Background

Vitamin D status and levels of insulin-like growth factor (IGF)-1 and C-peptide have been implicated in colorectal carcinogenesis. However, in contrast to vitamin D IGF-1 is not an easily modifiable risk factor.

Methods

Combining data from the Health Professionals Follow up Study (HPFS) and the Nurses' Health Study cohort (NHS) additive and multiplicative interactions were examined between plasma 25-hydroxyvitamin D (25(OH)D) and IGF-1, IGFBP-3 as well as C-peptide levels in 499 cases and 992 matched controls. For the various analytes, being high or low was based on being either above (or equal) or below the medians, respectively.

Results

Compared to participants with high 25(OH)D and low IGF-1/IGFBP-3 ratio (reference group), participants with a high IGF-1/IGFBP-3 ratio were at elevated risk of colorectal cancer when 25(OH)D was low (odds ratio (OR): 2.05 (95% CI: 1.43 to 2.92), but not when 25(OH)D was high (OR:1.20 (95% CI: 0.84 to 1.71, p(interaction): additive  = 0.06, multiplicative  = 0.25). Similarly, compared to participants with high 25(OH)D and low molar IGF-1/IGFBP-3 ratio and low C-peptide levels (reference group), participants with a combination of either high IGF-1/IGFBP-3 ratio or high C-peptide were at elevated risk for colorectal cancer when 25(OH)D was low (OR = 1.90, 95% CI: 1.22 to 2.94) but not when 25(OH)D was high (OR = 1.15, 95% CI: 0.74 to 1.77, p(interaction): additive = 0.004; multiplicative  = 0.04).

Conclusion

The results from this study suggest that improving vitamin D status may help lower risk of colorectal cancer associated with higher IGF-1/IGFBP-3 ratio or C-peptide levels.

Background

There is increasing evidence suggesting that female hormones may play a significant role in lung cancer (LC) development. We evaluated the associations between reproductive factors, exogeneous hormone use, and LC incidence in the Nurses’ Health Study (NHS).

Methods

We assessed age at menopause, age at menarche, type of menopause, parity, age at first birth, postmenopausal hormone (PMH) use and past oral contraceptive use in 107,171 postmenopausal women. Cox models were used to estimate the hazard ratios (HR) for each exposure, adjusted for smoking and other covariates.

Results

We identified 1,729 LC cases during follow up from 1984 to 2006. Menopause onset before 44 years of age (HR=1.39, 95%CI 1.14-1.70) and past oral contraceptive use for greater than 5 years (HR=1.22, 95%CI 1.05-1.42) were associated with increased LC risk. These associations were strongest in current smokers and small cell histology. In never smokers, increased parity was associated with decreased risk among parous women (p-trend=0.03), whereas in current smokers, older age at first birth was associated with increased risk (p-trend=0.02). PMH use was not associated with overall LC incidence. However, nonsignificant results of increased risk in adenocarcinoma were seen with current PMH use.

Conclusions

Our findings suggest female hormones may influence lung carcinogenesis though the effect is likely modest, varied by histologic subtype and altered by smoking.

Impact

Further investigation of the pathophysiology of female hormones in LC subtypes and their interaction with smoking will lead to better understanding of lung carcinogenesis.

Context

No research has been conducted on bicycle riding and weight control in comparison to walking.

Objective

To assess the association between bicycle riding and weight control in premenopausal women.

Design, Setting, and Participants

This was a 16-year follow-up of 18, 414 women in the Nurses’ Health Study II.

Main Outcome Measures

Weight change between 1989 and 2005 was the primary outcome and odds of gaining >5% of baseline body weight (BBW) by 2005 the secondary outcome.

Results

At baseline, only 39% walked briskly while only 1.2% bicycled for ≥30 min/d. For a 30 min/d increase in activity between 1989 and 2005, weight gain was significantly less for brisk walking (−1.81 kg; 95% confidence interval (CI) = −2.05,−1.56), bicycling (−1.59 kg; 95%CI= −2.09, −1.08), and other activities (−1.45 kg; 95%CI= −1.66, −1.24) but not for slow walking (+0.06 kg; 95%CI= −0.22, 0.35). Women who reported no bicycling in 1989 and increased to as little as 5 minutes/day in 2005 gained less weight (−0.74 kg; 95%CI= −1.41, −0.07, P-trend<0.01) than those who remained non-bikers. Normal weight women who bicycled ≥ 4 hours/week in 2005 had lower odds of gaining >5% of their BBW (Odds Ratio (OR) =0.74, 95%CI=0.56–0.98) compared with those who reported no bicycling; overweight/obese women had lower odds at 2–3 hours/week (OR=0.54, 95%CI=0.34–86).

Conclusions

Bicycling, similar to brisk walking, is associated with less weight gain and an inverse dose-response relationship exists, especially among overweight/obese women. Future research should focus on brisk walking but also on greater time spent bicycling.

Background

Systemic lupus erythematosus (SLE) has been associated with an increased risk of cardiovascular disease. However, prospective population-based data addressing this association have been lacking.

Methods

We conducted a prospective cohort study among 119,332 women participating in the Nurses’ Health Study who were free of cardiovascular disease and SLE at baseline in 1976. Incident SLE was confirmed by medical record review. Cardiovascular events included fatal and nonfatal myocardial infarction, stroke, coronary artery bypass grafting and angioplasty. The relative risk of cardiovascular events among participants with SLE as compared to those without was estimated using Cox proportional hazards models.

Results

Over 28 years of follow-up (2.9 million person-years) 8,169 cardiovascular events occurred and 148 women developed incident SLE. Mean age at SLE diagnosis was 52.6 years, and 20 participants with SLE developed a subsequent cardiovascular event. After adjusting for potential confounding factors, including age, race, cardiovascular risk factors and medication use, the relative risk (RR) of a cardiovascular event in women with SLE compared with those without was 2.26 (95% CI 1.45–3.52). When endpoints were analyzed separately, the RR for coronary heart disease was 2.25; 95% CI 1.37–3.69, and the RR for stroke was 2.29; 95% CI 0.85–6.15.

Conclusion

In this prospective population-based study, we found a statistically significant over 2-fold increased risk of cardiovascular disease among participants with SLE. The risk was not as high as has been previously reported, which may be due to the relatively high age at diagnosis of SLE in this cohort.

The type and amount of physical activity needed for prevention of weight regain are not well understood. We prospectively examined the associations between patterns of discretionary physical activity and 6-year maintenance of intentional weight loss among 4,558 healthy premenopausal women who were 26–45 years old in 1991 and had lost >5% of their body weight in the previous two years. Participants reported their physical activity and weight in 1991 and 1997. The outcome was weight regain, defined as regaining in 1997 >30% of the lost weight between 1989 and 1991. Between 1991 and 1997, 80% of women regained >30% of their previous intentional weight loss. An increase of 30 minutes/day in total discretionary activity between 1991 and 1997 was associated with less weight regain (−1.36kg, 95% confidence interval (CI) = −1.61, −1.12), particularly among overweight women (body mass index ≥25) (−2.45kg, −3.12 to −1.78). Increased jogging or running was associated with less weight regain (−3.26kg; −4.41 to −2.10) than increased brisk walking (−1.69kg; −2.15 to −1.22) or other activities (−1.26kg; −1.65 to −0.87). Compared to women who remained sedentary, women were less likely to regain >30% of the lost weight if they maintained 30+ minutes/day of discretionary physical activity (OR=0.69, 0.53 to 0.89) or increased to this activity level (OR=0.48, 0.39 to 0.60). Conversely, risk was elevated in women who decreased their activity. Increased physical activity, particularly high intensity activities, is associated with better maintenance of weight loss. The benefits of activity were greater among overweight/obese than normal weight women.

Rotating night shift work disrupts circadian rhythms and is associated with coronary heart disease. The relation between rotating night shift work and ischemic stroke is unclear. The Nurses’ Health Study, an ongoing cohort study of registered female nurses, assessed in 1988 the total number of years the nurses had worked rotating night shifts. The majority (69%) of stroke outcomes from 1988 to 2004 were confirmed by physician chart review. The authors used Cox proportional hazards models to assess the relation between years of rotating night shift work and ischemic stroke, adjusting for multiple vascular risk factors. Of 80,108 subjects available for analysis, 60% reported at least 1 year of rotating night shift work. There were 1,660 ischemic strokes. Rotating night shift work was associated with a 4% increased risk of ischemic stroke for every 5 years (hazard ratio = 1.04, 95% confidence interval: 1.01, 1.07; Ptrend = 0.01). This increase in risk was similar when limited to the 1,152 confirmed ischemic strokes (hazard ratio = 1.03, 95% confidence interval: 0.99, 1.07; Ptrend = 0.10) and may be confined to women with a history of 15 or more years of rotating shift work. Women appear to have a modestly increased risk of stroke after extended periods of rotating night shift work.

Background

To date, no prospective studies have explored the relationship between the use of aspirin, other non-steroidal anti-inflammatory medications (NSAIDs), and acetaminophen and endometrial adenocarcinoma.

Methods

Of the 82,971 women enrolled in a prospective cohort study, 747 developed medical record–confirmed invasive endometrial cancer over a 24-year period. Use of aspirin was queried from 1980 to 2004, and for other NSAIDs and acetaminophen 1990 to 2004. Cox regression models calculated multivariate relative risks (MV RR), controlling for body mass index (BMI), postmenopausal hormone (PMH) use, and other endometrial cancer risk factors.

Results

Currency, duration, and quantity of aspirin were not associated with endometrial cancer risk overall (current use MV RR 1.03, 95% confidence interval [CI] 0.83–1.27; >10 years of use, MV RR 1.01, 95% CI 0.78–1.30; and cumulative average > 7 tablets per week MV RR 1.10, 95%CI 0.84–1.44). However, stratified analyses showed that a lower risk of endometrial cancer among obese (BMI ≥ 30 kg/m2) women was seen with current aspirin use (MV RR 0.66, 95% CI 0.46–0.95) The greatest risk reduction for current aspirin users was seen in postmenopausal obese women who had never used PMH (MV RR 0.43, 95% CI 0.26–0.73). The use of other NSAIDs or acetaminophen was not associated with endometrial cancer.

Conclusion

Our data suggest use of aspirin or other NSAIDs does not play an important role in endometrial cancer risk overall. However, risk was significantly lower for current aspirin users who were obese or who were postmenopausal and had never used postmenopausal hormones; these subgroup findings require further confirmation.

Summary

Night shift work suppresses melatonin production and has been associated with an increased risk of major diseases including hormonally related tumors. Experimental evidence suggests that light at night acts through endocrine disruption, likely mediated by melatonin. To date, no observational study has addressed the effect of night work on osteoporotic fractures, another condition highly sensitive to sex steroid exposure. Our study, to our knowledge the first to address this question, supports the hypothesis that night shift work may negatively affect bone health, adding to the growing list of ailments that have been associated with shift work.

Introduction

We evaluated the association between night shift work and fractures at the hip and wrist in postmenopausal nurses.

Methods

The study population was drawn from Nurses’ Health Study participants who were working full or part time in nursing in 1988 and had reported their total number of years of rotating night shift work. Through 2000, 1,223 incident wrist and hip fractures involving low or moderate trauma were identified among 38,062 postmenopausal women. We calculated multivariate relative risks (RR) of fracture over varying lengths of follow-up in relation to years of night shift work.

Results

Compared with women who never worked night shifts, 20+ years of night shift work was associated with a significantly increased risk of wrist and hip fractures over eight years of follow-up (RR = 1.37, 95% confidence interval [CI], 1.04–1.80). This risk was strongest among women with a lower BMI (<24) who never used hormone replacement therapy (RR = 2.36; 95% CI, 1.33–4.20). The elevated risk was no longer apparent with twelve years of follow-up after the baseline single assessment of night shift work.

Conclusions

Long durations of rotating night shift work may contribute to risk of hip and wrist fractures, although the potential for unexplained confounding cannot be ruled out.

BACKGROUND

Studies of the association between physical activity (PA) and weight maintenance have been inconsistent.

METHODS

We prospectively examined the association between PA patterns and prevention of weight gain among 46,754 healthy premenopausal women, aged 25–43 years in 1989. Participants reported their PA and weight in 1989 and 1997. The primary outcome was gaining >5% of baseline weight by 1997 (62% of the population).

RESULTS

Compared with women who maintained <30 minutes/day of total discretionary activity over 8 years, women were less likely to gain weight if they sustained 30+ minutes/day (Odds Ratio OR=0.68, 95% confidence interval [CI] 0.64–0.73) or increased to 30+ minutes/day in 1997 (OR=0.64, 95%CI=0.60–0.68). Among women whose only reported activity was walking, risk of gaining weight was lower in those who sustained 30+ minutes/day over 8 years (OR=0.66, 95%CI=0.49–0.91), and brisk walking pace independently predicted less weight gain. For a 30 minutes/day increase between 1989 and 1997, jogging/running was associated with less weight gain than brisk walking or other activities. Greater duration of PA was associated with progressively less weight gain, but even an 11–20 minutes/day increase was beneficial; the benefits appeared stronger among those initially overweight. Sedentary behavior independently predicted weight gain.

CONCLUSIONS

Sustained PA for at least 30 minutes/day, particularly if more intense, is associated with a reduction in long-term weight gain, and greater duration is associated with less weight gain. Sedentary women of any baseline weight who increase their PA will benefit, but overweight women appear to benefit the most.

Purpose

Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.

Methods

We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.

Results

Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.

Conclusion

Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.

Objectives

Vitamin D has immune-modulating effects and may protect against the development of Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA).

Methods

We identified incident cases of SLE and RA among 186,389 women followed from 1980-2002 in the Nurses' Health Study and Nurses' Health Study II cohorts. We excluded subjects with non-confirmed SLE or RA by medical record review, and those who failed to return questionnaires. Semi-quantitative food frequency questionnaires assessed vitamin D intake from food and supplements. We used cumulative-updated total energy-adjusted dietary exposures for each two year cycle.

Relationships between vitamin D intake and incident SLE and RA were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results were pooled using meta-analysis random effects models.

Results

We confirmed 190 incident cases of SLE and 722 of RA with dietary information. Increasing levels of vitamin D intake had no relationship to the relative risk of developing either SLE or RA.

Conclusions

Vitamin D intake was not associated with risk of SLE or RA in these large prospective cohorts of women.

Background

Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.

Methods and Findings

We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.

Conclusions

These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.

Michael Thun and colleagues pooled and analyzed comprehensive data on lung cancer incidence and death rates among never-smokers to examine what factors other than active smoking affect lung cancer risk.

Editors' Summary

Background.

Every year, more than 1.4 million people die from lung cancer, a leading cause of cancer deaths worldwide. In the US alone, more than 161,000 people will die from lung cancer this year. Like all cancers, lung cancer occurs when cells begin to divide uncontrollably because of changes in their genes. The main trigger for these changes in lung cancer is exposure to the chemicals in cigarette smoke—either directly through smoking cigarettes or indirectly through exposure to secondhand smoke. Eighty-five to 90% of lung cancer deaths are caused by exposure to cigarette smoke and, on average, current smokers are 15 times more likely to die from lung cancer than lifelong nonsmokers (never smokers). Furthermore, a person's cumulative lifetime risk of developing lung cancer is related to how much they smoke, to how many years they are a smoker, and—if they give up smoking—to the age at which they stop smoking.

Why Was This Study Done?

Because lung cancer is so common, even the small fraction of lung cancer that occurs in lifelong nonsmokers represents a large number of people. For example, about 20,000 of this year's US lung cancer deaths will be in never-smokers. However, very little is known about how age, sex, or race affects the incidence (the annual number of new cases of diseases in a population) or death rates from lung cancer among never-smokers. A better understanding of the patterns of lung cancer incidence and death rates among never-smokers could provide useful information about the factors other than cigarette smoke that increase the likelihood of not only never-smokers, but also former smokers and current smokers developing lung cancer. In this study, therefore, the researchers pooled and analyzed a large amount of information about lung cancer incidence and death rates among never smokers to examine what factors other than active smoking affect lung cancer risk.

What Did the Researchers Do and Find?

The researchers analyzed information on lung cancer incidence and/or death rates among nearly 2.5 million self-reported never smokers (men and women) from 13 large studies investigating the health of people in North America, Europe, and Asia. They also analyzed similar information for women taken from cancer registries in ten countries at times when very few women were smokers (for example, the US in the late 1930s). The researchers' detailed statistical analyses reveal, for example, that lung cancer death rates in African Americans and in Asians living in Korea and Japan (but not among Asians living in the US) are higher than those in people of the European continental ancestry group. They also show that men have higher death rates from lung cancer than women irrespective of racial group, but that women aged 40–59 years have a slightly higher incidence of lung cancer than men of a similar age. This difference disappears at older ages. Finally, an analysis of lung cancer incidence and death rates at different times during the past 70 years shows no evidence of an increase in the lung cancer burden among never smokers over time.

What Do These Findings Mean?

Although some of the findings described above have been hinted at in previous, smaller studies, these and other findings provide a much more accurate picture of lung cancer incidence and death rates among never smokers. Most importantly the underlying data used in these analyses are now freely available and should provide an excellent resource for future studies of lung cancer in never smokers.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050185.

The US National Cancer Institute provides detailed information for patients and health professionals about all aspects of lung cancer and information on smoking and cancer (in English and Spanish)

Links to other US-based resources dealing with lung cancer are provided by MedlinePlus (in English and Spanish)

Cancer Research UK provides key facts about the link between lung cancer and smoking and information about all other aspects of lung cancer

Many cancers have long latency periods, and dietary factors in adolescence may plausibly affect cancer occurrence in adulthood. Because of a lack of prospective data, retrospective collection of data on adolescent diet is essential. The authors evaluated a 124-item high school food frequency questionnaire (HS-FFQ) assessing diet during high school (15–35 years in the past) that was completed in 1998 by 45,947 US women in the Nurses' Health Study II (NHSII) cohort. To assess reproducibility, the authors readministered the HS-FFQ approximately 4 years later to 333 of these women. The mean Pearson correlation for 38 nutrient intakes was 0.65 (range, 0.50–0.77), and the mean Spearman rank correlation for food intakes was 0.60 (range, 0.37–0.77). Current adult diet was only weakly correlated with recalled adolescent diet (for nutrient intakes, mean r = 0.20). For assessment of validity, 272 mothers of the NHSII participants were asked to report information on their daughters' adolescent diets using the HS-FFQ. In this comparison, the mean Pearson correlation was 0.40 (range, 0.13–0.59) for nutrients, and the mean Spearman rank correlation for foods was 0.30 (range, 0.10–0.61). While further studies are warranted, these findings imply that this food frequency questionnaire provides a reasonable record of adolescent diet.

A recent prospective study showed that higher consumption of red meat and total protein was associated with increased risk for inflammatory polyarthritis. We therefore prospectively examined the relationship between diet (in particular, protein, iron, and corresponding food sources) and incident rheumatoid arthritis (RA) among 82,063 women in the Nurses' Health Study. From 1980 to 2002, 546 incident cases of RA were confirmed by a connective tissue disease screening questionnaire and medical record review for American College of Rheumatology criteria for RA. Diet was assessed at baseline in 1980 and five additional times during follow up. We conducted Cox proportional hazards analyses to calculate the rate ratio of RA associated with intakes of protein (total, animal, and vegetable) and iron (total, dietary, from supplements, and heme iron) and their primary food sources, adjusting for age, smoking, body mass index, and reproductive factors. The multivariate models revealed no association between RA and any measure of protein or iron intake. In comparisons of highest with lowest quintiles of intake, the rate ratio for total protein was 1.17 (95% confidence interval 0.89–1.54; P for trend = 0.11) and for total iron it was 1.04 (95% confidence interval 0.77–1.41; P for trend = 0.82). Red meat, poultry, and fish were also not associated with RA risk. We were unable to confirm that there is an association between protein or meat and risk for RA in this large female cohort. Iron was also not associated with RA in this cohort.

Objective To examine the association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture.

Design Prospective cohort study.

Setting Nurses’ Health Study, which originally recruited from the 11 most populous states in the US.

Participants 79 899 postmenopausal women enrolled in the Nurses’ Health Study who provided data on the use of PPIs and other risk factors biennially since 2000 and were followed up to 1 June 2008.

Main outcome measure Incident hip fracture

Results During 565 786 person years of follow-up, we documented 893 incident hip fractures. The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users. Compared with non-users, the risk of hip fracture among women who regularly used PPIs for at least two years was 35% higher (age adjusted hazard ratio 1.35 (95% confidence interval 1.13 to 1.62)), with longer use associated with increasing risk (Ptrend<0.01). Adjustment for risk factors, including body mass index, physical activity, and intake of calcium did not materially alter this association (hazard ratio 1.36 (1.13 to 1.63)). These associations were also not changed after accounting for reasons for PPI use. The relation between PPI use and fracture differed by smoking history (Pinteraction=0.03). Among current and former smokers, PPI use was associated with greater than 50% increase in risk of fracture, with a multivariate hazard ratio for fracture of 1.51 (1.20 to 1.91). In contrast, among women who never smoked there was no association (multivariate hazard ratio 1.06 (0.77 to 1.46)). In a meta-analysis of these results with 10 prior studies, the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.25 to 1.36).

Conclusion Chronic use of PPIs is associated with increased risk of hip fracture, particularly among women with a history of smoking.