Obesity, weight gain, and the risk of kidney stones

Context  Larger body size may result in increased urinary excretion of calcium, oxalate, and uric acid, thereby increasing the risk for calcium-containing kidney stones. It is unclear if obesity increases the risk of stone formation, and it is not known if weight gain influences risk. Objective  To determine if weight, weight gain, body mass index (BMI), and waist circumference are associated with kidney stone formation. Design, Setting, and Participants  A prospective study of 3 large cohorts: the Health Professionals Follow-up Study (N = 45 988 men; age range at baseline, 40-75 years), the Nurses’ Health Study I (N = 93 758 older women; age range at baseline, 34-59 years), and the Nurses’ Health Study II (N = 101 877 younger women; age range at baseline, 27-44 years). Main Outcome Measures  Incidence of symptomatic kidney stones. Results  We documented 4827 incident kidney stones over a combined 46 years of follow-up. After adjusting for age, dietary factors, fluid intake, and thiazide use, the relative risk (RR) for stone formation in men weighing more than 220 lb (100.0 kg) vs men less than 150 lb (68.2 kg) was 1.44 (95% confidence interval [CI], 1.11-1.86; P = .002 for trend). In older and younger women, RRs for these weight categories were 1.89 (95% CI, 1.52-2.36; P<.001 for trend) and 1.92 (95% CI, 1.59-2.31; P<.001 for trend), respectively. The RR in men who gained more than 35 lb (15.9 kg) since age 21 years vs men whose weight did not change was 1.39 (95% CI, 1.14-1.70; P = .001 for trend). Corresponding RRs for the same categories of weight gain since age 18 years in older and younger women were 1.70 (95% CI, 1.40-2.05; P<.001 for trend) and 1.82 (95% CI, 1.50-2.21; P<.001 for trend). Body mass index was associated with the risk of kidney stone formation: the RR for men with a BMI of 30 or greater vs those with a BMI of 21 to 22.9 was 1.33 (95% CI, 1.08-1.63; P<.001 for trend). Corresponding RRs for the same categories of BMI in older and younger women were 1.90 (95% CI, 1.61-2.25; P<.001 for trend) and 2.09 (95% CI, 1.77-2.48; P<.001 for trend). Waist circumference was also positively associated with risk in men (P = .002 for trend) and in older and younger women (P<.001 for trend for both). Conclusions  Obesity and weight gain increase the risk of kidney stone formation. The magnitude of the increased risk may be greater in women than in men.      

Adult weight change and risk of postmenopausal breast cancer

Context  Endogenous hormones are a primary cause of breast cancer. Adiposity affects circulating hormones, particularly in postmenopausal women, and may be a modifiable risk factor for breast cancer. Objective  To assess the associations of adult weight change since age 18 years and since menopause with the risk of breast cancer among postmenopausal women. Design, Setting, and Participants  Prospective cohort study within the Nurses' Health Study. A total of 87 143 postmenopausal women, aged 30 to 55 years and free of cancer, were followed up for up to 26 years (1976-2002) to assess weight change since age 18 years. Weight change since menopause was assessed among 49 514 women who were followed up for up to 24 years. Main Outcome Measure  Incidence of invasive breast cancer. Results  Overall, 4393 cases of invasive breast cancer were documented. Compared with those who maintained weight, women who gained 25.0 kg or more since age 18 years were at an increased risk of breast cancer (relative risk [RR], 1.45; 95% confidence interval [CI], 1.27-1.66; P<.001 for trend), with a stronger association among women who have never taken postmenopausal hormones (RR,1.98; 95% CI, 1.55-2.53). Compared with weight maintenance, women who gained 10.0 kg or more since menopause were at an increased risk of breast cancer (RR, 1.18; 95% CI, 1.03-1.35; P  = .002 for trend). Women who had never used postmenopausal hormones, lost 10.0 kg or more since menopause, and kept the weight off were at a lower risk than those who maintained weight (RR, 0.43; 95% CI, 0.21-0.86; P = .01 for weight loss trend). Overall, 15.0% (95% CI, 12.8%-17.4%) of breast cancer cases in this population may be attributable to weight gain of 2.0 kg or more since age 18 years and 4.4% (95% CI, 3.6%-5.5%) attributable to weight gain of 2.0 kg or more since menopause. Among those who did not use postmenopausal hormones, the population attributable risks are 24.2% (95% CI, 19.8%-29.1%) for a weight gain since age 18 years and 7.6% (95% CI, 5.9%-9.7%) for weight gain since menopause. Conclusions  These data suggest that weight gain during adult life, specifically since menopause, increases the risk of breast cancer among postmenopausal women, whereas weight loss after menopause is associated with a decreased risk of breast cancer. Thus, in addition to other known benefits of healthy weight, our results provide another reason for women approaching menopause to maintain or lose weight, as appropriate.      

Folate intake and the risk of incident hypertension among US women

Context  Folate has important beneficial effects on endothelial function, but there is limited information about folate intake and risk of incident hypertension. Objective  To determine whether higher folate intake is associated with a lower risk of incident hypertension. Design, Setting, and Participants  Two prospective cohort studies of 93 803 younger women aged 27 to 44 years in the Nurses’ Health Study II (1991-1999) and 62 260 older women aged 43 to 70 years in the Nurses’ Health Study I (1990-1998), who did not have a history of hypertension. Baseline information on dietary folate and supplemental folic acid intake was derived from semiquantitative food frequency questionnaires and was updated every 4 years. Main Outcome Measure  Relative risk of incident self-reported hypertension during 8 years of follow-up. Results  We identified 7373 incident cases of hypertension in younger women and 12 347 cases in older women. After adjusting for multiple potential confounders, younger women who consumed at least 1000 µg/d of total folate (dietary plus supplemental) had a decreased risk of hypertension (relative risk [RR], 0.54; 95% confidence interval [CI], 0.45-0.66; P for trend <.001) compared with those who consumed less than 200 µg/d. Younger women’s absolute risk reduction (ARR) was approximately 8 cases per 1000 person-years (6.7 vs 14.8 cases). The multivariable RR for the same comparison in older women was 0.82 (95% CI, 0.69-0.97; P for trend = .05). Older women’s ARR was approximately 6 cases per 1000 person-years (34.7 vs 40.4 cases). When the analysis was restricted to women with low dietary folate intake (<200 µg/d), the multivariable RR for younger women with total folate intake at least 800 µg/d compared with less than 200 µg/d was 0.55 (95% CI, 0.32-0.94; P for trend = .03), and 0.61 (95% CI, 0.34-1.11; P for trend = .05) in the older cohort. Among women who did not take folic acid–containing supplements, dietary folate intake of 400 µg/d or more was not significantly associated with risk of hypertension. Conclusion  Higher total folate intake was associated with a decreased risk of incident hypertension, particularly in younger women.      

Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons. Objective  To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years. Intervention  Administration of 600 IU of natural-source vitamin E on alternate days. Main Outcome Measures  Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer. Results  During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR,  1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53). Conclusions  The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.      

Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer. Objective  To examine the effect of aspirin on the risk of cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39 876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years. Intervention  A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942) administered every other day. Main Outcome Measures  Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points. Results  No effect of aspirin was observed on total cancer (n = 2865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found. Conclusions  Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.      

Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women

Context  Evidence is limited on the effects of different patterns of use of postmenopausal hormone therapy on fracture incidence and particularly on the effects of ceasing use. Objective  To investigate the effect of different patterns of hormone therapy use on fracture incidence. Design, Setting, and Participants  Prospective study of 138 737 postmenopausal women aged 50 to 69 years recruited from the UK general population in 1996-1998 (the Million Women Study) and followed up for 1.9 to 3.9 years (average, 2.8 years) for fracture incidence. Main Outcome Measure  Adjusted relative risk (RR) for incident fracture (except fracture of the fingers, toes, and ribs) in hormone therapy users compared with never users at baseline. Results  A total of 5197 women (3.7%) reported 1 or more fractures, 79% resulting from falls. Current users of hormone therapy at baseline had a significantly reduced incidence of fracture (RR, 0.62; 95% confidence interval [CI], 0.58-0.66; P<.001). This protection was evident soon after hormone therapy began, and the RR decreased with increasing duration of use (P = .001). Among current users at baseline the RR of fracture did not vary significantly according to whether estrogen-only, estrogen-progestin, or other types of hormones were used (RR [95% CI], 0.64 [0.58-0.71], 0.58 [0.53-0.64], and 0.67 [0.56-0.80], respectively; P = .19), nor did it vary significantly according to estrogen dose or estrogen or progestin constituents. The RR associated with current use of hormone therapy did not vary significantly according to 11 personal characteristics of study participants, including their age at menopause, body mass index, and physical activity. Past users of hormone therapy at baseline experienced no significant protection against fractures (RR, 1.07; 95% CI, 0.99-1.15); incidence rates returned to those of never-users within about a year of ceasing use. Conclusions  All types of hormone therapy studied confer substantial protection against fracture while they are used. This protection appears rapidly after use commences and wears off rapidly after use ceases. The older women are, the greater is their absolute reduction in fracture incidence while using hormone therapy.      

Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease

Context  Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk. Objective  To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD. Design, Setting, and Subjects  Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998. Main Outcome Measures  Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents. Results  Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P = .03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P = .003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses. Conclusions  Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.      

Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies

Context  Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. Objective  To evaluate the association between dietary fiber intake and risk of colorectal cancer. Design, Setting, and Participants  From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725 628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. Main Outcome Measure  Incident colorectal cancer. Results  During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07). Conclusions  In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.      

Hormone Replacement Therapy and Risk of Breast Cancer With a Favorable Histology: Results of the Iowa Women's Health Study

Context  Long-term, postmenopausal use of hormone replacement therapy (HRT) appears to increase breast cancer risk. Whether the effect of HRT use on risk of breast cancer varies among histological types of invasive carcinoma is unknown. Objective  To determine associations between HRT use and risk of ductal carcinoma in situ (DCIS), invasive carcinoma with favorable histology, and invasive ductal or lobular carcinoma. Design  Prospective cohort study whose participants were followed up continuously for 11 years from January 1986 to December 1996. Setting and Participants  Iowa Women's Health Study, a population-based random sample of postmenopausal women aged 55 to 69 years in 1986. A total of 1520 incident breast cancer cases occurred in the at-risk cohort of 37,105 women. Main Outcome Measures  Multivariate-adjusted relative risk (RR) of tumor-specific breast cancers associated with duration of ever, current, or past HRT use. Results  Duration of ever HRT use was associated with risk of invasive carcinoma with a favorable histology, with an RR of 1.81 (95% confidence interval [CI], 1.07-3.07) for those who used HRT 5 or fewer years vs an RR of 2.65 (95% CI, 1.34-5.23) for those who used HRT for more than 5 years (P for trend=.005) after adjustment for age and other breast cancer risk factors. There was no association between ever HRT use and the incidence of DCIS or invasive ductal or lobular carcinoma. Among current hormone users, after adjusting for age and other breast cancer risk factors, the RRs (95% CIs) of invasive carcinoma with a favorable histology were 4.42 (2.00-9.76) and 2.63 (1.18-5.89) for 5 or fewer years of use and for more than 5 years of use, respectively. Risk of invasive ductal or lobular carcinoma was associated with current use (5 years) of HRT with an RR of 1.38 (95% CI, 1.03-1.85). Conclusions  Exposure to HRT was associated most strongly with an increased risk of invasive breast cancer with a favorable prognosis. These data add important clinical information for assessing the risks and benefits of HRT use.      

Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy

Context  Drug intervention in placebo-controlled trials has been beneficial in isolated systolic hypertension. Objective  To test the hypothesis that losartan improves outcome better than atenolol in patients with isolated systolic hypertension and electrocardiographically documented left ventricular hypertrophy (ECG-LVH). Design  Double-blind, randomized, parallel-group study conducted in 1995-2001. Setting and Participants  A total of 1326 men and women aged 55 through 80 years (mean, 70 years) with systolic blood pressure of 160 to 200 mm Hg and diastolic blood pressure of less than 90 mm Hg (mean, 174/83 mm Hg) and ECG-LVH, recruited from 945 outpatient settings in the Nordic countries, the United Kingdom, and the United States. Interventions  Patients were randomly assigned to receive once-daily losartan (n = 660) or atenolol (n = 666) with hydrochlorothiazide as the second agent in both arms, for a mean of 4.7 years. Main Outcome Measure  Composite end point of cardiovascular death, stroke, or myocardial infarction. Results  Blood pressure was reduced by 28/9 and 28/9 mm Hg in the losartan and atenolol arms. The main outcome was reduced by 25% with losartan compared with atenolol, 25.1 vs 35.4 events per 1000 patient-years (relative risk [RR], 0.75; 95% confidence interval [CI], 0.56-1.01; P = .06, adjusted for risk and degree of ECG-LVH; unadjusted RR, 0.71; 95% CI, 0.53-0.95; P = .02). Patients receiving losartan had reductions in the following without a difference in the incidence of myocardial infarction: cardiovascular mortality (8.7 vs 16.9 events per 1000 patient-years; RR, 0.54; 95% CI, 0.34-0.87; P = .01), nonfatal and fatal stroke (10.6 vs 18.9 events per 1000 patient-years; RR, 0.60; 95% CI, 0.38-0.92; P = .02), new-onset diabetes (12.6 vs 20.1 events per 1000 patient-years; RR, 0.62; 95% CI, 0.40-0.97; P = .04), and total mortality (21.2 vs 30.2 events per 1000 patient-years; RR, 0.72; 95% CI, 0.53-1.00; P = .046). Losartan decreased ECG-LVH more than atenolol (P<.001) and was better tolerated. Conclusion  These data suggest that losartan is superior to atenolol for treatment of patients with isolated systolic hypertension and ECG-LVH.      

Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study

Context  Women who are physically active have a decreased risk for breast cancer, but the types, amounts, and timing of activity needed are unknown. Objective  To prospectively examine the association between current and past recreational physical activity and incidence of breast cancer in postmenopausal women. Design, Setting, and Patients  Prospective cohort study in 74 171 women aged 50 to 79 years who were recruited by 40 US clinical centers from 1993 through 1998. Main Outcome Measure  Incident invasive and in situ breast cancer. Results  We documented 1780 newly diagnosed cases of breast cancer over a mean follow-up of 4.7 years. Compared with less active women, women who engaged in regular strenuous physical activity at age 35 years had a 14% decreased risk of breast cancer (relative risk [RR], 0.86; 95% confidence interval [CI], 0.78-0.95). Similar but attenuated findings were observed for strenuous physical activity at ages 18 years and 50 years. An increasing total current physical activity score was associated with a reduced risk for breast cancer (P = .03 for trend). Women who engaged in the equivalent of 1.25 to 2.5 hours per week of brisk walking had an 18% decreased risk of breast cancer (RR, 0.82; 95% CI, 0.68-0.97) compared with inactive women. Slightly greater reduction in risk was observed for women who engaged in the equivalent of 10 hours or more per week of brisk walking. The effect of exercise was most pronounced in women in the lowest tertile of body mass index (BMI) (<24.1), but also was observed for women in the middle tertile of BMI (24.1-28.4). Conclusions  These data suggest that increased physical activity is associated with reduced risk for breast cancer in postmenopausal women, longer duration provides most benefit, and that such activity need not be strenuous.      

Exercise type and intensity in relation to coronary heart disease in men

Context  Studies have shown an inverse relationship between exercise and risk of coronary heart disease (CHD), but data on type and intensity are sparse. Objective  To assess the amount, type, and intensity of physical activity in relation to risk of CHD among men. Design, Setting, and Participants  A cohort of 44 452 US men enrolled in the Health Professionals' Follow-up Study, followed up at 2-year intervals from 1986 through January 31, 1998, to assess potential CHD risk factors, identify newly diagnosed cases of CHD, and assess levels of leisure-time physical activity. Main Outcome Measure  Incident nonfatal myocardial infarction or fatal CHD occurring during the follow-up period. Results  During 475 755 person-years, we documented 1700 new cases of CHD. Total physical activity, running, weight training, and rowing were each inversely associated with risk of CHD. The RRs (95% confidence intervals [CIs]) corresponding to quintiles of metabolic equivalent tasks (METs) for total physical activity adjusted for age, smoking, and other cardiovascular risk factors were 1.0, 0.90 (0.78-1.04), 0.87 (0.75-1.00), 0.83 (0.71-0.96), and 0.70 (0.59-0.82) (P<.001 for trend). Men who ran for an hour or more per week had a 42% risk reduction (RR, 0.58; 95% CI, 0.44-0.77) compared with men who did not run (P<.001 for trend). Men who trained with weights for 30 minutes or more per week had a 23% risk reduction (RR, 0.77; 95% CI, 0.61-0.98) compared with men who did not train with weights (P = .03 for trend). Rowing for 1 hour or more per week was associated with an 18% risk reduction (RR, 0.82; 05% CI, 0.68-0.99). Average exercise intensity was associated with reduced CHD risk independent of the total volume of physical activity. The RRs (95% CIs) corresponding to moderate (4-6 METs) and high (6-12 METs) activity intensities were 0.94 (0.83-1.04) and 0.83 (0.72-0.97) compared with low activity intensity (<4 METs) (P = .02 for trend). A half-hour per day or more of brisk walking was associated with an 18% risk reduction (RR, 0.82; 95% CI, 0.67-1.00). Walking pace was associated with reduced CHD risk independent of the number of walking hours. Conclusions  Total physical activity, running, weight training, and walking were each associated with reduced CHD risk. Average exercise intensity was associated with reduced risk independent of the number of MET-hours spent in physical activity.      

Magnesium intake in relation to risk of colorectal cancer in women

Context  Animal studies have suggested that dietary magnesium may play a role in the prevention of colorectal cancer, but data in humans are lacking. Objective  To evaluate the hypothesis that a high magnesium intake reduces the risk of colorectal cancer in women. Design, Setting, and Participants  The Swedish Mammography Cohort, a population-based prospective cohort of 61 433 women aged 40 to 75 years without previous diagnosis of cancer at baseline from 1987 to 1990. Main Outcome Measure  Incident invasive colorectal cancer. Results  During a mean of 14.8 years (911 042 person-years) of follow-up, 805 incident colorectal cancer cases were diagnosed. After adjustment for potential confounders, we observed an inverse association of magnesium intake with the risk of colorectal cancer (P for trend = .006). Compared with women in the lowest quintile of magnesium intake, the multivariate rate ratio (RR) was 0.59 (95% confidence interval [CI], 0.40-0.87) for those in the highest quintile. The inverse association was observed for both colon (RR, 0.66; 95% CI, 0.41-1.07) and rectal cancer (RR, 0.45; 95% CI, 0.22-0.89). Conclusion  This population-based prospective study suggests that a high magnesium intake may reduce the occurrence of colorectal cancer in women.      

Familial risk of lung carcinoma in the Icelandic population

Context  The dominant role of tobacco smoke as a causative factor in lung carcinoma is well established; however, an inherited predisposition may also be an important factor in the susceptibility to lung carcinoma. Objective  To investigate the contribution of genetic factors to the risk of developing lung carcinoma in the Icelandic population. Design, Setting, and Participants  Risk ratios (RRs) of lung carcinoma for first-, second-, and third-degree relatives of patients with lung carcinoma were estimated by linking records from the Icelandic Cancer Registry (ICR) of all 2756 patients diagnosed with lung carcinoma within the Icelandic population from January 1, 1955, to February 28, 2002, with an extensive genealogical database containing all living Icelanders and most of their ancestors since the settlement of Iceland. The RR for smoking was similarly estimated using a random population-based cohort of 10 541 smokers from the Reykjavik Heart Study who had smoked for more than 10 years. Of these smokers, 562 developed lung cancer based on the patients with lung cancer list from the ICR. Main Outcome Measures  Estimation of RRs of close and distant relatives of patients with lung carcinoma and comparison with RRs for close and distant relatives of smokers. Results  A familial factor for lung carcinoma was shown to extend beyond the nuclear family, as evidenced by significantly increased RR for first-degree relatives (for parents: RR, 2.69; 95% confidence interval [CI], 2.20-3.23; for siblings: RR, 2.02; 95% CI, 1.77-2.23; and for children: RR, 1.96; 95% CI, 1.53-2.39), second-degree relatives (for uncles/aunts: RR, 1.34; 95% CI, 1.15-1.49; and for nephews/nieces: RR, 1.28; 95% CI, 1.10-1.43), and third-degree relatives (for cousins: RR, 1.14; 95% CI, 1.05-1.22) of patients with lung carcinoma. This effect was stronger for relatives of patients with early-onset disease (age at onset 60 years) (for parents: RR, 3.48; 95% CI, 1.83-8.21; for siblings: RR, 3.30; 95% CI, 2.19-4.58; and for children: RR, 2.84; 95% CI, 1.34-7.21). The hypothesis that this increased risk is solely due to the effects of smoking was rejected for all relationships, except cousins and spouses, with a single-sided test of the RRs for lung carcinoma vs RRs for smoking. Conclusions  These results underscore the importance of genetic predisposition in the development of lung carcinoma, with its strongest effect in patients with early-onset disease. However, tobacco smoke plays a dominant role in the pathogenesis of this disease, even among those individuals who are genetically predisposed to lung carcinoma.      

Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ

Context  The distribution of BRCA1 and BRCA2 mutations in women diagnosed with noninvasive breast carcinoma is unknown. Objective  To estimate the BRCA1 and BRCA2 mutation prevalence in women with ductal carcinoma in situ (DCIS), unselected for age, family history, or ethnicity. Design, Setting, and Participants  The data were 369 DCIS cases diagnosed among female residents aged 20 to 79 years from the state of Connecticut between September 15, 1994, and March 14, 1998. These women were participants in a large population-based case-control study of breast carcinoma in situ. Telephone interviews were used to collect risk factor information and blood or buccal specimens were collected for BRCA1 and BRCA2 mutation testing. Main Outcome Measures  Prevalence of disease-associated mutations of BRCA1 and BRCA2 in women diagnosed with DCIS. Results  Three (0.8%) and 9 (2.4%) of 369 DCIS cases had disease-associated mutations in BRCA1 or BRCA2, respectively. One woman had a mutation in both genes (BRCA1 W321X and BRCA2 3398del5). Carriers were significantly more likely than noncarriers to report a first-degree (mother, sister, or daughter) family history of breast cancer (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.4), as well as a personal history of ovarian cancer. In addition, carriers were more likely than noncarriers to be diagnosed at an early age (<50 years) (OR, 3.4; 95% CI, 1.0-11.7), as well as to report at least 1 first-degree relative diagnosed with breast cancer before 50 years (OR, 10.6; 95% CI, 3.0-37.0). Conclusions  Ductal carcinoma in situ is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer. These findings suggest that patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer.      

Dietary intake of antioxidants and risk of Alzheimer disease

Context  Laboratory findings have suggested that oxidative stress may contribute to the pathogenesis of Alzheimer disease. Therefore, the risk of Alzheimer disease might be reduced by intake of antioxidants that counteract the detrimental effects of oxidative stress. Objective  To determine whether dietary intake of antioxidants is related to risk of Alzheimer disease. Design and Setting  The Rotterdam Study, a population-based, prospective cohort study conducted in the Netherlands. Participants  A total of 5395 participants who, at baseline (1990-1993), were aged at least 55 years, free of dementia, and noninstitutionalized and had reliable dietary assessment. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for incident dementia. Main Outcome Measures  Incidence of Alzheimer disease, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria, associated with dietary intake of beta carotene, flavonoids, vitamin C, and vitamin E. Results  After a mean follow-up of 6 years, 197 participants developed dementia, of whom 146 had Alzheimer disease. When adjustments were made for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of antioxidative supplements, high intake of vitamin C and vitamin E was associated with lower risk of Alzheimer disease (rate ratios [RRs] per 1-SD increase in intake were 0.82 [95% confidence interval {CI}, 0.68-0.99] and 0.82 [95% CI, 0.66-1.00], respectively). Among current smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 0.37-1.14] and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake of beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95% CI, 0.31-0.96]). The associations did not vary by education or apolipoprotein E genotype. Conclusion  High dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer disease.      

Physical activity, obesity, height, and the risk of pancreatic cancer

Context  Diabetes mellitus and elevated postload plasma glucose levels have been associated with an increased risk of pancreatic cancer in previous studies. By virtue of their influence on insulin resistance, obesity and physical inactivity may increase risk of pancreatic cancer. Objective  To examine obesity, height, and physical activity in relation to pancreatic cancer risk. Design and Setting  Two US cohort studies conducted by mailed questionnaire, the Health Professionals Follow-up Study (initiated in 1986) and the Nurses' Health Study (initiated in 1976), with 10 to 20 years of follow-up. Participants  A total of 46 648 men aged 40 to 75 years and 117 041 women aged 30 to 55 years who were free of prior cancer at baseline and had complete data on height and weight. Main Outcome Measures  Relative risk of pancreatic cancer, analyzed by self-reported body mass index (BMI), height, and level of physical activity. Results  During follow-up, we documented 350 incident pancreatic cancer cases. Individuals with a BMI of at least 30 kg/m² had an elevated risk of pancreatic cancer compared with those with a BMI of less than 23 kg/m² (multivariable relative risk [RR], 1.72; 95% confidence interval [CI], 1.19-2.48). Height was associated with an increased pancreatic cancer risk (multivariable RR, 1.81; 95% CI, 1.31-2.52 for the highest vs lowest categories). An inverse relation was observed for moderate activity (multivariable RR, 0.45; 95% CI, 0.29-0.70 for the highest vs lowest categories; P for trend <.001). Total physical activity was not associated with risk among individuals with a BMI of less than 25 kg/m² but was inversely associated with risk among individuals with a BMI of at least 25 kg/m² (pooled multivariable RR, 0.59; 95% CI, 0.37-0.94 for the top vs bottom tertiles of total physical activity; P for trend = .04). Conclusion  In 2 prospective cohort studies, obesity significantly increased the risk of pancreatic cancer. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight.      

Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial

Context  Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. Objective  To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE–The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. Intervention  Daily dose of natural source vitamin E (400 IU) or matching placebo. Main Outcome Measures  Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. Results  Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. Conclusion  In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.      

Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril

Context  Few cardiovascular outcome data are available for blacks with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs). Objective  To determine whether an ACE inhibitor or CCB is superior to a thiazide-type diuretic in reducing cardiovascular disease (CVD) incidence in racial subgroups. Design, Setting, and Participants  Prespecified subgroup analysis of ALLHAT, a randomized, double-blind, active-controlled, clinical outcome trial conducted between February 1994 and March 2002 in 33 357 hypertensive US and Canadian patients aged 55 years or older (35% black) with at least 1 other cardiovascular risk factor. Interventions  Antihypertensive regimens initiated with a CCB (amlodipine) or an ACE inhibitor (lisinopril) vs a thiazide-type diuretic (chlorthalidone). Other medications were added to achieve goal blood pressures (BPs) less than 140/90 mm Hg. Main Outcome Measures  The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined CVD (CHD death, nonfatal MI, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. Results  No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone only, HF was the only prespecified clinical outcome that differed significantly (overall: relative risk [RR], 1.37; 95% confidence interval [CI], 1.24-1.51; blacks: RR, 1.46; 95% CI, 1.24-1.73; nonblacks: RR, 1.32; 95% CI, 1.17-1.49; P<.001 for each comparison) with no difference in treatment effects by race (P = .38 for interaction). For lisinopril vs chlorthalidone, results differed by race for systolic BP (greater decrease in blacks with chlorthalidone), stroke, and combined CVD outcomes (P<.001, P = .01, and P = .04, respectively, for interactions). In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI, 1.17-1.68) and 1.00 (95% CI, 0.85-1.17) and for combined CVD were 1.19 (95% CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13). For HF, the RRs were 1.30 (95% CI, 1.10-1.54) and 1.13 (95% CI, 1.00-1.28), with no significant interaction by race. Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks. Conclusions  In blacks and nonblack subgroups, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary CHD or any other prespecified clinical outcome, and diuretic-based treatment resulted in the lowest risk of heart failure. While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks, thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients.      

The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial

Context  Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. Objective  To determine whether women taking raloxifene have a lower risk of invasive breast cancer. Design and Setting  The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe. Participants  A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded. Intervention  Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets. Main Outcome Measures  New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review. Results  Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor–positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor–negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7). Conclusion  Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.