Sunbeds and sunlamps: who used them and their risk for melanoma.

Sunbed/sunlamp use was recently classified as carcinogenic. This report considers characteristics of those who use sunbeds/sunlamps and the effect of sunbed/sunlamp use on their risk for melanoma within a large case-control study carried out in 1991-1992. Females were more likely than males to have used sunbeds/sunlamps. Use by females increased strongly and significantly with younger ages and with the perceived ability to tan. For females, the individual risk for melanoma increased with typical session time and frequency of sessions. Use before age 20, current use and years of use were not significant. The use patterns of occasional and frequent users were very different. We estimate that typical 5-min sessions would increase the risk for melanoma by 19% for frequent users (10+ sessions) and by 3% for occasional users (1-9 sessions). Body sites that are not generally exposed to sunlight were more common sites of primary melanomas for frequent sunbed/sunlamp users. For males, measures of sunbed/sunlamp use were not significantly associated with melanoma risk.

Assessment of lifetime cumulative sun exposure using a self-administered questionnaire: reliability of two approaches.

Few studies have evaluated the reliability of lifetime sun exposure estimated from inquiring about the number of hours people spent outdoors in a given period on a typical weekday or weekend day (the time-based approach). Some investigations have suggested that women have a particularly difficult task in estimating time outdoors in adulthood due to their family and occupational roles. We hypothesized that people might gain additional memory cues and estimate lifetime hours spent outdoors more reliably if asked about time spent outdoors according to specific activities (an activity-based approach). Using self-administered, mailed questionnaires, test-retest responses to time-based and to activity-based approaches were evaluated in 124 volunteer radiologic technologist participants from the United States: 64 females and 60 males 48 to 80 years of age. Intraclass correlation coefficients (ICC) were used to evaluate the test-retest reliability of average number of hours spent outdoors in the summer estimated for each approach. We tested the differences between the two ICCs, corresponding to each approach, using a t test with the variance of the difference estimated by the jackknife method. During childhood and adolescence, the two approaches gave similar ICCs for average numbers of hours spent outdoors in the summer. By contrast, compared with the time-based approach, the activity-based approach showed significantly higher ICCs during adult ages (0.69 versus 0.43, P = 0.003) and over the lifetime (0.69 versus 0.52, P = 0.05); the higher ICCs for the activity-based questionnaire were primarily derived from the results for females. Research is needed to further improve the activity-based questionnaire approach for long-term sun exposure assessment.

Reproducibility and correlations of multiplex cytokine levels in asymptomatic persons.

RATIONALE: Cytokines are humoral regulatory molecules that act together in immunologic pathways underlying pathogenesis. Grossly elevated blood levels characterize certain diseases; variations within physiologic ranges could also have significance. We therefore evaluated the performance characteristics of a multiplex cytokine immunoassay. METHODS: We used a fluorescent bead-based (Luminex) immunoassay kit to simultaneously measure interleukin (IL) 1beta, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12p70, IL13, IFNgamma, granulocyte colony-stimulating factor, and tumor necrosis factor-alpha. We tested identical aliquots of serum from 38 asymptomatic individuals on three different days and matched sets of serum, heparinized plasma, and acid citrate dextrose plasma from an additional 38 healthy donors expected to have low cytokine concentrations. We applied multiple imputation to calculate unbiased reproducibility estimates for measurements below the limits of detection. Correlations among the cytokines were assessed by Spearman rank order coefficients and principal components analyses. RESULTS: Of the 13 cytokines, 3 were undetectable (IL1beta, IL2, IL5) in more than half of the serum samples. Coefficients of variation for replicate serum measurements ranged from 18% to 44%, with intraclass correlation coefficients ranging from 55% to 98%. Only IL4, IL6, and IL8 had statistically significant correlations (Spearman rho, 0.42-0.94) between serum and acid citrate dextrose or heparin plasma levels. CONCLUSIONS: Interindividual differences outweigh substantial laboratory variation for these assays, yielding high intraclass correlation coefficients despite unimpressive coefficients of variation. Plasma measurements generally are not reflective of serum levels and hence are not interchangeable. With their small volume, low cost per test, and multiplex capacity, Luminex-based cytokine assays have potential utility for epidemiologic studies.

Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma.

Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4 196 197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.

Endogenous sex hormones and the risk of prostate cancer: a prospective study.

Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case-control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Delta4-A), testosterone (T), sex hormone-binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha-diolG). A total of 727 incident Caucasian prostate cancer cases (age >/= 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (p(trend) = 0.01), mostly related to risk in older men (>/=65 years, p(trend) = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50-5.09]. No clear patterns were noted for Delta4-A and 3alpha-diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear. (c) 2008 Wiley-Liss, Inc.

IGF-1 and IGFBP-3: Risk of prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

IGF-1 and IGFBP-3 may influence risk of prostate cancer through their roles in cellular growth, metabolism and apoptosis, however, epidemiologic results have been inconsistent. The role of obesity in prostate cancer risk is not clearly understood, but hyperinsulinemia-related increases in bioactive IGF-1 levels, associated with obesity, could be a component of the relationship between the IGF-axis and prostate cancer. We conducted a nested case-control study in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to examine associations between IGF-1 and IGFBP-3 and risk of prostate cancer. A total of 727 incident prostate cancer cases and 887 matched controls were selected for this analysis. There was no clear overall association between IGF-1, IGFBP-3 and IGF-1:IGFBP-3 molar ratio (IGFmr) and prostate cancer risk, however, IGFmr was associated with risk in obese men (BMI > 30, p-trend = 0.04), with a greater than 2-fold increased risk in the highest IGFmr quartile (OR 2.34, 95% CI 1.10-5.01). Risk was specifically increased for aggressive disease in obese men (OR 2.80, 95% CI 1.11-7.08). In summary, our large prospective study showed no overall association between the insulin-like growth factor axis and prostate cancer risk, however, IGFmr was related to risk for aggressive prostate cancer in obese men.

Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry.

There is an increasing trend to apply gas chromatography combined with mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) assay methods to large-scale epidemiologic studies for the measurement of serum sex steroids. These methods are generally considered the gold standard for sex steroid measurements because of their accuracy, sensitivity, turnaround time, and ability to assess a more complete panel of steroid metabolites in the same run. In this report, we evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility, of steroid hormone measurements determined by GC-MS and LC-MS/MS assays and RIA and compared measurements among these methods. Specifically, 282 overnight fasting serum samples from 20 male volunteers were analyzed for 12 steroid metabolites by GC-MS or LC-MS/MS in one lab over a 4-month period. Six of the analytes were also measured by RIA in another lab. Unconjugated hormones, including testosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione, androst-5-ene-3beta,17beta-diol, estrone, and estradiol, were measured by GC-MS, whereas conjugated hormones, including DHEA sulfate, androsterone glucuronide, 5alpha-androstane-3alpha,17beta-diol 3-glucuronide, 5alpha-androstane-3alpha,17beta-diol 17-glucuronide, and estrone sulfate, were measured by LC-MS/MS. A subset of these hormones, including testosterone, dihydrotestosterone, androstenedione, 5alpha-androstane-3alpha,17beta-diol 17-glucuronide, estrone, and estradiol, were also measured by RIA following extraction and chromatography. We used the coefficient of variation (CV) and the intraclass correlation coefficient (ICC) to assess within- and between-batch assay variations. For the 12 analytes measured by GC-MS or LC-MS/MS, CVs and ICCs for within- and between-batch measurements were similar, with CVs ranging from 6.1% to 21.4% and ICCs ranging from 87.6% to 99.2%. The six analytes measured by RIA had good CVs and ICCs, with CVs <10% and ICCs >70% (range, 71.7-99.7%). For the six metabolites that were measured by both methods, the CVs were similar, whereas the ICCs were generally higher with the GC-MS method. The absolute values for each analyte measured by RIA and GC-MS differed, with RIAs usually yielding markedly higher levels than GC-MS, although the Pearson and Spearman correlation coefficients for these six analytes were near one and all were significant (P < 0.001). Our results show that RIA, GC-MS, and LC-MS/MS assays for androgens and estrogens in the two labs included in the study have good reproducibility, as measured by small CVs (<15%) and high ICCs (>80%), with the exception of estradiol (71.7%) when measured by RIA. Despite substantial differences in absolute measurements of sex steroid hormones by RIA and MS methods, correlations between the two assays for the six sex steroids measured in the two labs were high (>0.9). However, it is important for future large epidemiologic studies to incorporate MS with high reproducibility and specificity to measure a more complete profile of androgen and estrogen metabolites to clarify the role of sex steroids in prostate cancer.

Agreement between contemporaneously recorded and subsequently recalled time spent outdoors: implications for environmental exposure studies.

PURPOSE: The aim of the study is to evaluate the agreement between contemporaneously recorded and subsequently recalled time spent outdoors during 1 week among members of an occupational cohort. METHODS: One hundred twenty-five radiologic technologists from northern and southern geographic areas in the United States recorded time spent outdoors for 7 consecutive days in a daily diary. Six months later, study participants completed a mailed self-administered questionnaire of the number of outdoor hours during the same 7-day period. We tested the agreement between questionnaire responses and diary entries. Logistic regression models were used to identify variables significantly affecting agreement. RESULTS: Time spent outdoors comprised one fifth of the total time recorded in the diaries. Agreement (weighted kappa [kappa(w)]) between reported outdoor time during weekdays (kappa(w) = 0.49; 95% confidence interval [CI], 0.39-0.59) was significantly (p < 0.05) higher than for weekends (kappa(w) = 0.23; 95% CI, 0.12-0.34). Similarly, agreement was lower for weekends compared with weekdays in multivariate analyses, reaching statistical significance (p = 0.05) in only the southern regions. CONCLUSIONS: Although our investigation was carried out among volunteers from the US radiologic technologist cohort, we believe retrospective questionnaires may be more accurate in reporting time spent outdoors for weekdays compared with weekends in any group of indoor workers. These differences have implications for the wording in future questionnaires about time spent outdoors and level and sources of uncertainty characterizing estimated time spent outdoors on weekdays versus weekend days.

Identifying individuals at high risk of melanoma: a practical predictor of absolute risk.

PURPOSE: We developed a model to estimate the 5-year absolute risk of melanoma to efficiently identify individuals at increased risk of melanoma for potential interventions. PATIENTS AND METHODS: We used data from a case-control study with 718 non-Hispanic white patients with invasive cutaneous melanoma from melanoma clinics in Philadelphia, PA and San Francisco, CA; matched controls were 945 patients from outpatient clinics with similar catchment areas. All participants underwent extensive interviews and skin examinations. We selected easily obtained clinical characteristics and responses to simple questions for study in order to develop sex-specific relative risk models. These models were combined with incidence and mortality rates by United States geographic areas to develop estimates of the absolute risk of developing melanoma within 5 years. RESULTS: Relative risk models yielded an attributable risk of 86% for men and 89% for women, using at most seven variables. Attributable risks did not vary by age, ultraviolet B flux or hours outdoors. The absolute individual risks varied widely, depending on age, other host characteristics, and geographic area. Individual absolute risk can be estimated using a program available online. CONCLUSION: Our procedures allow for estimating the absolute risk of developing melanoma to assist in the identification of patients at high risk. Such high-risk individuals could undergo interventions including a complete skin examination, counseling to avoid sun exposures, regular self and professional surveillance, or participation in prevention trials. It is important to emphasize that these projections are not intended to identify current melanoma cases.

A reproducibility study for a fluoride assay in bone.

Osteosarcoma is a rare malignancy of largely unknown etiology. Although there is no consistent evidence for an association between fluoridation and cancer, some concerns remain about osteosarcoma. As part of the design of a collaborative study, bone samples were collected to allow for an evaluation of the association between osteosarcoma risk and individual fluoride exposure measured by levels of fluoride in bone. In this report, we provide the results of pilot experiments to consider issues that arose during the study design and to assess the reliability of the bone assays. Correlations of fluoride levels between normal bone near the affected area and iliac crest bone were strong and positive. The day-to-day laboratory analysis of fluoride in human and deer jaw bone yielded acceptable average coefficients of variation below 10% and an overall estimate of 5%. The intraclass correlation (ICC) is of particular importance to epidemiologists because it indicates the effect of measurement error on study results. Here, the estimated ICC is 0.86, and the estimated downward bias is only 14%. Hence, the ICC is strong enough so that the estimates of the relative risk will suffer little attenuation from lab measurements.

Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States.

The age-adjusted incidence of multiple myeloma (MM) is 2-fold higher in African Americans than in whites. A few small studies have reported a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS) in African Americans versus whites. Etiologic factors for MGUS and determinants for transformation of MGUS to MM are unknown. We quantified the prevalence of MGUS and subsequent risk of MM among 4 million African American and white male veterans admitted to Veterans Affairs (VA) hospitals. The age-adjusted prevalence ratio of MGUS in African Americans compared with whites was 3.0 (2.7-3.3 95% confidence interval). Among 2046 MGUS cases, the estimated cumulative risk of MM during the first 10 years of follow-up was similar (P = .37) for African Americans (17%) and whites (15%). In the largest study to date, we suggest that the excess risk of MM in African Americans results from an increase in risk of MGUS rather than an increased risk of progression from MGUS to MM.

Standard errors for attributable risk for simple and complex sample designs.

Adjusted attributable risk (AR) is the proportion of diseased individuals in a population that is due to an exposure. We consider estimates of adjusted AR based on odds ratios from logistic regression to adjust for confounding. Influence function methods used in survey sampling are applied to obtain simple and easily programmable expressions for estimating the variance of AR. These variance estimators can be applied to data from case-control, cross-sectional, and cohort studies with or without frequency or individual matching and for sample designs with subject samples that range from simple random samples to (sample) weighted multistage stratified cluster samples like those used in national household surveys. The variance estimation of AR is illustrated with: (i) a weighted stratified multistage clustered cross-sectional study of childhood asthma from the Third National Health and Examination Survey (NHANES III), and (ii) a frequency-matched case-control study of melanoma skin cancer.

Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology and end results database.

PURPOSE: To evaluate risk factors for the development of and factors influencing survival in pediatric melanoma. PATIENTS AND METHODS: We evaluated 1,255 children (age < 20 years) and 2,673 young adults (age 20 to 24 years) with melanoma in the 2001 National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database. We estimated exposure to UV radiation based on Environmental Protection Agency (EPA) measurements. RESULTS: The incidence of pediatric melanoma increased 46% (95% CI, 40 to 52) per year of age and 2.9% (95% CI, 2.1 to 3.6) per year from 1973 to 2001. Incidence rates were lower in black patients (-95%; 95% CI, -98 to -90) compared with white patients and in male patients (-39%; 95% CI -46 to -31) compared with females. Increased ambient UV radiation was associated with elevated risk (19% per kJ; 95% CI, 9 to 30). Children with melanoma had a 5-year melanoma-specific survival of 93.6% (95% CI, 91.9 to 94.9), which improved from 1973 to 2001. The hazard ratio of death from melanoma increased with male sex; older age; advanced disease; location of the primary other than extremities or torso; earlier year of diagnosis; and previous cancer. CONCLUSION: The incidence of melanoma in the United States is increasing rapidly in children. Risk factors for pediatric melanoma include being white, being female, increasing age, and environmental UV radiation. Survival is decreased for children and adolescents with unfavorable prognostic factors (male sex, unfavorable site, and/or second primary or regional or distant metastasis). More effective therapeutic strategies are needed for these groups.

Urinary estrogen metabolites and their ratio among Asian American women.

Controversy persists regarding the role of a low ratio of 2-hydroxyestone (2-OHE(1))/16alpha-hydroxyestrone (16alpha-OHE(1)) as a potential estrogen metabolism marker of increased risk for breast cancer. Most of the evidence has been provided by case-control studies, where tumor effects on hormone metabolism are not known. Studies in populations at various risk of breast cancer are not consistent, with some suggesting that levels of the ratio may be altered by changes in diet and exercise. We studied Asian American women participating as controls in a case-control study of breast cancer in which migration history--a composite of the subject's place of birth, type of residence in Asia (urban or rural), length of time living in the West, and grandparents' place of birth--was associated with a 6-fold risk gradient that paralleled the historical differences in incidence rates between the United States and Asian countries. This population offered the possibility to address whether the ratio of 2-OHE(1):16alpha-OHE(1) differs according to recognized breast cancer risk factors, including migration history. Overnight 12-hour urines were obtained from 368 premenopausal and 143 naturally postmenopausal women of Chinese, Japanese, or Filipino descent who donated urines between 1985 and 1988. The estrogen metabolites 2-OHE(1) and 16alpha-OHE(1) were measured with an ELISA kit and adjusted for creatinine levels. In each ethnic group, the ratio of 2-OHE(1):16alpha-OHE(1) was consistently lower in women born in the West than in those who had migrated from Asia. For premenopausal women, the ratio declined 20% due to lower levels of 2-OHE(1). Among postmenopausal women, the ratio was 23% lower in those born in the West, but no consistent patterns based on place of birth were observed for either 2-OHE(1) or 16alpha-OHE(1). The ratio did not vary with most recognized breast cancer risk factors, except for lower metabolite ratios in women with a younger age at first birth and more children, which runs contrary to the hypothesis, because both characteristics reduce breast cancer risk. Our study suggests that the ratio of 2-OHE(1):16alpha-OHE(1) may be a marker for lifestyle influences on estrogen metabolism associated with westernization.

Serum carotenoids and alpha-tocopherol and risk of nonmelanoma skin cancer.

BACKGROUND: Carotenoids and tocopherols have been hypothesized to protect against cancer. METHODS: We prospectively evaluated associations of several carotenoids and alpha-tocopherol with risk of nonmelanoma skin cancer using serum collected at baseline from 302 subjects in the Isotretinoin-Basal Cell Carcinoma Prevention Trial. All subjects had at least two BCCs in the 5 years prior to randomization. During 5 years of follow-up, 70 subjects did not develop a nonmelanoma skin cancer, 221 developed a BCC, and 85 developed a squamous cell carcinoma (SCC). Cox proportional hazards models were used to estimate risk ratios. Models were stratified by clinical center and gender and adjusted for age, solar damage, skin type, number of prior BCCs and/or SCCs, treatment group, body mass index, and serum low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol. RESULTS: Risk of developing a subsequent BCC was not related to serum levels of any of the carotenoids measured or to alpha-tocopherol. Serum levels of alpha-carotene, beta-carotene, lycopene, and alpha-tocopherol also were not independently related to risk of a subsequent SCC. However, serum lutein, zeaxanthin, and beta-cryptoxanthin were positively related to SCC risk; risk ratios for subjects in the highest versus lowest tertiles of these micronutrients were 1.63 [95% confidence interval (95% CI) 0.88-3.01; P for trend = 0.01], 2.40 (95% CI 1.30-4.42; P for trend = 0.01), and 2.15 (95% CI 1.21-3.83; P for trend = 0.09), respectively. CONCLUSION: Additional research is needed on the relationship of carotenoids to SCC risk in the general population and in subsets of the population who are at increased risk.

Fertility in women treated with cranial radiotherapy for childhood acute lymphoblastic leukemia.

BACKGROUND: Fertility impairments among women treated during childhood for cancer are known to occur after some, but not all, types of anticancer therapy. Although leukemia is the most common cancer of childhood, until now fertility in survivors has not been comprehensively assessed. PROCEDURE: We investigated functional impairment of fertility in women who were long-term survivors of acute lymphoblastic leukemia (ALL) with a retrospective cohort study. Proven fertility (defined as ever pregnant) was evaluated by self-report among 182 females treated on protocols of the Children's Cancer Group (age at interview, 22.6 years on average) and 170 controls drawn from among the survivors' female siblings (23.4 years). The interview included psychosocial inventories designed to detect mood problems. RESULTS: Significant fertility deficits were noted in female survivors treated with cranial radiotherapy (CRT) at any dose around the time of menarche (relative fertility (RF)) = 0.27, 95% CI = 0.09, 0.82, P = 0.03). Controlling for marital status, mood at interview, and many fertility-related situations did not change the association. CONCLUSION: This study provides evidence for fertility deficits after treatment for ALL with CRT, and, in addition, for the first time, suggests that girls treated around the time of menarche are especially at risk. Clinical confirmation of these results is needed. If gonadal damage occurs in women receiving these treatments, their risk for further sequelae, such as osteoporosis and heart disease, may be significantly raised, requiring active management and intervention.

Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood.

Fertility impairments among men treated during childhood for cancer are known to occur after some, but not all, types of anti-cancer therapy. This is the first study to evaluate proven fertility among adult male survivors of childhood acute lymphoblastic leukemia (ALL). In a retrospective cohort study, proven fertility (ever fathered a pregnancy) was evaluated by self-report among 213 men treated for ALL before age 18 on protocols of the Children's Cancer Group (CCG). Controls (N = 145) were drawn from among male siblings. Overall, with a proportional hazards analysis, proven fertility of male survivors was not different from that of controls (relative fertility (RF) = 0.95, 95% CI 0.63-1.43). However, married men treated before age 10 with high dose (24 cGy) cranial radiotherapy (RT), without spinal RT, had only 9% of the fertility of controls (Relative risk, RR = 0.09, 95% CI 0.01-0.82). High dose cranial RT at older ages was not associated with a statistically significant fertility deficit (RR = 0.56, 95% CI 0.25-1.28). In this first study of proven fertility among men treated for childhood leukemia, the majority of survivors showed no evidence of fertility impairment compared to controls. However, men treated at a young age with high dose cranial RT may have impaired fertility. These results suggest that further investigation of men with these treatments is needed to confirm and extend these findings.