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Following our previous report on the radiation dose-response for prostate cancer incidence rates in the Life Span Study (LSS) cohort of atomic bomb survivors, we re-evaluated the radiation-related risk adjusting for differences in baseline cancer incidence rates among three subsets of the LSS cohort defined by the timing of their first participation in biennial health examinations offered to the Adult Health Study (AHS) sub-cohort members and prostate-specific-antigen (PSA) testing status for AHS participants: 1. non-AHS participants, 2. AHS participants before receiving PSA test, and 3. AHS participants after receiving PSA test. We found a 2.9-fold increase in the baseline incidence rates among AHS participants after receiving PSA test. After adjusting for the PSA-testing-status effects on the baseline rates the estimated excess relative risk (ERR) per Gy was 0.54 (95% CI: 0.15, 1.05), which was almost identical to the previously reported unadjusted ERR estimate (0.57, 95% CI: 0.21, 1.00). The current results confirmed that, while the PSA testing among AHS participants increased the baseline incidence rates, it did not impact the radiation risk estimate, strengthening the previously reported dose-response relationship for prostate cancer incidence in the LSS. As the use of PSA tests continue in screening and medical settings, analyses of possible effects of PSA testing should be an important aspect of future epidemiological studies of the association between radiation exposure and prostate cancer.

Although NSAIDs have been associated with both reduced and increased cutaneous melanoma risk, few studies have examined these associations by ultraviolet radiation (UVR) or personal sun-sensitivity. We examined the associations between NSAID use and first primary invasive cutaneous melanoma among 58,227 non-Hispanic white participants in the United States Radiologic Technologists cohort study. Poisson regression was used to calculate rate ratios (RR) and 95% likelihood-based confidence intervals (CI), adjusting for attained age, birth cohort, and ambient UVR. No significant association of melanoma was observed for any use of NSAIDs (RR, 0.87; 95% CI, 0.71–1.09). The relative risks of melanoma for the highest categories of aspirin and other NSAID use (≥5 times per month vs. none) were 0.93 (95% CI, 0.74–1.16) and 1.02 (95% CI, 0.83–1.25), respectively. Further analyses did not reveal dose–response for trends in frequency of NSAID use or interactions with sex, UVR, eye and hair color, and skin complexion. In this large nationwide study, NSAID use was not associated with melanoma risk.Prevention Relevance:NSAIDs have been associated with both reduced and increased melanoma risk. However, few studies have examined the role of UVR or personal sun-sensitivity on these associations. Our findings strengthen the evidence that NSAID use is not associated with melanoma risk, even in sun-sensitive subgroups.

This file includes Supplementary tables describing 1) Concordance of Medicare claims and SRTR malignancy reports, 2011-2013; 2) SEER diagnosis codes and groupings; and 3) Hazard ratios for selected SEER diagnoses by diagnosis of KC among 118,440 solid organ transplant recipients.

Immune condition associations with squamous cell carcinoma of the skin stratified by keratinocyte cancer (KC) diagnosis in Medicare prior to 2012

Background: Elevated keratinocyte carcinoma risk is present with several immune-related conditions, e.g., solid organ transplantation and non-Hodgkin lymphoma. Because many immune-related conditions are rare, their relationships with keratinocyte carcinoma have not been studied.Methods: We used Medicare claims to identify cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases in 2012, and controls matched on sex and age. All subjects were aged 65 to 95 years, of white race, and had attended ≥1 dermatologist visit in 2010–2011. Immune-related conditions were identified during 1999–2011 using Medicare claims. Associations were estimated with logistic regression, with statistical significance determined after Bonferroni correction for multiple comparisons.Results: We included 258,683 SCC and 304,903 BCC cases. Of 47 immune-related conditions, 21 and 9 were associated with increased SCC and BCC risk, respectively. We identified strongly elevated keratinocyte carcinoma risk with solid organ transplantation (SCC OR = 5.35; BCC OR = 1.94) and non-Hodgkin lymphoma (SCC OR = 1.62; BCC OR = 1.25). We identified associations with common conditions, e.g., rheumatoid arthritis [SCC OR = 1.06, 95% confidence interval (95% CI), 1.04–1.09] and Crohn's disease (SCC OR = 1.33, 95% CI, 1.27–1.39; BCC OR = 1.10, 95% CI, 1.05–1.15), and rare or poorly characterized conditions, e.g., granulomatosis with polyangiitis (SCC OR = 1.88; 95% CI, 1.61–2.19), autoimmune hepatitis (SCC OR = 1.81; 95% CI, 1.52–2.16), and deficiency of humoral immunity (SCC OR = 1.51, 95% CI, 1.41–1.61; BCC OR = 1.22, 95% CI, 1.14–1.31). Most conditions were more positively associated with SCC than BCC. Associations were generally consistent regardless of prior keratinocyte carcinoma history.Conclusions: Many immune-related conditions are associated with elevated keratinocyte carcinoma risk and appear more tightly linked to SCC.Impact: Immunosuppression or immunosuppressive treatment may increase keratinocyte carcinoma risk, particularly SCC. Cancer Epidemiol Biomarkers Prev; 26(7); 998–1007. ©2017 AACR.

Solid organ transplant recipients have increased risk for developing keratinocyte cancers, including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, keratinocyte cancers are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on keratinocyte cancer occurrence, with 15 state cancer registries. Risk of developing malignancies after keratinocyte cancer was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n = 6,169) was associated with 1.44-fold increased risk [95% confidence interval (CI), 1.31–1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx (HR, 5.60; 95% CI, 4.18–7.50) and lung (HR, 1.66; 95% CI, 1.16–2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR, 2.77; 95% CI, 1.29–5.96) and female genital cancers (HR, 3.43; 95% CI, 1.44–8.19). In contrast, BCC (n = 3,669) was not associated with overall risk of later malignancy (HR, 0.98; 95% CI, 0.87–1.12), including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk. Cancer Res; 77(15); 4196–203. ©2017 AACR.

This study revised the thyroid doses for 2582 Ukrainian in utero cohort members exposed to Chornobyl fallout (the Ukrainian in utero cohort) based on revision of: (i) 131I thyroid activity measured in the Ukrainian population, (ii) thyroid dosimetry system for entire Ukraine, and (iii) 131I ground deposition densities in Ukraine. Other major improvements included: (i) assessment of uncertainties in the thyroid doses considering shared and unshared error, and (ii) accounting for intake of short-lived radioisotopes of tellurium and iodine (132Te+132I and 133I). Intake of 131I was the major pathway for thyroid exposure, its median contribution to the thyroid dose was 97.4%. The mean prenatal and postnatal thyroid dose from 131I was 87 mGy (median = 17 mGy), higher than previous deterministic dose of 72 mGy (median = 12 mGy). For 39 individuals (1.5%) the dose exceeded 1.0 Gy, while the highest dose among the cohort members was 2.7 Gy. The geometric standard deviation (GSD) of 1000 individual stochastic doses varied from 1.9 to 5.2 with a mean of 3.1 and a median of 3.2. The lowest uncertainty (mean GSD = 2.3, median GSD = 2.2) was found for the subjects whose mothers were measured for 131I thyroid activity, while for individuals, whose mothers were not measured, the mean and median GSDs were 3.4. Uncertainties in thyroid doses were driven by shared errors associated with the parameters of the ecological model.

A large excess risk of thyroid cancer was observed among Belarusian/Russian/Baltic Chornobyl cleanup workers. A more recent study of Ukraine cleanup workers found more modest excess risks of thyroid cancer. Dose errors in this data are substantial, associated with model uncertainties and questionnaire response. Regression calibration is often used for dose-error adjustment, but may not adequately account for the full error distribution. We aimed to examine the impact of exposure-assessment uncertainties on thyroid cancer among Ukrainian cleanup workers using Monte Carlo maximum likelihood, and compare with results derived using regression calibration. Analyses assessed the sensitivity of results to various components of internal and external dose. Regression calibration yielded an excess odds ratio per Gy (EOR/Gy) of 0.437 (95% CI - 0.042, 1.577, p = 0.100), compared with the EOR/Gy using Monte Carlo maximum likelihood of 0.517 (95% CI - 0.039, 2.035, p = 0.093). Trend risk estimates for follicular morphology tumors exhibited much more extreme effects of full-likelihood adjustment, the EOR/Gy using regression calibration of 3.224 (95% CI - 0.082, 30.615, p = 0.068) becoming ~ 50% larger, 4.708 (95% CI - 0.075, 85.143, p = 0.066) when using Monte Carlo maximum likelihood. Results were sensitive to omission of external components of dose. In summary, use of Monte Carlo maximum likelihood adjustment for dose error led to increases in trend risks, particularly for follicular morphology thyroid cancers, where risks increased by ~ 50%, and were borderline significant. The unexpected finding for follicular tumors needs to be replicated in other exposed groups.

Thyroid doses from intake of radioiodine isotopes (131I, 132Te+132I, and 133I) and associated uncertainties were revised for the 13,204 Ukrainian-American cohort members exposed in childhood and adolescence to fallout from the Chornobyl nuclear power plant accident. The main changes related to the revision of the 131I thyroid activity measured in cohort members, the use of thyroid-mass values specific to the Ukrainian population, and the revision of the 131I ground deposition densities in Ukraine. Uncertainties in doses were assessed considering shared and unshared errors in the parameters of the dosimetry model. Using a Monte-Carlo simulation procedure, 1,000 individual stochastic thyroid doses were calculated for each cohort member. The arithmetic mean of thyroid doses from intake of 131I, 132Te+132I, and 133I for the entire cohort was 0.60 Gy (median = 0.22 Gy). For 9,474 subjects (71.6% of the total), the thyroid doses were less than 0.5 Gy. Thyroid doses for 42 cohort members (0.3% of the total) exceeded 10 Gy while the highest dose was 35 Gy. Intake of 131I contributed around 95% to internal thyroid exposure from radioiodine isotopes. The geometric standard deviation of individual stochastic thyroid doses varied among cohort members from 1.4 to 4.3 with an arithmetic mean of 1.6 and a median of 1.4. It was shown that the contribution of shared errors to the dose uncertainty was small. The revised thyroid doses resulted, in average, in around 40% decrease for cohort members from Zhytomyr Oblast and an increase of around 24% and 35% for the cohort members from Kyiv and Chernihiv Oblast, respectively. Arithmetic mean of TD20 doses for the cohort was around 8% less than that estimated in TD10, 0.60 Gy vs. 0.65 Gy, respectively; however, global median of TD20 doses somewhat increased compared to TD10: 0.22 Gy vs. 0.19 Gy, respectively. The difference between TD10 and TD20 was mainly due to a revision of the individual 131I thyroid activity measured in the cohort members.

Although NSAIDs have been associated with both reduced and increased cutaneous melanoma risk, few studies have examined these associations by ultraviolet radiation (UVR) or personal sun-sensitivity. We examined the associations between NSAID use and first primary invasive cutaneous melanoma among 58,227 non-Hispanic white participants in the United States Radiologic Technologists cohort study. Poisson regression was used to calculate rate ratios (RR) and 95% likelihood-based confidence intervals (CI), adjusting for attained age, birth cohort, and ambient UVR. No significant association of melanoma was observed for any use of NSAIDs (RR, 0.87; 95% CI, 0.71–1.09). The relative risks of melanoma for the highest categories of aspirin and other NSAID use (≥5 times per month vs. none) were 0.93 (95% CI, 0.74–1.16) and 1.02 (95% CI, 0.83–1.25), respectively. Further analyses did not reveal dose–response for trends in frequency of NSAID use or interactions with sex, UVR, eye and hair color, and skin complexion. In this large nationwide study, NSAID use was not associated with melanoma risk. Prevention Relevance: NSAIDs have been associated with both reduced and increased melanoma risk. However, few studies have examined the role of UVR or personal sun-sensitivity on these associations. Our findings strengthen the evidence that NSAID use is not associated with melanoma risk, even in sun-sensitive subgroups.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

Background The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. Methods We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the two-month period of radioiodine fallout (April 26, 1986 - June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. Results The SIR was non-significantly elevated for women lactating at the time of accident (SIR = 1.30, 95% CI: 0.40; 3.01), but not for women initiating lactation within the two months of the accident (SIR = 0.82, 95% CI: 0.32; 1.65) or women pregnant at the time of the accident (SIR = 0.75, 95% CI: 0.44; 1.18). Conclusions The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

Background Recent studies have suggested that Kaposi sarcoma (KS) rates might be increasing in some racial/ethnic groups, age groups, and US regions. We estimated recent US trends in KS incidence among people living with human immunodeficiency virus (HIV; PLWH). Methods Incident KS patients aged 20–59 years were obtained from 36 cancer registries and assumed to be living with HIV. The number of PLWH was obtained from national HIV surveillance data from 2008 to 2016. Age-standardized KS rates and annual percent changes (APCs) in rates were estimated by age, sex, race/ethnicity, state, and region. Results Between 2008 and 2016, the age-adjusted KS rate among PLWH was 116/100 000. Rates were higher among males, in younger age groups, and among white PLWH. Washington, Maine, and California had the highest KS rates among PLWH. KS rates among PLWH decreased significantly (average APC = −3.2% per year, P Conclusions KS incidence rates among PLWH have decreased nationally between 2008 and 2016. Though there were no statistically significant increases in KS rates in any demographic or geographic group, nondecreasing/stagnant KS trends in some states and among younger and black PLWH highlight the need for early diagnosis and treatment of HIV infection.

The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the 2-month period of radioiodine fallout (April 26, 1986-June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. The SIR was not significant for women pregnant at the time of the accident (SIR = 0.75; 95% CI 0.44, 1.18) or for women lactating anytime within 2 months of the accident (SIR = 0.96; 95% CI 0.48, 1.68). However, there was a non-significantly elevated risk for women lactating at the time of accident (SIR = 1.30, 95% CI 0.40, 3.01). The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

STUDY QUESTION Are reproductive factors and exogenous hormone use associated with incidence of cutaneous melanoma while accounting for ultraviolet radiation (UVR) exposure across different life periods and sun sensitivity factors? SUMMARY ANSWER Earlier age at menarche and late age at first birth, but not other estrogen-related factors were associated with an increased incidence rate of melanoma, with higher risks observed for earlier age at menarche and light hair color at age 15 years. WHAT IS KNOWN ALREADY Although estrogens have been recognized as photosensitizing, previous studies have reported inconsistent findings for the association of melanoma with estrogen-related factors. Most have not collected detailed skin cancer risk factors and have not thoroughly investigated effect modification by ambient UVR and sun sensitivity. STUDY DESIGN, SIZE, DURATION Participants in the US Radiologic Technologists study, an occupational cohort of 146 022 radiologic technologists (73% women), were included and followed during the four time periods (1983–1989, 1994–1998, 2003–2005 and 2012–2014). PARTICIPANTS/MATERIALS, SETTING, METHODS Non-Hispanic white female participants who completed both the second (baseline) and third questionnaires, and did not report having cancer (except keratinocyte carcinoma) at baseline, were included and followed from their age at completion of the second (baseline) questionnaire until the earlier of first primary cancer diagnosis, including invasive melanoma of the skin, or completion of either the third or fourth questionnaire. Reproductive and exogenous hormonal factors were ascertained from the second (baseline) questionnaire, which also collected information on demographic, lifestyle factors and sun sensitivity factors. Ambient UVR was assigned by linking geocoded residential locations, based on self-reported residential history information collected from the third questionnaire to satellite-based ambient UVR data from the National Aeronautics and Space Administration’s Total Ozone Mapping Spectrometer database. To examine the association of reproductive factors, exogenous hormone use, and first primary invasive melanoma of the skin, we used Poisson regression to calculate rate ratios (RRs) and 95% likelihood-based CIs, adjusting for attained age, birth cohort, lifetime average annual ambient UVR, contraceptives and menopausal hormone therapy use. To address the effect modification of ambient UVR exposure and sun sensitivities on melanoma risk, we conducted likelihood-ratio tests for multiplicative interaction. MAIN RESULTS AND THE ROLE OF CHANCE Over a median follow-up time of 17.1 years, 0.95% of eligible participants had an incident first primary melanoma (n = 444). Higher melanoma incidence rates were observed in participants with older attained age, blue/green/gray eye color, blonde/red/auburn natural hair color at age 15, fair skin complexion, and higher UVR. We found an increased incidence rate of melanoma in women who experienced menarche at an earlier age (13, 12 and LIMITATIONS, REASONS FOR CAUTION Information on reproductive history and exogenous hormone use was self-reported. We did not have information on specific doses or formulations of exogenous hormone medications or breastfeeding. WIDER IMPLICATIONS OF THE FINDINGS Women residing in areas of high ambient UVR and those with blonde/red/auburn natural hair color may constitute an additional high-risk group in need of more frequent skin cancer screening. Identifying susceptible periods of exposure or factors that modify UVR susceptibility may aid in guiding more targeted guidelines for melanoma prevention. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

ObjectivesTo evaluate cumulative occupational radiation dose response and haematopoietic malignancy mortality risks in the US radiologic technologist cohort.MethodsAmong 110 297 radiologic technologists (83 655 women, 26 642 men) who completed a baseline questionnaire sometime during 1983–1998, a retrospective cohort study was undertaken to assess cumulative, low-to-moderate occupational radiation dose and haematopoietic malignancy mortality risks during 1983–2012. Cumulative bone marrow dose (mean 8.5 mGy, range 0–430 mGy) was estimated based on 921 134 badge monitoring measurements during 1960–1997, work histories and historical data; 35.4% of estimated doses were based on badge measurements. Poisson regression was used to estimate excess relative risk of haematopoietic cancers per 100 milligray (ERR/100 mGy) bone-marrow absorbed dose, adjusting for attained age, sex and birth year.ResultsDeaths from baseline questionnaire completion through 2012 included 133 myeloid neoplasms, 381 lymphoid neoplasms and 155 leukaemias excluding chronic lymphocytic leukaemia (CLL). Based on a linear dose-response, no significant ERR/100 mGy occurred for acute myeloid leukaemia (ERR=0.0002, 95% CI 0.5, 85 cases) or leukaemia excluding CLL (ERR=0.05, 95% CI 0.5, 112 cases). Findings did not differ significantly by demographic factors, smoking or specific radiological procedures performed.ConclusionAfter follow-up averaging 22 years, there was little evidence of a relationship between occupational radiation exposure and myeloid or lymphoid haematopoietic neoplasms.

The Trinity nuclear test, conducted in 1945, exposed residents of New Mexico to varying degrees of radioactive fallout. Companion papers in this issue have detailed the results of a dose reconstruction that has estimated tissue-specific radiation absorbed doses to residents of New Mexico from internal and external exposure to radioactive fallout in the first year following the Trinity test when more than 90% of the lifetime dose was received. Estimated radiation doses depended on geographic location, race/ethnicity, and age at the time of the test. Here, these doses were applied to sex- and organ-specific risk coefficients (without applying a dose and dose rate effectiveness factor to extrapolate from a population with high-dose/high-dose rates to those with low-dose/low-dose rates) and combined with baseline cancer rates and published life tables to estimate and project the range of radiation-related excess cancers among 581,489 potentially exposed residents of New Mexico. The total lifetime baseline number of all solid cancers [excluding thyroid and non-melanoma skin cancer (NMSC)] was estimated to be 183,000 from 1945 to 2034. Estimates of ranges of numbers of radiation-related excess cancers and corresponding attributable fractions from 1945 to 2034 incorporate various sources of uncertainty. We estimated 90% uncertainty intervals (UIs) of excess cancer cases to be 210 to 460 for all solid cancers (except thyroid cancer and NMSC), 80 to 530 for thyroid cancer, and up to 10 for leukemia (except chronic lymphocytic leukemia), with corresponding attributable fractions ranging from 0.12% to 0.25%, 3.6% to 20%, and 0.02% to 0.31%, respectively. In the counties of Guadalupe, Lincoln, San Miguel, Socorro, and Torrance, which received the greatest fallout deposition, the 90% UI for the projected fraction of thyroid cancers attributable to radioactive fallout from the Trinity test was estimated to be from 17% to 58%. Attributable fractions for cancer types varied by race/ethnicity, but 90% UIs overlapped for all race/ethnicity groups for each cancer grouping. Thus, most cancers that have occurred or will occur among persons exposed to Trinity fallout are likely to be cancers unrelated to exposures from the Trinity nuclear test. While these ranges are based on the most detailed dose reconstruction to date and rely largely on methods previously established through scientific committee agreement, challenges inherent in the dose estimation, and assumptions relied upon both in the risk projection and incorporation of uncertainty are important limitations in quantifying the range of radiation-related excess cancer risk.

Thyroid doses were estimated for 607 subjects of the case-control study of thyroid cancer nested in the cohort of 150,813 male Ukrainian cleanup workers, who were exposed to radiation as a result of the 1986 Chernobyl nuclear power plant accident. Individual thyroid doses due to external irradiation, inhalation of (131)I and short-lived radioiodine and radiotellurium isotopes ((132)I, (133)I, (135)I, (131m)Te and (132)Te) during the cleanup mission, and intake of (131)I during residence in contaminated settlements were calculated for all study subjects, along with associated uncertainty distributions. The average thyroid dose due to all exposure pathways combined was estimated to be 199 mGy (median dose of 47 mGy; range: 0.15 mGy to 9.0 Gy), with averages of 140 mGy (median of 20 mGy; range: 0.015 mGy to 3.6 Gy) from external irradiation during the cleanup mission, 44 mGy (median of 12 mGy; range: ~0 mGy to 1.7 Gy) due to (131)I inhalation, 42 mGy (median of 7.3 mGy; range: 0.001 mGy to 3.4 Gy) due to (131)I intake during residence, and 11 mGy (median of 1.6 mGy; range: ~0 mGy to 0.38 Gy) due to inhalation of short-lived radionuclides. Internal exposure of the thyroid gland to (131)I contributed more than 50% of the total thyroid dose in 45% of the study subjects. The uncertainties of the individual stochastic doses were characterized by a mean GSD of 2.0, 1.8, 2.0 and 2.6 for external irradiation, inhalation of (131)I, inhalation of short-lived radionuclides and residential exposure, respectively. The models used for dose calculations were validated against instrumental measurements done shortly after the accident. Results of the validation showed that thyroid doses could be estimated retrospectively for Chernobyl cleanup workers two-three decades after the accident with a reasonable degree of reliability.

Background Basal cell carcinoma of the skin (BCC) is the most common cancer in populations of European ancestry. Although consistently linked with basal cell carcinoma of the skin in case-control studies, few prospective cohort studies have evaluated the shape of the exposure-response of basal cell carcinoma associated with cumulative radiant solar ultraviolet exposure (UVR). Methods We followed 63,912 white cancer-free US radiologic technologists from entry (1983–1998) to exit (2003–2005) with known ultraviolet irradiance at up to 5 residential locations. Using generalized-additive and relative risk models we analyzed the exposure-response of basal cell carcinomas associated with ambient cumulative ultraviolet radiant exposure using ground-based National Solar Radiation database Average Daily Total Global data and satellite-based National Aeronautics and Space Administration Total Ozone Mapping Spectrometer data. Results There were 2151 technologists with an incident primary basal cell carcinoma. Risk of basal cell carcinoma rose with increasing cumulative ultraviolet radiation exposure using both measures, such that 1 MJ cm− 2 increased basal cell carcinoma risk by 8.48 (95% CI 5.22, 11.09, p p Conclusions We observed increases in risk of basal cell carcinoma and a similar exposure-response for ground-based and satellite ultraviolet radiation measures. Our observations suggest that interventions should concentrate on persons with higher levels of ultraviolet radiation exposure.

The characterization of the effects of solar UVR on a broad set of circulating markers in systemic immunity and inflammation may provide insight into the mechanisms responsible for the UVR associations observed for several benign and malignant diseases. We examined the associations between exposure to solar UVR and circulating levels of 78 markers among 1,819 individuals aged 55–74 years who participated in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial using multiplex assays. Solar UVR was derived by linking the geocoded locations of 10 screening centers across the continental United States and the date of blood draw to the National Solar Radiation Database from 1993 to 2005. We assessed associations between ambient solar UVR and dichotomized marker levels using adjusted weighted logistic regression models and applied a 5% false discovery rate criterion to P-values. UVR exposure was associated (P < 0.05) with 9 of the 78 markers. CCL27, CCL4, FGF2, GM-CSF, IFN-γ, soluble IL4R, IL-7, and IL-11 levels were lower with increasing UVR tertile, with adjusted ORs ranging from 0.66 to 0.80, and the significant association for CCL27 withstood multiple comparison correction. In contrast, CRP levels were elevated with increasing UVR. Solar UVR was associated with alterations in systemic immune and inflammation marker levels., Graphical abstract

Background Pregnancy and lactation may constitute radiation-sensitive reproductive periods due to rapid cell proliferation and concentration of radioiodine in the lactating breast. However, there are limited epidemiological data among women exposed to radiation during these periods. Methods We examined incidence of breast cancer in a cohort of 3214 women who were pregnant and/or lactating within 2 months (26 April to 30 June 1986) of the Chernobyl accident and residing in contaminated regions of Belarus. There were 33 breast cancers identified through linkage with the Belarusian National Cancer Registry. Breast cancer rates among women who were either pregnant and/or lactating were compared with population rates by calculating standardized incidence ratios (SIR) and 95% confidence intervals (CI) adjusting for attained age, oblast, urban/rural residence and calendar year. Results Among women who were lactating, we found a greater than 2-fold increased risk of breast cancer compared with the general population, SIR = 2.49 (95% CI: 1.55, 3.75). In contrast, women who were pregnant were not at increased risk (SIR = 0.84 95% CI: 0.46, 1.38). The SIR was highest in women who were exposed at a younger age and at the earliest time period since the accident, though stratified analyses had limited sample sizes. Conclusions We found a significantly increased risk of breast cancer among women residing in contaminated areas of Belarus who were lactating at the time of the accident and may have had elevated exposure to radioiodine, when compared with the general population. Studies of breast cancer with individual radiation dose estimates among women exposed during lactation are warranted.

BACKGROUND: Ionizing radiation is a known cause of female breast cancer, but there have been few studies of the risk after prolonged radiation exposure at low dose rates. METHODS: This population-based case-control study estimated breast cancer risk after ∼25 years’ exposure to radiation from the Chernobyl accident. Cases (n = 468) were women ≤55 years old when first diagnosed with invasive breast cancer during October 2008 through February 2013, who lived in Bryansk Oblast, Russia at the time of the accident and their diagnoses. Controls, individually matched to cases on birth year, administrative district of residence and urban vs non-urban settlement during the accident, were women without breast cancer who lived in Bryansk Oblast at the time of the accident and on their cases’ diagnosis dates (n = 468). Subjects were interviewed regarding residence, dietary and food source histories to support individualized estimation of their radiation doses to the breast, which ranged from 0.04 − 41 centigray (cGy) (mean 1.3 cGy). RESULTS: In multivariable analyses, the odds ratio for breast cancer risk was 3.0 [95% confidence interval (CI): 1.3, 7.0] and 2.7 (95% CI: 1.0, 7.3) in the seventh and eighth dose octiles, respectively, relative to the lowest octile. Analyses of dose effect modification suggested that radiation-related risk may have been higher in women who were younger at the time of the accident and/or at the time of diagnosis. CONCLUSIONS: This study suggests that prolonged exposure to ionizing radiation at low dose rates can increase risk of breast cancer.

Solid organ transplant recipients have an increased risk of lip cancer, but the reasons are uncertain. Using data from the Transplant Cancer Match Study, we describe the epidemiology of lip cancer among 261,500 transplant recipients in the United States. Two-hundred thirty-one lip cancers were identified, corresponding to elevated risks for both invasive and in situ lip cancers (standardized incidence ratios of 15.3 and 26.2, respectively). Invasive lip cancer incidence was associated with male sex (adjusted incidence rate ratio [aIRR] 2.01, 95%CI 1.44–2.82), transplanted organ (0.33, 0.20–0.57, for liver transplants and 3.07, 1.96–4.81, for lung transplants, compared with kidney transplants), and racial/ethnic groups other than non-Hispanic whites (0.09, 0.04–0.20). In addition, incidence increased with age and during the first three years following transplant, and was higher in recipients prescribed cyclosporine/azathioprine maintenance therapy (aIRR 1.79, 95%CI 1.09–2.93, compared with use of tacrolimus/mycophenolate mofetil) and following a diagnosis of cutaneous squamous cell carcinoma (4.21, 2.69–0.94). The elevation in lip cancer incidence is consistent with an effect of immunosuppression. Notably, the very strong associations with white race and history of prior skin cancer point to an important role for ultraviolet radiation exposure, and cyclosporine and azathioprine may contribute as photosensitizing or DNA damaging agents.

Following the Chernobyl nuclear power plant explosion in Ukraine in 1986, increased childhood exposure to radioactive iodine (131I), which occurred primarily through contaminated food sources, has been consistently associated with increased risk of developing papillary thyroid carcinoma (PTC). Increased frequency of cervical lymph node metastases (LNM) is well recognized in pediatric PTC, including pediatric cases following the Chernobyl accident. We recently leveraged the collection of fresh-frozen tumor tissues from the Chernobyl Tissue Bank to conduct a genomic landscape analysis of 440 cases of PTC that provided new insights into radiation-related molecular characteristics of PTC occurring after the accident (Morton et al., Science 2021). Here, we extend that study to conduct a genomic landscape analysis of LNMs for a subset of 48 PTC cases to investigate the specific genomic alterations occurring in LNM. The analysis set comprised 144 samples, including fresh-frozen treatment-naïve primary and LNM PTC tumor samples as well as matched normal tissue or blood. Overall, the mutational load was highly concordant between primary and metastatic PTC. On average, 50% of somatic single nucleotide variants and 97% structural variants were shared between primary and metastatic PTCs. In contrast, the burden of somatic copy number alterations (SCNA) between primary tumor and LNM pairs was less concordant, particularly for copy number gains, whereas most of the copy number loss was found to be shared between matched pairs. PTC is usually driven by one driver mutation, most often involving the mitogen-activated protein kinase (MAPK) pathway. All driver mutations were shared between primary and metastatic PTC and were clonal; thus, no additional driver mutations were detected in metastatic PTC. Notably, however, the matched pairs in this study disproportionately had fusion drivers (77%), whereas only 23% of the drivers were BRAF V600E and none were RAS mutations. Transcriptome analysis revealed differentially expressed genes (DEGs) in metastatic PTC compared to primary PTC; three-quarters of the DEGs were overexpressed in metastatic PTC. Half of the LNM overexpressed DEGs were members of the HOXC family, which has been linked with epithelial-mesenchymal transition in cancer progression. There was also reduced expression in LNM for the DLX family, which relates to TGF-beta signaling. Our findings did not reveal a relationship between radiation dose and expression profiles in the LNM, comparable to our findings for the primary PTCs. We still observe that the efficiency of the radiation-induced PTC is paramount and subsequent events are directly related to the drivers in the MAPK pathway. For the cervical LNMs, we observed expression profiles not observed in the primary PTC that could give new insights into PTC local metastases. Citation Format: Olivia W. Lee, Danielle M. Karyadi, Chip Stewart, Tetiana I. Bogdanova, Jieqiong Dai, Stephen W. Hartley, Sara J. Schonfeld, Vidushi Kapoor, Marko Krznaric, Meredith Yeager, Amy Hutchinson, Belynda D. Hicks, Casey L. Dagnall, Julie M. Gastier-Foster, Jay Bowen, Mitchell J. Machiela, Elizabeth K. Cahoon, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Y. Zurnadzhy, Amy Berrington de González, Gad Getz, Gerry A. Thomas, Mykola D. Tronko, Lindsay M. Morton, Stephen J. Chanock. Genomic characterization of lymph node metastases in papillary thyroid carcinoma following the Chernobyl accident reveals an expression profile specific to metastatic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 980.

IMPORTANCE: Nonkeratinocyte skin cancers are an important cause of morbidity and mortality for immunosuppressed solid organ transplant recipients (SOTRs), but the spectrum of disease and risk factor characteristics are unknown. OBJECTIVE: To characterize the spectrum of disease and risk factors for common and rare nonkeratinocyte skin cancers in SOTRs. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included 444 497 SOTRs who underwent a transplant in the US between January 1, 1987, and December 31, 2017, using linked data from the national transplant registry and 32 cancer registries. Data analysis was conducted from April 1, 2021, to September 30, 2021. MAIN OUTCOMES AND MEASURES: Standardized incidence ratios (SIRs) were used to assess risk relative to the general population, and Poisson regression was used to evaluate risk factors. RESULTS: A total of 2380 nonkeratinocyte skin cancers were identified among 444 497 SOTRs (median age at transplant, 50 years; range, 0-96 years; 274 276 [61.7%] male; 272 241 [61.2%] non-Hispanic White). Melanoma was the most common cancer (1471 [61.8%]), followed by Merkel cell carcinoma (334 [14.0%]), Kaposi sarcoma (186 [7.8%]), sebaceous carcinoma (170 [7.1%]), and cutaneous lymphomas (108 [4.5%]). Risks were most strongly elevated for cancers associated with viruses, including Kaposi sarcoma (SIR, 20.5; 95% CI, 17.7-23.7), Merkel cell carcinoma (SIR, 16.2; 95% CI, 14.5-18.1), and extranodal natural killer/T-cell lymphoma (SIR, 44.3; 95% CI, 5.37-160). Risks were also significantly elevated for sebaceous carcinoma (SIR, 15.2; 95% CI, 13.0-17.7), anaplastic large cell lymphoma (SIR, 6.82; 95% CI, 4.53-9.85), and diffuse large B-cell lymphoma (SIR, 5.17; 95% CI, 3.28-7.76). Several characteristics were independently associated with greater risk for multiple skin cancer types, including male sex, older age at transplant, factors associated with UV radiation exposure (non-Hispanic White race and ethnicity, living in an area with higher UV radiation exposure, and posttransplant diagnosis of keratinocyte carcinoma), and increasing time since transplantation. Treatment with mammalian target of rapamycin inhibitors was associated with reduced melanoma incidence (incidence rate ratio, 0.75; 95% CI, 0.57-0.98). A total of 847 skin cancers (39.4%) occurred on the head and neck. CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that viruses, UV radiation exposure, and immunosuppression are associated with the development of skin cancer in SOTRs. Certain high-risk subgroups may benefit from increased skin surveillance, and treatment with mammalian target of rapamycin inhibitors could be effective for melanoma chemoprevention in the transplant population.

BACKGROUND: Children and adolescents exposed to radioactive iodine-131 (I-131) in fallout from the 1986 Chernobyl nuclear accident appear to be at increased risk of thyroid cancer and benign thyroid nodules. The prenatal period is also considered radiosensitive, and the fetal thyroid can absorb I-131 from the maternal circulation. OBJECTIVES: We aimed to estimate the risk of malignant and benign thyroid nodules in individuals exposed prenatally. METHODS: We studied a cohort of 2582 subjects in Ukraine with estimates of I-131 prenatal thyroid dose (mean = 72.6 mGy), who underwent two standardized thyroid screening examinations. To evaluate the dose-response relationship, we estimated the excess OR (EOR) using logistic regression. RESULTS: Based on a combined total of eight cases diagnosed at screenings from 2003 to 2006 and 2012 to 2015, we found a markedly elevated, albeit not statistically significant, dose-related risk of thyroid cancer (EOR/Gy = 3.91, 95% CI: –1.49, 65.66). At cycle 2 (n = 1,786), there was a strong and significant association between I-131 thyroid dose and screen-detected large benign nodules (≥10 mm) (EOR/Gy = 4.19, 95% CI: 0.68, 11.62; P = 0.009), but no significant increase in risk for small nodules (

Due to treatment with immunosuppressive medications, solid organ transplant recipients have elevated risk for Kaposi sarcoma (KS), which is caused by human herpesvirus 8 (HHV8). Other risk factors for KS are poorly understood. We linked the United States solid organ transplant registry with 17 population-based cancer registries to ascertain KS incidence among 244,964 transplant recipients from 1987-2014. To compare incidence rates of KS according to patient and transplant characteristics, we calculated incidence rate ratios (IRRs) using Poisson regression. To compare associations of KS with other skin cancers occurring before or within 12 months of KS diagnosis, we computed odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. All statistical tests were two-sided. We identified 163 KS cases during follow-up. Among transplant recipients, we found significantly increased risk of KS associated with male sex (IRR = 1.87; 95%CI:1.32,2.71), nonwhite race (IRR = 2.67; 95%CI:1.92,3.72), non-US citizenship (IRR = 2.10; 95%CI:1.19,3.47), lung transplant (IRR = 2.22; 95%CI:1.03,4.24, vs. kidney), and older age at transplant. KS risk decreased significantly with time since transplant and recent calendar year, however, no specific induction or maintenance medication was associated with KS. KS incidence was not significantly associated with ambient ultraviolet radiation (IRR = 1.32 95%CI:0.87,2.02, tertile 3 vs. 1). KS incidence has decreased in recent calendar years. In a cross-sectional sample, we found cutaneous squamous cell carcinoma was associated with KS (OR = 4.83; 95%CI:1.30,14.69). KS risk factors included those potentially associated with HHV8 infection and increased immunosuppression. Our findings suggest that transplant recipients with a non-KS skin cancer may also be at high KS risk.

Although much is known about the radiation-related risk of thyroid cancer in those exposed at young ages, less is known about the risk due to adult exposure, particularly in men. We aimed to examine the association between thyroid radiation dose received during adulthood and thyroid cancer risk in men. We conducted a nested case-control study (149 cases; 458 controls) of male, Ukrainian cleanup workers who first worked in the Chornobyl zone between ages 18 and 59 years, with cases identified through linkage with the National Cancer Registry of Ukraine from 1988 to 2012. Individual thyroid doses due to external and internal exposure during the cleanup mission and during residence in contaminated settlements were estimated (total dose mean 199 mGy; range 0.15 mGy to 9.0 Gy). The excess odds ratio per gray (EOR/Gy) for overall thyroid cancer was 0.40 (95% CI: - 0.05, 1.48; p-value = 0.118). Time since exposure was borderline significant (p-value = 0.061) in modifying this association so that less time since exposure was associated with a stronger EOR/Gy. An elevated, but nonsignificant association was observed for follicular thyroid cancer (EOR/Gy = 1.72; 95% CI: - 0.25, 13.69; p-value = 0.155) based on a small number of cases (n = 24). Our findings for radiation-related overall thyroid cancer risk are consistent with evidence of increased risks observed in most of the other studies of adult exposure, though the magnitude of the effect in this study is lower than in the previous case-control study of Chornobyl cleanup workers.

Radiation doses of parents exposed from the Chornobyl accident as cleanup workers or evacuees were estimated in the National Cancer Institute-National Research Center for Radiation Medicine trio (i.e. father, mother, offspring) study aimed at investigating the radiation effects on germline de novo mutations in children as well as other outcomes. Paternal (testes) and maternal (ovaries) gonadal doses were calculated along with associated uncertainty distributions for the following exposure pathways: (a) external irradiation during the cleanup mission, (b) external irradiation during residence in Pripyat, and (c) external irradiation and (d) ingestion of radiocesium isotopes, such as 134Cs and 137Cs, during residence in settlements other than Pripyat. Gonadal doses were reconstructed for 298 trios for the periods from the time of the accident on 26 April 1986 to two time points before the child’s date of birth (DOB): 51 (DOB-51) and 38 (DOB-38) weeks. The two doses, DOB-51 and DOB-38 were equal (within 1 mGy) in most instances, except for 35 fathers where the conception of the child occurred within 3 months of exposure or during exposure. The arithmetic mean of gonadal DOB-38 doses was 227 mGy (median: 11 mGy, range 0–4080 mGy) and 8.5 mGy (median: 1.0 mGy, range 0–550 mGy) for fathers and mothers, respectively. Gonadal doses varied considerably depending on the exposure pathway, the highest gonadal DOB-38 doses being received during the cleanup mission (mean doses of 376 and 34 mGy, median of 144 and 7.4 mGy for fathers and mothers, respectively), followed by exposure during residence in Pripyat (7.7 and 13 mGy for mean, 7.2 and 6.2 mGy for median doses) and during residence in other settlements (2.0 and 2.1 mGy for mean, 0.91 and 0.81 mGy for median doses). Monte Carlo simulations were used to estimate the parental gonadal doses and associated uncertainties. The geometric standard deviations (GSDs) in the individual parental stochastic doses due to external irradiation during the cleanup mission varied from 1.2 to 4.7 (mean of 1.8), while during residence in Pripyat they varied from 1.4 to 2.8 (mean of 1.8), while the mean GSD in doses received during residence in settlements other than Pripyat was 1.3 and 1.4 for external irradiation and ingestion of radiocesium isotopes, respectively.

Background: Cutaneous basal cell carcinoma (BCC) has long been associated with UV radiation (UVR) exposure, but data are limited on risks by anatomic site. Methods: We followed 63,912 cancer-free White U.S. radiologic technologists from cohort entry (1983–1989/1994–1998) to exit (date first BCC via 2003–2005 questionnaire). We estimated associations between cumulative ambient UVR and relative/absolute risks of self-reported BCC by anatomic location via Poisson models. Results: For incident first primary BCC in 2,124 subjects (mean follow-up, 16.9 years) log[excess relative risks] (ERR) of BCC per unit cumulative ambient UVR = 1.27/MJ cm–2 [95% confidence interval (CI): 0.86–1.68; Ptrend < 0.001] did not vary by anatomic site (P = 0.153). However, excess absolute risks of BCC per unit cumulative ambient UVR were large for the head/neck = 5.46/MJ cm–2/104 person-year (95% CI: 2.92–7.36; Ptrend < 0.001), smaller for the trunk (2.56; 95% CI: 1.26–3.33; Ptrend = 0.003), with lesser increases elsewhere. There were lower relative risks, but higher absolute risks, for those with Gaelic ancestry (P < 0.001), also higher absolute risks among those with fair complexion, but relative and absolute risks were not generally modified by other constitutional, lifestyle or medical factors for any anatomic sites. Excess absolute and relative risk was concentrated 5–15 years before time of follow-up. Conclusions: BCC relative and absolute risk rose with increasing cumulative ambient UVR exposure, with absolute risk highest for the head/neck, to a lesser extent in the trunk. Impact: These associations should be evaluated in other White and other racial/ethnic populations along with assessment of possible modification by time outdoors, protective, and behavioral factors.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

Epidemiological evidence for a radiation effect on prostate cancer risk has been inconsistent and largely indicative of no or little effect. Here we studied prostate cancer incidence among males of the Life Span Study cohort of atomic bomb survivors in a follow-up from 1958 to 2009, eleven years more than was previously reported. During this period there were 851 incident cases of prostate cancer among 41,544 male subjects, doubling the total number of cases in the cohort. More than 50% of the cases were diagnosed among those who were less than 20 years of age at the time of the bombings and who were at, or near, the ages of heightened prostate cancer risks during the last decade of follow-up. In analyses of the radiation dose response using Poisson regression methods, we used a baseline-rate model that allowed for calendar period effects corresponding to the emergence of prostate-specific antigen screening in the general population as well as effects of attained age and birth cohort. The model also allowed for markedly increased baseline rates among the Adult Health Study participants between 2005 and 2009, a period during which a prostate-specific antigen test was included in Adult Health Study biennial health examinations. We found a significant linear dose response with an estimated excess relative risk (ERR) per Gy of 0.57 (95% CI: 0.21, 1.00, P = 0.001). An estimated 40 of the observed cases were attributed to radiation exposure from the bombings. There was a suggestion of the ERR decreasing with increasing age at exposure (P = 0.09). We found no indication of effects of smoking, alcohol consumption and body mass index on the baseline risk of prostate cancer. The observed dose response strengthens the evidence of a radiation effect on the risk of prostate cancer incidence in the atomic bomb survivors.

There is limited evidence concerning the association between radiation exposure and ovarian cancer. We evaluated radiation risk of ovarian cancer between 1958 and 2009 among 62,534 female atomic bomb survivors in the Life Span Study cohort, adding 11 years of follow-up from the previously reported study. Poisson regression methods were used to estimate excess relative risk per Gy (ERR/Gy) for total ovarian cancer and according to tumor type. We assessed the modifying effect of follow-up period and other factors on the radiation risk. We ascertained 288 first primary ovarian cancers including 77 type 1 epithelial cancers, 75 type 2 epithelial cancers, 66 epithelial cancers of undetermined type and 70 other cancers. Radiation dose was positively, although not significantly, associated with risk of total ovarian cancer [ERR/Gy = 0.30, 95% confidence interval (CI): -0.22 to 1.11]. There was a suggestion of heterogeneity in radiation effects (P = 0.08) for type 1 (ERR/Gy = -0.32, 95% CI

Importance Risk of sebaceous carcinoma (SC), a rare skin cancer associated with Muir-Torre syndrome, is elevated among solid organ transplant recipients (SOTRs). However, population studies evaluating this association and assessing survival for posttransplant cases are lacking, and further understanding of SC epidemiology in this immunosuppressed population could provide etiologic and clinical insights. Objective To assess SC incidence and patient survival after solid organ transplantation. Design, Setting, and Participants This cohort study, conducted from January 1, 1987, to December 31, 2017, used data from the Transplant Cancer Match Study, which links transplant and cancer registry data for 17 states and 1 metropolitan area in the United States. Altogether, these registries account for approximately 46% of all US transplants. Data on demographic and transplant characteristics as well as induction and initial maintenance immunosuppressive therapies were obtained from the transplant registry. Standardized incidence ratios (SIRs) comparing SC incidence among SOTRs to the general population were calculated. Incidence rate ratios (IRRs) comparing SC risk between SOTR subgroups were calculated using multivariate Poisson regression. Cox regression was used to compare overall survival between SC cases in SOTRs and other individuals. Main Outcomes and Measures Sebaceous carcinoma incidence and overall patient survival after transplantation compared with the general population. Results A total of 326 282 transplant procedures were performed for 301 075 patients (No. [%] age at transplant, 126 550 [38.8%] aged 0-44 years; 82 394 [25.3%] aged 45-54 years; 82 082 [25.5%] aged 55-64 years; 35 256 [10.8%] aged ≥65 years; 201 354 male patients [61.7%]; 202 557 White patients [62.1%]). A total of 102 SCs were diagnosed in 301 075 SOTRs, corresponding to a 25-fold increased incidence (SIR, 24.8; 95% CI, 20.2-30.1). Incidence was especially elevated among lung recipients (SIR, 47.7; 95% CI, 20.6-94.0) and after a posttransplant diagnosis of cutaneous squamous cell carcinoma (SIR, 104.0; 95% CI, 62.8-163.0). Among SOTRs, factors independently associated with SC risk included male sex (IRR, 2.46; 95% CI, 1.48-4.07; P

Author(s): Chirikova, Ekaterina; Cahoon, Elizabeth K; Rozhko, Alexander; Drozdovitch, Vladimir; Little, Mark P; McConnell, Robert J; Minenko, Victor; Veyalkin, Ilya; Yauseyenka, Vasilina; Hatch, Maureen; O’Kane, Patrick; Zablotska, Lydia B | Abstract: Abstract Thyroid enlargement can cause problems with swallowing or breathing and a decrease in accuracy of screening for thyroid cancer. Exposure to radioactive iodines after the 1986 Chernobyl accident is known to increase risk of thyroid cancer in those exposed at a young age, but little is known about its effects on thyroid volume, which could have important clinical implications. The objective of this study is to characterize the dose-response association between iodine-131 (131I) exposure and thyroid volume using data from a Belarusian-American cohort study of residents of Belarus exposed during childhood. Persons exposed to Chernobyl fallout in Belarus at the age of 18 years or younger had individual 131I doses to the thyroid gland estimated from direct thyroid activity measurements, radioecological and biokinetic models, and interview data on whereabouts and dietary habits collected during baseline screening in 1996-2001 (N=11,970; median age 21 years). Thyroid volume was estimated from thyroid ultrasound measurements during screening. Individuals with diagnoses of benign or malignant tumors of thyroid gland, any thyroid surgery or aplasia, and missing thyroid volume measurements were excluded (n=1,104). Dose and thyroid volume were log-transformed due to right-skewed distributions. We used a multivariable linear regression to estimate the dose-response association between 131I dose to the thyroid and thyroid volume accounting for confounding effects of sex, age at screening, and place of residence at the time of screening, a proxy for endemic iodine deficiency. To examine nonlinear effects, we added a quadratic term for the log-transformed dose. Among 10,866 participants, dose to thyroid ranged from 0.0005 to 39 gray (Gy) (median=0.3 Gy). In a linear regression model adjusted for confounders, log thyroid volume was best described by a linear-quadratic function of log dose (pl0.001 for log dose and log dose-squared coefficients). The largest effect was observed for doses 0.3-0.6 Gy (14%), then gradually decreased. Subjects with thyroid dose of 1 Gy had an average thyroid volume 13.6% (95% CI 8- 19.2%) higher compared to those with dose 1 mGy. Thyroid volume increased with age and was significantly higher for males compared to females and for those from Minsk city and area compared to other regions (both pl0.001). The adjusted R2-value was 30%, suggesting unaccounted factors that might better explain this association. This is the first study to assess the dose-response association between exposure to 131I and thyroid volume. Although statistically significant, the observed increase in thyroid volume with dose was small. Availability of measurements of iodine deficiency and dietary habits around the time of an accident in the future studies of nuclear accidents will be essential for understanding the mechanism of association between radiation dose and thyroid volume in young people.

The Trinity nuclear test, conducted in 1945, exposed residents of New Mexico to varying degrees of radioactive fallout. Companion papers in this issue have detailed the results of a dose reconstruction that has estimated tissue-specific radiation absorbed doses to residents of New Mexico from internal and external exposure to radioactive fallout in the first year following the Trinity test when more than 90% of the lifetime dose was received. Estimated radiation doses depended on geographic location, race/ethnicity, and age at the time of the test. Here, these doses were applied to sex- and organ-specific risk coefficients (without applying a dose and dose rate effectiveness factor to extrapolate from a population with high-dose/high-dose rates to those with low-dose/low-dose rates) and combined with baseline cancer rates and published life tables to estimate and project the range of radiation-related excess cancers among 581,489 potentially exposed residents of New Mexico. The total lifetime baseline number of all solid cancers [excluding thyroid and non-melanoma skin cancer (NMSC)] was estimated to be 183,000 from 1945 to 2034. Estimates of ranges of numbers of radiation-related excess cancers and corresponding attributable fractions from 1945 to 2034 incorporate various sources of uncertainty. We estimated 90% uncertainty intervals (UIs) of excess cancer cases to be 210 to 460 for all solid cancers (except thyroid cancer and NMSC), 80 to 530 for thyroid cancer, and up to 10 for leukemia (except chronic lymphocytic leukemia), with corresponding attributable fractions ranging from 0.12% to 0.25%, 3.6% to 20%, and 0.02% to 0.31%, respectively. In the counties of Guadalupe, Lincoln, San Miguel, Socorro, and Torrance, which received the greatest fallout deposition, the 90% UI for the projected fraction of thyroid cancers attributable to radioactive fallout from the Trinity test was estimated to be from 17% to 58%. Attributable fractions for cancer types varied by race/ethnicity, but 90% UIs overlapped for all race/ethnicity groups for each cancer grouping. Thus, most cancers that have occurred or will occur among persons exposed to Trinity fallout are likely to be cancers unrelated to exposures from the Trinity nuclear test. While these ranges are based on the most detailed dose reconstruction to date and rely largely on methods previously established through scientific committee agreement, challenges inherent in the dose estimation, and assumptions relied upon both in the risk projection and incorporation of uncertainty are important limitations in quantifying the range of radiation-related excess cancer risk.

Sebaceous carcinoma is an aggressive skin cancer with a 5-year overall survival rate of 78% for localized/regional disease and 50% for metastatic disease. The incidence of this cancer has been increasing in the United States for several decades, but the underlying reasons for this increase are unclear. In this article, we review the epidemiology and genetics of sebaceous carcinoma, including recent population data and tumor genomic analyses that provide new insights into underlying tumor biology. We further discuss emerging evidence of a possible viral etiology for this cancer. Finally, we review the clinical implications of recent advances in sebaceous carcinoma research for screening, prevention, and treatment.

This population-based cohort study examines associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas in recipients of lung transplants., Key Points Question What is the association between voriconazole, an antifungal used to treat aspergillosis infections, and the risk of keratinocyte carcinomas among recipients of lung transplants? Findings In a population-based cohort study of 9599 non-Hispanic white recipients of 9793 lung transplants in the United States (2007-2016) with linkage to pharmacy claims, increasing cumulative voriconazole exposure was associated with an increased risk of cutaneous squamous cell carcinoma. Meaning These findings suggest that physicians caring for lung transplant recipients at high risk for aggressive keratinocyte carcinomas should limit voriconazole exposure when possible and encourage skin protection behaviors and more frequent cancer screenings., Importance The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC). Objective To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients. Design, Setting, and Participants This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019. Exposures Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months. Main Outcomes and Measures Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication. Results Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41). Conclusions and Relevance In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.

Sebaceous carcinoma (SC) is an aggressive skin tumor. Although ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000–2016). There were 3503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio [per UVR quartile] = 1.15, 95% confidence interval = 1.11 to 1.19; two-sided P

Thyroid radiation doses were estimated for a cohort of 2,965 Belarusian persons who were exposed in utero and during early life to fallout from the Chernobyl nuclear power plant accident. Prenatal and postnatal doses to the thyroid due to intake of iodine-131 ((131)I), external irradiation from radionuclides deposited on the ground and ingestion of cesium isotopes ((134)Cs and (137)Cs) were calculated for all cohort members. Dose estimation was based on personal interviews with subjects’ mothers which collected data on subjects’ residential history, consumption by mothers during time of pregnancy and breastfeeding, as well as consumption by subjects after birth. Direct instrumental measurement of radioactivity in mothers and the study subjects, if available, were also used for calculation of doses. Intake of (131)I by mother was found to be the predominant pathway for thyroid exposure for the study subjects. The average thyroid dose due to all exposure pathways was estimated to be 137 milli-Gray (mGy) (median dose of 25 mGy, maximal dose of 14.8 Gy), including 130 mGy (median dose of 17 mGy, maximal dose of 14.8 Gy) from (131)I intake, 4.9 mGy (median dose of 3.0 mGy, maximal dose of 102 mGy) due to external irradiation, and 2.5 mGy (median dose of 1.7 mGy, maximal dose of 47 mGy) due to ingestion of (134, 137)Cs. The dose estimates will be used to evaluate the radiation-related risk of thyroid cancer and other thyroid diseases in this unique cohort.

In April 1986, the Chernobyl nuclear accident resulted in wide-scale contamination of Belarus with significantly elevated levels of radioiodine isotopes, mainly iodine-131 (131I), and long-lived radiocaesium isotopes, mainly caesium-137 (137Cs). Various groups of the population were affected by exposure to ionising radiation, including pregnant women and their foetuses. This paper describes the methods and results related to the establishment of a cohort of 2965 Belarusian people exposed in utero due to Chernobyl fallout. The cohort consists of individuals whose mothers resided in the most radioactively contaminated areas in Belarus at the time of the accident. Prenatal and postnatal doses to the thyroid due to intake of 131I, external irradiation and ingestion of radiocaesium isotopes were estimated for all cohort members. Ongoing research on this unique cohort will provide important information on adverse health effects following prenatal and postnatal exposure to radioiodine and radiocaesium isotopes, for which available epidemiological data are scant.

BACKGROUND: Few well-established factors are associated with risk of amyotrophic lateral sclerosis (ALS). We comprehensively evaluate prescription drugs use in administrative health claims from U.S. Medicare beneficiaries in relation to ALS risk to generate hypotheses for further research. METHODS: This is a population-based case–control study of 10,450 U.S. Medicare participants (ages 66–89 years) diagnosed with ALS, based on Medicare Parts A and B fee-for-service claims, between 1 January 2008, and 31 December 2014, and 104,500 controls (1:10 ratio) frequency-matched on age, sex, and selection year. Odds ratios (ORs) for the ALS association with 685 prescription drugs were estimated using logistic regression models for both a one- and three-year lag period. Covariates included demographic characteristics and key comorbidities, among other factors. Prescription drug use was based on Medicare Part D claims. We adjusted for multiple comparisons using a Bonferroni correction. Additional a priori analyses of sex hormone drugs were also undertaken. RESULTS: In the large drug screen, we found 10 drugs significantly associated with lower ALS risk after the multiple-testing correction in a one-year and three-year lag analysis. These included several drugs for hypertension, diabetes, and cardiovascular disease. In a separate a priori inquiry of sex hormone drugs, tamoxifen was related to lower ALS risk, and testosterone to a higher risk in women. CONCLUSIONS: These associations warrant replication in databases that include information on the severity and duration of medical conditions underlying drug use, and drug use over a longer portion of individuals’ lifespans, to further help evaluate confounding by indication.

There are well-documented associations of glaucoma with high-dose radiation exposure, but only a single study suggesting risk of glaucoma, and less conclusively macular degeneration, associated with moderate-dose exposure. We assessed risk of glaucoma and macular degeneration associated with occupational eye-lens radiation dose, using participants from the US Radiologic Technologists Study, followed from the date of surveys in 1994–1998, 2003–2005 to the earliest of diagnosis of glaucoma or macular degeneration, cancer other than non-melanoma skin cancer, or date of last survey (2012–2014). We excluded those with baseline disease or previous radiotherapy history. Cox proportional hazards models with age as timescale were used. There were 1631 cases of newly self-reported doctor-diagnosed cases of glaucoma and 1331 of macular degeneration among 69,568 and 69,969 eligible subjects, respectively. Estimated mean cumulative eye-lens absorbed dose from occupational radiation exposures was 0.058 Gy. The excess relative risk/Gy for glaucoma was −0.57 (95% CI −1.46, 0.60, p = 0.304) and for macular degeneration was 0.32 (95% CI −0.32, 1.27, p = 0.381), suggesting that there is no appreciable risk for either endpoint associated with low-dose and low dose-rate radiation exposure. Since this is the first examination of glaucoma and macular degeneration associated with low-dose radiation exposure, this result needs to be replicated in other low-dose studies.