Faculty Bibliography

OBJECTIVE: To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke. DESIGN: Prospective cohort study with more than 50 years of follow-up. SETTING: Atomic bomb survivors in Hiroshima and Nagasaki, Japan. PARTICIPANTS: 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy). MAIN OUTCOME MEASURES: Mortality from stroke or heart disease as the underlying cause of death and dose-response relations with atomic bomb radiation. RESULTS: About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen. CONCLUSION: Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.

BACKGROUND: Radiotherapy during childhood increases long-term cancer risk, but the risk from radiation as a result of relatively higher dose diagnostic procedures remains less well known. This study, which evaluates breast cancer incidence in a cohort treated with "lower dose" chest radiotherapy over 50 years ago, can assist with estimating lifetime breast cancer risk in young children exposed to radiation from procedures such as chest computed tomography (CT) or treatment with recent "lower dose" chest radiotherapy protocols. METHODS: A population-based, longitudinal cohort of subjects exposed to thymic irradiation during infancy from 1926 to 1957 and of their unexposed siblings was re-established. Previously followed until 1987, we resurveyed cohort members from 2004 to 2008. Poisson regression models compared breast cancer incidence rates between women in the cohort by treatment and dose category groups. RESULTS: Breast cancer occurred in 96 treated (mean breast dose, 0.71 Gy) and 57 untreated women during 159,459 person-years of follow-up. After adjusting for attained age and treatment/birth cohort, the rate ratio was 3.01 (2.18-4.21). The adjusted excess relative risk per Gy was 1.10 (95% confidence interval, 0.61-1.86). Traditional breast cancer risk factors did not contribute significantly to multivariate model fit. CONCLUSION: Our results show that at radiation doses between those received by the breast from chest CT and cancer therapy during early childhood, breast cancer incidence rates remain elevated >50 years after exposure. This implies that increased breast cancer risk will remain a lifelong concern in females treated during childhood with currently reduced radiotherapy doses and for infants receiving multiple chest CTs.

Although the Japanese atomic bomb study and radiotherapy studies have clearly documented cancer risks from high-dose radiation exposures, radiation risk assessment groups have long recognized that protracted or low exposures to low-linear energy transfer radiations are key radiation protection concerns because these are far more common than high-exposure scenarios. Epidemiologic studies of human populations with low-dose or low dose-rate exposures are one approach to addressing those concerns. A number of large studies of radiation workers (Chernobyl clean-up workers, U.S. and Chinese radiological technologists, and the 15-country worker study) or of persons exposed to environmental radiation at moderate to low levels (residents near Techa River, Semipalatinsk, Chernobyl, or nuclear facilities) have been conducted. A variety of studies of medical radiation exposures (multiple-fluoroscopy, diagnostic (131)I, scatter radiation doses from radiotherapy, etc.) also are of interest. Key results from these studies are summarized and compared with risk estimates from the Japanese atomic bomb study. Ideally, one would like the low-dose and low dose-rate studies to guide radiation risk estimation regarding the shape of the dose-response curve, DDREF (dose and dose-rate effectiveness factor), and risk at low doses. However, the degree to which low-dose studies can do so is subject to various limitations, especially those pertaining to dosimetric uncertainties and limited statistical power. The identification of individuals who are particularly susceptible to radiation cancer induction also is of high interest in terms of occupational and medical radiation protection. Several examples of studies of radiation-related cancer susceptibility are discussed, but none thus far have clearly identified radiation-susceptible genotypes.

BACKGROUND: It has been proposed that a shift toward 2-hydroxyestrone from 16alpha-hydroxyestrone metabolic pathway may be inversely associated with breast cancer risk because 2-hydroxyestrone is thought to be less genotoxic and estrogenic than 16alpha-hydroxyestrone. METHODS: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone, 16alpha-hydroxyestrone, and the 2-hydroxyestrone:16alpha-hydroxyestrone ratio in a case-control study on premenopausal women nested within a prospective cohort the New York University Women's Health Study. The serum levels of 2-hydroxyestrone and 16alpha-hydroxyestrone were measured in 377 incident premenopausal breast cancer cases and 377 premenopausal controls, who were matched on age at enrollment, number and dates of blood donations, and day and phase of menstrual cycle. RESULTS: Overall, no significant associations were observed between breast cancer risk and serum levels of 2-hydroxyestrone, 16alpha-hydroxyestrone, or their ratio. The 2-hydroxyestrone:16alpha-hydroxyestrone ratio was positively associated with risk for estrogen receptor-positive breast cancer in the analyses controlling for matching factors. However, the association was attenuated and not significant after adjustment for potential confounders (odds ratio for the highest versus the lowest quartile, 2.15; 95% CI, 0.88-5.27; P(trend) = 0.09). CONCLUSIONS: The results of the current study do not support the hypothesis that a metabolic shift from 16alpha-hydroxyestrone toward 2-hydroxyestrone in premenopausal women is associated with reduced risk for breast cancer. The association between the 2-hydroxy:16alpha-hydroxyestrone ratio and estrogen receptor-positive breast cancer needs to be explored in future studies

SUMMARY: Methods for the analysis of individually matched case-control studies with location-specific radiation dose and tumor location information are described. These include likelihood methods for analyses that just use cases with precise location of tumor information and methods that also include cases with imprecise tumor location information. The theory establishes that each of these likelihood based methods estimates the same radiation rate ratio parameters, within the context of the appropriate model for location and subject level covariate effects. The underlying assumptions are characterized and the potential strengths and limitations of each method are described. The methods are illustrated and compared using the WECARE study of radiation and asynchronous contralateral breast cancer.

There is a growing interest in the role that cancer biomarkers, metastasis-related molecules, and chemokines may play in the development and progression of various cancers. However, few studies have addressed the reliability of such biomarkers in healthy individuals over time. The objective of this study was to investigate the temporal reliability of multiple proteins in serum samples from healthy women who donated blood over successive years. Thirty five, postmenopausal women with two, repeated annual visits, and thirty, premenopausal women with three, repeated annual visits were randomly selected among eligible subjects from an existing, prospective cohort. Multiplexing Luminex xMAPTM technology was used to measure the levels of 55 serum proteins representing cancer antigens, chemokines, angiogenic and anti-angiogenic factors, proteases, adipokines, apoptotic molecules, and other markers in these women. The biomarkers with high detection rates (> 60%) and acceptable reliability (intraclass correlation coefficient, ICCs > or = 0.55) using xMAPTM method were: cancer antigens: AFP, CA 15-3, CEA, CA-125, SCC, SAA; growth factors/related molecules: ErbB2, IGFBP-1; proteases and adhesion molecules: MMP-1, 8, 9, sE-selectin, human kallikreins (KLK) 8,10, ICAM-1, VCAM-1, chemokines: fractalkine, MCP-1,2, RANTES, MIP-1alpha, MIP-1beta, Eotaxin, GRO-alpha, IP-10; inhibitors of angiogenesis: angiostatin and endostatin; adipokines leptin and resistin; apoptotic factor: Fas, and other proteins mesothelin, myeloperoxidase (MPO), and PAI-1. The rest of the biomarkers under investigation either had ICCs less than 0.55 or had low levels of detection (< 60%). These included cancer antigens: CA 19-9, CA 72-4, MICA, S100, TTR, ULBP1, ULBP2, ULBP3; proteases: MMP 2, 3, 7, 12, 13; chemokines: MCP-3, MIF, MIG; adipokines: leptin and resistin; apoptotic factors: FasL, DR5, Cyfra 21-1; and inhibitors of angiogenesis and other markers: thrombospondin and heat shock protein (HSP) 27. In conclusion, 34 out of the 55 biomarkers investigated were present in detectable levels in > 60% of the samples, and with an ICC > or = 0.55, indicating that a single serum measurement can be used in prospective epidemiological studies using the xMAPTM method

BACKGROUND: In most studies, circulating biomarkers are usually assessed from a single sample, assuming that this single measurement represents the long-term biomarker status of the individual. Such an assumption is rarely tested although it may not be valid for all biomarkers. The objective of this study was to investigate the temporal reproducibility of a panel of cytokines and growth factors. METHODS: Thirty-five postmenopausal women with two annual visits and 30 premenopausal women with three annual visits were randomly selected from the participants in an existing prospective cohort. A total of 23 serum cytokines, nine growth factors and C-reactive protein (CRP) were measured using the Luminex xMap technology. In addition, for eight biomarkers, regular and high sensitivity (hs) assays were compared. RESULTS: The biomarkers with adequate (>60%) detection rates and acceptable (> or =0.55) intra-class correlation coefficients (ICCs) were: hsIL-1beta, IL-1RA, hsIL-2, hsIL-4, hsIL-5, hsIL-6, hsIL-10, IL-12p40, hsIL-12p70, hsTNF-alpha, TNF-R1, TNF-R2, CRP, HGF, NGF, and EGFR. The remaining biomarkers either had low temporal reproducibility or were undetectable in more than 40% of samples. CONCLUSIONS: The results suggest that 16 of the 41 biomarkers measured with Luminex technology showed sufficient sensitivity and temporal reproducibility in sera

Observational epidemiologic studies and randomized trials have reported a protective effect of oral hormonal replacement therapy on risk of colorectal cancer. Only one previous prospective study, the Women's Health Initiative Observational Study, has reported on the relationship between endogenous hormones and incident colorectal cancer. Contrary to expectation, the investigators found that women with higher circulating estradiol levels were at increased risk of developing colorectal cancer. We conducted a case-control study nested within the New York University Women's Health Study prospective cohort to evaluate the association between endogenous levels of estrone, estradiol, and sex hormone-binding globulin (SHBG) with risk of colorectal cancer. We measured hormones and SHBG in serum samples collected at enrollment from a total of 148 women who subsequently developed colorectal cancer and 293 matched controls. Circulating estrone levels were positively associated with risk of colorectal cancer: The odds ratio for the highest versus lowest quartile of estrone was 1.8 (95% confidence interval, 1.0-3.3). We found a nonsignificant inverse association between SHBG and colorectal cancer, which disappeared after adjusting for body mass index. We did not find an association between estradiol and colorectal cancer risk, but we cannot rule out a potential association because of substantial laboratory error in the measurement. Our results suggest that endogenous estrone is associated with increased risk of colorectal cancer in postmenopausal women

We conducted a nested case-control study within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Health and Disease Study, to examine the association between prediagnostic circulating levels of 25-hydroxy vitamin D (25(OH)D) and the risk of subsequent invasive epithelial ovarian cancer (EOC). The 25(OH)D levels were measured in serum or plasma from 170 incident cases of EOC and 373 matched controls. Overall, circulating 25(OH)D levels were not associated with the risk of EOC in combined cohort analysis: adjusted OR for the top tertile versus the reference tertile, 1.09 (95% CI, 0.59-2.01). In addition, there was no evidence of an interaction effect between VDR SNP genotype or haplotype and circulating 25(OH)D levels in relation to ovarian cancer risk, although more complex gene-environment interactions may exist