Laura E. Beane Freeman

Body-mass index and mortality among 1.46 million white adults.

BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

Recent trends in incidence of cutaneous melanoma among US Caucasian young adults.

TO THE EDITOR: Recent findings suggest that non-melanoma skin cancer (NMSC) incidence in young adults is rising, particularly among U.S. young women (Christenson et al., 2005). This raises the important question of whether incidence of cutaneous melanoma, the most lethal form of skin cancer, is similarly increasing in young adults. While melanoma incidence among U.S. older adults has been increasing for several decades, there have been indications that incidence may be stabilizing for birth cohorts born after 1945 (Dennis et al., 1993;Hall et al., 1999). However, in an analysis of melanoma trends between 1973 and 1997 in the Surveillance, Epidemiology, and End Results (SEER) Program, Jemal et al. noted evidence of an increase among women born after 1960 (Jemal et al., 2001). Since that analysis, an additional seven years of SEER data have been collected. To better understand recent trends in melanoma incidence among young adults, we report findings from a re-analysis of SEER data, extended through 2004. Our analysis was restricted to Caucasians from the nine registries that have contributed data to the SEER Program since 1973 (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle, Utah). We calculated annual age-adjusted incidence (SEER Progam, 2007a) and mortality rates (SEER Program, 2007b) of invasive cutaneous melanoma among men and women aged 15–39, standardized to the 2000 U.S. population, using the software SEER*Stat version 6.3.6 (National Cancer Institute: http://seer.cancer.gov/seerstat/). We assessed trends in greater detail using joinpoint regression models, which identify changes in trends over successive segments of time and describe the estimated annual percent change (EAPC) in incidence within each segment (Kim et al., 2000), using the software Joinpoint version 3.0 (National Cancer Institute: http://srab.cancer.gov/joinpoint/). Joinpoint analyses stratifying by melanoma stage (localized vs. regional/distant) and thickness (≤1mm vs. >1mm) were also performed. To describe age-specific trends by year of birth, we calculated incidence by five-year age groups and time periods, and plotted age-specific incidence by calendar year of birth (calculated from the age group midpoint). Additionally, age-period-cohort modeling was used to simultaneously adjust age-specific incidence trends for both calendar period and birth cohort effects (Tarone and Chu, 2000). All p-values are two-sided. Overall, the age-adjusted annual incidence of melanoma among young men increased from 4.7 cases per 100,000 persons (95% confidence limits 3.8, 5.7) in 1973 to 7.7 per 100,000 in 2004 (6.8, 8.7). Among women, age-adjusted annual incidence per 100,000 increased from 5.5 (4.5, 6.6) in 1973 to 13.9 (12.7, 15.2) in 2004. Melanoma incidence increased among young men (EAPC=6.6; 95% CL 2.9, 10.4) and women (9.2; 6.8, 11.7) during the 1970s (Figure 1, Table 1). Starting around 1980, this pattern changed. For men, incidence leveled off between 1980 and 2004 (0.4; −0.2, 0.9). For women, the rate of increase in incidence declined from 1978 to 1987 (2.6; 1.5, 3.8) and stabilized from 1987 to 1992 (−0.6; −3.7, 2.6). After 1992, however, incidence began climbing again (2.7; 2.1, 3.4). Incidence among women from the 1990s onward increased both for thinner and thicker melanomas (≤1mm: 3.1; 2.5, 3.6. >1mm: 2.8; 1.6, 4.0), and was greater for regional and distant tumors (9.2; 3.8, 14.9) compared to localized lesions (1.9; 1.6, 2.3). Melanoma mortality rates for men and women declined from 1981 onward (men: −3.6; −4.5, −2.7. women: −2.3; −3.1, −1.5). Figure 1 Age-adjusted (to 2000 U.S. population) annual cutaneous melanoma incidence and mortality rates among Caucasian males and females aged 15–39 in the Surveillance, Epidemiology, and End Results Program areas from 1973 through 2004. The segments of ... Table 1 Estimated annual percent changes (EAPC) in incidence of melanoma and melanoma mortality among Caucasian males and females aged 15–39 in the SEER Program from 1973 through 2004. Age-specific incidence patterns by year of birth are presented in Figure 2. Male age-specific incidence rose steadily with each successive birth cohort until 1950, at which time incidence appeared to level off or decrease slightly. Female age-specific incidence by birth cohort increased steadily until around 1950; thereafter, incidence appeared to climb at a slower pace until 1965, at which point incidence appeared to begin accelerating. After adjustment for age and period effects, age-period-cohort modeling confirmed a change in the effect of birth cohort for women born between 1960 and 1965 (Supplementary Figure; slope change parameter = 0.2146; 95% CL 0.0576, 0.3716; p=0.007). Figure 2 Age-specific melanoma incidence among Caucasians stratified by sex and birth-cohort year in the SEER program from 1975–1979 through 2000–2004. The points vertically above each cohort year portray the cohort’s age-specific incidence ... It is important to consider whether these trends may reflect changes in data quality, diagnosis or surveillance. There is evidence of increased underreporting of melanoma over time within the SEER program, with estimates as high as 17% of all cases (including in situ lesions) in two registries, although such a trend in underreporting cannot explain the observed increase in incidence among women (Seiffert, 1992;Merlino et al., 1997). It is unlikely that a change in melanoma diagnostic criteria would account for our finding, since the effect of such a change would not be expected to be sex-specific. Changes in screening patterns may have led to earlier detection within this time period, with a higher rate of increase seen among superficial localized tumors compared to thicker lesions and regional or metastatic disease overall (Jemal et al., 2001;Welch et al., 2005). Indeed, the observed decrease in melanoma mortality rates after 1981 and previously reported evidence of general improvement in survival by stage over this time period are consistent with a shift towards earlier detection of disease through increased surveillance (Jemal et al., 2001). However, in our analysis, the increasing trend among young women from the early 1990s onward was also observed for thicker and regional/distant tumors, which are less susceptible to misclassification. Moreover, our age-period-cohort analysis suggested that, after adjusting for age and period effects (the latter of which is reflective of changes in disease surveillance), the observed increase in incidence among women born after 1965 is consistent with a birth cohort effect (indicative of changes in disease risk factor prevalence across birth cohorts; (Tarone and Chu, 2000)). Thus, our findings are compatible with a real increase in incidence among young women, although we cannot rule out the effects of changes in surveillance. The recent increase in incidence among young women parallels reported trends in exposure to ultraviolet radiation (UVR), the primary environmental cause of melanoma (Armstrong and Kricker, 2001). The prevalence of sunburn is increasing among U.S. adult men and women overall, although trends by age group have not been reported (Robinson et al., 1997;Saraiya et al., 2007). Among adolescents aged 16–18, both the prevalence of sunburn and the average number of days spent at the beach increased between sun surveys conducted in 1998 and 2004 (Cokkinides et al., 2006). Tanning bed usage, which has been recently evaluated as a probable cause of melanoma (International Agency for Research on Cancer, 2007), is increasing among U.S. adults and is most prevalent among young women (Robinson et al., 1997;Lazovich and Forster, 2005). In conclusion, our analysis of SEER data suggests that melanoma incidence is increasing among young women. Additional studies are needed in order to clarify whether the increasing trends for melanoma and NMSC (Christenson et al., 2005) are the result of changes in UVR exposure in this population.

Obesity and Thyroid Cancer Risk among U.S. Men and Women: A Pooled Analysis of Five Prospective Studies

Background: Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain. Methods: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex. Results: Over follow-up (mean = 10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08–1.24); HR in men, 1.21 (95% CI, 0.97–1.49)]. There was no significant heterogeneity between studies (both P > 0.05). For women and men combined, the HRs for overweight (25.0–29.9 kg/m2) and obesity (≥30 kg/m2) compared with normal-weight (18.5–24.9 kg/m2) were 1.20 (95% CI, 1.04–1.38) and 1.53 (95% CI, 1.31–1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18–20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03–1.35)]. Conclusion: BMI was positively associated with thyroid cancer risk in both men and women. Impact: Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer. Cancer Epidemiol Biomarkers Prev; 20(3); 464–72. ©2011 AACR.

Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries: The National Cancer Institute Cohort

BACKGROUND Formaldehyde exposure is associated with leukemia in some epidemiological studies. In the National Cancer Institutes formaldehyde cohort, previously followed through December 31, 1979, and updated through December 31, 1994, formaldehyde exposure was associated with an increased risk for leukemia, particularly myeloid leukemia, that increased with peak and average intensity of exposure. METHODS We extended follow-up through December 31, 2004 (median follow-up = 42 years), for 25 619 workers employed at one of 10 formaldehyde-using or formaldehyde-producing plants before 1966. We used Poisson regression to calculate relative risk (RR) estimates and 95% confidence intervals (CIs) to examine associations between quantitative formaldehyde exposure estimates (peak exposure, average intensity and cumulative exposure) and death from lymphohematopoietic malignancies. All statistical tests were two-sided and considered to be significant at P = .05. RESULTS When follow-up ended in 2004, there were statistically significant increased risks for the highest vs lowest peak formaldehyde exposure category (> or =4 parts per million [ppm] vs >0 to <2.0 ppm) and all lymphohematopoietic malignancies (RR = 1.37; 95% CI = 1.03 to 1.81, P trend = .02) and Hodgkin lymphoma (RR = 3.96; 95% CI = 1.31 to 12.02, P trend = .01). Statistically nonsignificant associations were observed for multiple myeloma (RR = 2.04; 95% CI = 1.01 to 4.12, P trend > .50), all leukemia (RR = 1.42; 95% CI = 0.92 to 2.18, P trend = .12), and myeloid leukemia (RR = 1.78; 95% CI = 0.87 to 3.64, P trend = .13). There was little evidence of association for any lymphohematopoietic malignancy with average intensity or cumulative exposure at the end of follow-up in 2004. However, disease associations varied over time. For peak exposure, the highest formaldehyde-related risks for myeloid leukemia occurred before 1980, but trend tests attained statistical significance in 1990 only. After the mid-1990s, the formaldehyde-related risk of myeloid leukemia declined. CONCLUSIONS Evaluation of risks over time suggests a possible link between formaldehyde exposure and lymphohematopoietic malignancies, particularly myeloid leukemia but also perhaps Hodgkin lymphoma and multiple myeloma. Observed patterns could be due to chance but are also consistent with a causal association within the relatively short induction-incubation periods characteristic of leukemogenesis. Further epidemiological study and exploration of potential molecular mechanisms are warranted.

Mortality From Lymphohematopoietic Malignancies and Brain Cancer Among Embalmers Exposed to Formaldehyde

BACKGROUND Excess mortality from lymphohematopoietic malignancies, in particular myeloid leukemia, and brain cancer has been found in surveys of anatomists, pathologists, and funeral industry workers, all of whom may have worked with formaldehyde. We investigated the relation of mortality to work practices and formaldehyde exposure levels among these professionals to address cancer risk in the funeral industry. METHODS Professionals employed in the funeral industry who died between January 1, 1960, and January 1, 1986, from lymphohematopoietic malignancies (n = 168) or brain tumors (n = 48) (ie, case subjects) were compared with deceased matched control subjects (n = 265) with regard to lifetime work practices and exposures in the funeral industry, which were obtained by interviews with next of kin and coworkers, and to estimated levels of formaldehyde exposure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by use of logistic regression. All statistical tests were two-sided. RESULTS Mortality from myeloid leukemia increased statistically significantly with increasing number of years of embalming (P for trend = .020) and with increasing peak formaldehyde exposure (P for trend = .036). Compared with subjects who performed fewer than 500 lifetime embalmings, mortality from myeloid leukemia was elevated among those who performed embalmings for more than 34 years (OR = 3.9, 95% CI = 1.2 to 12.5, P = .024), who performed more than 3068 embalmings (OR = 3.0, 95% CI = 1.0 to 9.2, P = .057), and those whose estimated cumulative formaldehyde exposure exceeded 9253 parts per million-hours (OR = 3.1; 95% CI = 1.0 to 9.6, P = .047). These exposures were not related to other lymphohematopoietic malignancies or to brain cancer. CONCLUSION Duration of embalming practice and related formaldehyde exposures in the funeral industry were associated with statistically significantly increased risk for mortality from myeloid leukemia.

Occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosome changes in cultured myeloid progenitor cells.

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing, and other industries. Epidemiologic studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on the ability of formaldehyde to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures. Cancer Epidemiol Biomarkers Prev; 19(1); 80–8.

An Update of Cancer Incidence in the Agricultural Health Study

Objective: Our objective is to reevaluate cancer incidence among Agricultural Health Study participants. Methods: Standardized incidence ratios (SIRs) and relative standardized ratios were calculated. Results: A significant excess of prostate cancer was seen for private and commercial applicators (SIR = 1.19, 95% CI 1.14, 1.25 and SIR = 1.28, 95% CI = 1.00, 1.61, respectively). Excesses were observed for lip cancer (SIR = 1.97, 95% CI = 1.02, 3.44) and multiple myeloma (SIR = 1.42, 95% CI = 1.00, 1.95) among private applicators from North Carolina and for marginal zone lymphoma among Iowa spouses (SIR = 2.34, 95% CI = 1.21, 4.09). Conclusions: Although lower rates of smoking and increased physical activity probably contribute to the lower overall cancer incidence, agricultural exposures including pesticides, viruses, bacteria, sunlight, and other chemicals may increase risks for specific cancer sites.

Epidemiologic studies in agricultural populations: observations and future directions

ABSTRACT This paper reviews epidemiologic studies of cancer among agricultural populations to identify possible associations and to provide a focus for future investigations. Meta-analyses of mortality surveys of farmers find excesses of several cancers, including connective tissue, non-Hodgkins lymphoma, Hodgkins disease, multiple myeloma and cancers of the skin, stomach, and brain, and deficits for total mortality, heart disease, total cancer, and cancers of the esophagus, colon, lung, and bladder. Meta-analyses of studies of individual cancers also support these findings, indicating a need to identify exposures and lifestyle factors that might account for this mortality pattern. Although cancer studies of other occupations that might have pesticide exposures in common with farmers show some similarities with observations among farmers, the overall patterns are quite different. This suggests that pesticides are not likely to fully explain the cancer and other disease patterns observed among farmers. Because exposures vary by type of farm operation, exposures for individual farmers can differ considerably. Studies in the future need to focus on the full range of exposures to fully understand the cancer pattern in farmers.

Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study

Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% CI, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% CI, 1.9- to 16.6-fold), 3.9-fold (95% CI, 1.5- to 10.0-fold), and 2.4-fold (95% CI, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis.

Body Mass Index and Risk of Second Obesity-Associated Cancers After Colorectal Cancer: A Pooled Analysis of Prospective Cohort Studies

PURPOSE To determine whether prediagnostic body mass index (BMI) is associated with risk of second obesity-associated cancers in colorectal cancer (CRC) survivors, and whether CRC survivors have increased susceptibility to obesity-associated cancer compared with cancer-free individuals. PATIENTS AND METHODS Incident first primary CRC cases (N = 11,598) were identified from five prospective cohort studies. We used Cox proportional hazards regression models to examine associations between baseline (prediagnostic) BMI and risk of second obesity-associated cancers (postmenopausal breast, kidney, pancreas, esophageal adenocarcinoma, endometrium) in CRC survivors, and compared associations to those for first obesity-associated cancers in the full cohort. RESULTS Compared with survivors with normal prediagnostic BMI (18.5-24.9 kg/m(2)), those who were overweight (25-29.9 kg/m(2)) or obese (30+ kg/m(2)) had greater risk of a second obesity-associated cancer (n = 224; overweight hazard ratio [HR], 1.39; 95% CI, 1.01 to 1.92; obese HR, 1.47; 95% CI, 1.02 to 2.12; per 5-unit change in BMI HR, 1.12; 95% CI, 0.98 to 1.29). The magnitude of risk for developing a first primary obesity-associated cancer was similar (overweight HR, 1.18; 95% CI, 1.14 to 1.21; obese HR, 1.61; 95% CI, 1.56 to 1.66; per 5-unit change in BMI HR, 1.23; 95% CI, 1.21 to 1.24). Before diagnosis CRC patients were somewhat more likely than the overall cohort to be overweight (44% v 41%) or obese (25% v 21%). CONCLUSION CRC survivors who were overweight or obese before diagnosis had increased risk of second obesity-associated cancers compared with survivors with normal weight. The risks were similar in magnitude to those observed for first cancers in this population, suggesting increased prevalence of overweight or obesity, rather than increased susceptibility, may contribute to elevated second cancer risks in colorectal cancer survivors compared with the general population. These results support emphasis of existing weight guidelines for this high-risk group.