest vs the lowest quintile of total fat intake had a 28% increased risk of ovarian cancer (RR(Q5 vs Q1)=1.28, 95% CI: 1.01-1.63). Fat intake from animal sources (RR(Q5 vs Q1)=1.30; 95% CI: 1.02-1.66), but not from plant sources, was positively associated with ovarian cancer risk. Saturated and monounsaturated fat intakes were not related to risk of ovarian cancer, but polyunsaturated fat intake showed a weak positive association. The association between total fat intake and ovarian cancer was stronger in women who were nulliparous or never used oral contraceptives. CONCLUSION: Fat intake, especially from animal sources, was related to an increased risk of ovarian cancer. The association may be modified by parity and oral contraceptive use, which warrants further investigation.

Alcohol consumption and risk of renal cell cancer: the NIH-AARP diet and health study.

BACKGROUND: The effect of moderate to heavy drinking (>15 g per day) on renal cell cancer (RCC) risk is unclear. METHOD: The relationship between alcohol consumption and RCC was examined in the NIH-AARP Diet and Health Study (n=49 2187, 1814 cases). RESULTS: Compared with >0 to <5 g per day of alcohol consumption, the multivariate relative risk (95% confidence intervals) for 15 to <30 and 30 g per day was, 0.75 (0.63-0.90) and 0.71 (0.59-0.85), respectively, in men and 0.67 (0.42-1.07) and 0.43 (0.22-0.84), respectively, in women. CONCLUSION: Alcohol consumption was inversely associated with RCC in a dose-response manner. The inverse association may be extended to 30 g per day of alcohol intake.

Male predominance of upper gastrointestinal adenocarcinoma cannot be explained by differences in tobacco smoking in men versus women.

BACKGROUND: Adenocarcinomas of the upper gastrointestinal tract (UGI) show remarkable male predominance. As smoking is a well-established risk factor, we investigated the role of tobacco smoking in the male predominance of UGI adenocarcinomas in the United States NIH-AARP Diet and Health Study. METHOD: A questionnaire was completed by 281,422 men and 186,133 women in 1995-1996 who were followed until 31st December 2003. Incident UGI adenocarcinomas were identified by linkage to state cancer registries. We present age-standardised cancer incidence rates per 100,000-person years and male/female ratios (M/F) calculated from age-adjusted Cox proportional hazards models, both with 95% confidence intervals (CI). RESULTS: After 2013,142-person years follow-up, 338 adenocarcinomas of the oesophagus, 261 of gastric cardia and 222 of gastric non-cardia occurred in men. In women, 23 tumours of oesophagus, 36 of gastric cardia and 88 of gastric non-cardia occurred in 1351,958-person years follow-up. The age-standardised incidence rate of all adenocarcinoma sites was 40.5 (37.8-43.3) and 11.0 (9.2-12.8) in men and women, respectively. Among smokers, the M/F of all UGI adenocarcinomas was 3.4 (2.7-4.1), with a M/F of 7.3 (4.6-11.7) for tumours in oesophagus, 3.7 (2.5-5.4) for gastric cardia and 1.7 (1.2-2.3) for gastric non-cardia. In non-smokers, M/F ratios were 14.2 (5.1-39.5) for oesophagus, 6.1 (2.6-14.7) for gastric cardia and 1.3 (0.8-2.0) for gastric non-cardia. The overall M/F ratio was 3.0 (2.2-4.3). CONCLUSION: The male predominance was similar in smokers and non-smokers for these cancer sites. These results suggest that the male predominance of upper GI adenocarcinomas cannot be explained by differences in smoking histories.

Tea, coffee, carbonated soft drinks and upper gastrointestinal tract cancer risk in a large United States prospective cohort study.

The authors investigated the relationship between hot tea, iced tea, coffee and carbonated soft drinks consumption and upper gastrointestinal tract cancers risk in the NIH-AARP Study. During 2,584,953 person-years of follow-up on 481,563 subjects, 392 oral cavity, 178 pharynx, 307 larynx, 231 gastric cardia, 224 gastric non-cardia cancer, 123 Oesophageal Squamous Cell Carcinoma (ESCC) and 305 Oesophageal Adenocarcinoma (EADC) cases were accrued. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated by multivariate-adjusted Cox regression. Compared to non-drinking, the hazard ratio for hot tea intake of > or =1 cup/day was 0.37 (95% CI: 0.20, 0.70) for pharyngeal cancer. The authors also observed a significant association between coffee drinking and risk of gastric cardia cancer (compared to <1 cup/day, the hazard ratio for drinking >3 cups/day was 1.57 (95% CI: 1.03, 2.39)), and an inverse association between coffee drinking and EADC for the cases occurring in the last 3 years of follow-up (compared to <1 cup/day, the hazard ratio for drinking >3 cups/day was 0.54 (95% CI: 0.31, 0.92)), but no association in earlier follow-up. In summary, hot tea intake was inversely associated with pharyngeal cancer, and coffee was directly associated with gastric cardia cancer, but was inversely associated with EADC during some follow-up periods.

Smoking duration, intensity, and risk of Parkinson disease.

OBJECTIVE: To evaluate the relative importance of smoking duration vs intensity in reducing the risk of Parkinson disease (PD). METHODS: The study included 305,468 participants of the NIH-AARP Diet and Health cohort, of whom 1,662 had a PD diagnosis after 1995. We estimated odds ratios (OR) and 95% confidence intervals from multivariate logistic regression models. RESULTS: Compared with never smokers, the multivariate ORs were 0.78 for past smokers and 0.56 for current smokers. Among past smokers, a monotonic trend toward lower PD risk was observed for all indicators of more smoking. Stratified analyses indicated that smoking duration was associated with lower PD risk within fixed intensities of smoking. For example, compared with never smokers, the ORs among past smokers who smoked >20 cigarettes/day were 0.96 for 1-9 years of smoking, 0.78 for 10-19 years, 0.64 for 20-29 years, and 0.59 for 30 years or more (p for trend = 0.001). In contrast, at fixed duration, the typical number of cigarettes smoked per day in general was not related to PD risk. Close examination of smoking behaviors in early life showed that patients with PD were less likely to be smokers at each age period, but if they smoked, they smoked similar numbers of cigarettes per day as individuals without PD. CONCLUSIONS: This large study suggests that long-term smoking is more important than smoking intensity in the smoking-Parkinson disease relationship.

Alcohol intake and risk of thyroid cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Certain studies suggest that alcohol may reduce the risk of thyroid cancer in women, but the effect in men remains unclear. METHODS: We analysed the association between alcohol and thyroid cancer in a large (n=490 159) prospective NIH-AARP Diet and Health Study with self-reported beer, wine, and liquor intakes. RESULTS: Over 7.5 years of follow-up (median), 170 men and 200 women developed thyroid cancer. Overall, the thyroid cancer risk decreased with greater alcohol consumption (> or =2 drinks per day vs none, relative risk=0.57, 95% CI 0.36-0.89, P-trend=0.01). CONCLUSIONS: These results suggest a potential protective role for alcohol consumption in thyroid cancer.

Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis.

Use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric or oesophageal adenocarcinomas. We examined the association between self-reported use of aspirin or non-aspirin NSAIDs in the earlier 12 months and gastric non-cardia (N=182), gastric cardia (N=178), and oesophageal adenocarcinomas (N=228) in a prospective cohort (N=311 115) followed for 7 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) come from Cox models adjusted for potential confounders. Use of any aspirin (HR, 95% CI: 0.64, 0.47-0.86) or other NSAIDs (0.68, 0.51-0.92) was associated with a significantly lower risk of gastric non-cardia adenocarcinoma. Neither aspirin (0.86, 0.61-1.20) nor other NSAIDs (0.91, 0.67-1.22) had a significant association with gastric cardia cancer. We found no significant association between using aspirin (1.00, 0.73-1.37) or other NSAIDs (0.90, 69-1.17) and oesophageal adenocarcinoma. We also performed a meta-analysis of the association between the use of NSAIDs and risk of gastric and oesophageal adenocarcinoma. In this analysis, aspirin use was inversely associated with both gastric and oesophageal adenocarcinomas, with summary odds ratios (95% CI) for non-cardia, cardia, and oesophageal adenocarcinomas of 0.64 (0.52-0.80), 0.82 (0.65-1.04), and 0.64 (0.52-0.79), respectively. The corresponding numbers for other NSAIDs were 0.68 (0.57-0.81), 0.80 (0.67-0.95), and 0.65 (0.50-0.85), respectively.

Associations between food patterns defined by cluster analysis and colorectal cancer incidence in the NIH-AARP diet and health study.

BACKGROUND/OBJECTIVES: To examine associations between food patterns, constructed with cluster analysis, and colorectal cancer incidence within the National Institutes of Health-AARP Diet and Health Study. SUBJECTS/METHODS: A prospective cohort, aged 50-71 years at baseline in 1995-1996, followed until the end of 2000. Food patterns were constructed, separately in men (n=293,576) and women (n=198,730), with 181 food variables (daily intake frequency per 1000 kcal) from a food frequency questionnaire. Four large clusters were identified in men and three in women. Cox proportional hazards regression examined associations between patterns and cancer incidence. RESULTS: In men, a vegetable and fruit pattern was associated with reduced colorectal cancer incidence (multivariate hazard ratio, HR: 0.85; 95% confidence interval, CI: 0.76, 0.94), when compared to less salutary food choices. Both the vegetable and fruit pattern and a fat-reduced foods pattern were associated with reduced rectal cancer incidence in men. In women, a similar vegetable and fruit pattern was associated with colorectal cancer protection (age-adjusted HR: 0.82; 95% CI: 0.70, 0.95), but the association was not statistically significant in multivariate analysis. CONCLUSIONS: These results, together with findings from previous studies support the hypothesis that micronutrient dense, low-fat, high-fiber food patterns protect against colorectal cancer.

Index-based dietary patterns and risk of colorectal cancer: the NIH-AARP Diet and Health Study.

The authors compared how four indexes-the Healthy Eating Index-2005, Alternate Healthy Eating Index, Mediterranean Diet Score, and Recommended Food Score-are associated with colorectal cancer in the National Institutes of Health-AARP Diet and Health Study (n = 492,382). To calculate each score, they merged data from a 124-item food frequency questionnaire completed at study entry (1995-1996) with the MyPyramid Equivalents Database (version 1.0). Other variables included energy, nutrients, multivitamins, and alcohol. Models were stratified by sex and adjusted for age, ethnicity, education, body mass index, smoking, physical activity, and menopausal hormone therapy (in women). During 5 years of follow-up, 3,110 incident colorectal cancer cases were ascertained. Although the indexes differ in design, a similarly decreased risk of colorectal cancer was observed across all indexes for men when comparing the highest scores with the lowest: Healthy Eating Index-2005 (relative risk (RR) = 0.72, 95% confidence interval (CI): 0.62, 0.83); Alternate Healthy Eating Index (RR = 0.70, 95% CI: 0.61, 0.81); Mediterranean Diet Score (RR = 0.72, 95% CI: 0.63, 0.83); and Recommended Food Score (RR = 0.75, 95% CI: 0.65, 0.87). For women, a significantly decreased risk was found with the Healthy Eating Index-2005, although Alternate Healthy Eating Index results were similar. Index-based dietary patterns that are consistent with given dietary guidelines are associated with reduced risk.

Alcohol and head and neck cancer risk in a prospective study.

We investigated the relation between head and neck cancer risk and alcohol consumption in the NIH-AARP Diet and Health Study. During 2,203,500 person-years of follow-up, 611 men and 183 women developed head and neck cancer. With moderate drinking (up to one alcoholic drink per day) as the referent group, non-drinkers showed an increased risk of head and neck cancer (men: hazard ratio (HR) 1.68, 95% confidence interval (95% CI) 1.37-2.06; women: 1.46, 1.02-2.08). Among male and female alcohol drinkers, we observed a significant dose-response relationship between alcohol consumption and risk. The HR for consuming >3 drinks per day was significantly higher in women (2.52, 1.46-4.35) than in men (1.48, 1.15-1.90; P for interaction=0.0036). The incidence rates per 100 000 person-years for those who consumed >3 drinks per day were similar in men (77.6) and women (75.3). The higher HRs observed in women resulted from lower incidence rates in the referent group: women (14.7), men (34.4). In summary, drinking >3 alcoholic beverages per day was associated with increased risk in men and women, but consumption of up to one drink per day may be associated with reduced risk relative to non-drinking.