Kiyohiko Mabuchi

Solid Cancer Incidence in Atomic Bomb Survivors: 1958–1998

Abstract Preston, D. L., Ron, E., Tokuoka, S., Funamoto, S., Nishi, N., Soda, M., Mabuchi, K. and Kodama, K. Solid Cancer Incidence in Atomic Bomb Survivors: 1958–1998. Radiat. Res. 168, 1–64 (2007). This is the second general report on radiation effects on the incidence of solid cancers (cancers other than malignancies of the blood or blood-forming organs) among members of the Life Span Study (LSS) cohort of Hiroshima and Nagasaki atomic bomb survivors. The analyses were based on 17,448 first primary cancers (including non-melanoma skin cancer) diagnosed from 1958 through 1998 among 105,427 cohort members with individual dose estimates who were alive and not known to have had cancer prior to 1958. Radiation-associated relative risks and excess rates were considered for all solid cancers as a group, for 19 specific cancer sites or groups of sites, and for five histology groups. Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, how these risks vary with gender, age at exposure, and attained age, and the evidence for inter-site variation in the levels and patterns of the excess risk. For all solid cancers as a group, it was estimated that about 850 (about 11%) of the cases among cohort members with colon doses in excess of 0.005 Gy were associated with atomic bomb radiation exposure. The data were consistent with a linear dose response over the 0- to 2-Gy range, while there was some flattening of the dose response at higher doses. Furthermore, there is a statistically significant dose response when analyses were limited to cohort members with doses of 0.15 Gy or less. The excess risks for all solid cancers as a group and many individual sites exhibit significant variation with gender, attained age, and age at exposure. It was estimated that, at age 70 after exposure at age 30, solid cancer rates increase by about 35% per Gy (90% CI 28%; 43%) for men and 58% per Gy (43%; 69%) for women. For all solid cancers as a group, the excess relative risk (ERR per Gy) decreases by about 17% per decade increase in age at exposure (90% CI 7%; 25%) after allowing for attained-age effects, while the ERR decreased in proportion to attained age to the power 1.65 (90% CI 2.1; 1.2) after allowing for age at exposure. Despite the decline in the ERR with attained age, excess absolute rates appeared to increase throughout the study period, providing further evidence that radiation-associated increases in cancer rates persist throughout life regardless of age at exposure. For all solid cancers as a group, women had somewhat higher excess absolute rates than men (F:M ratio 1.4; 90% CI 1.1; 1.8), but this difference disappears when the analysis was restricted to non-gender-specific cancers. Significant radiation-associated increases in risk were seen for most sites, including oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system and thyroid. Although there was no indication of a statistically significant dose response for cancers of the pancreas, prostate and kidney, the excess relative risks for these sites were also consistent with that for all solid cancers as a group. Dose–response estimates for cancers of the rectum, gallbladder and uterus were not statistically significant, and there were suggestions that the risks for these sites may be lower than those for all solid cancers combined. However, there was emerging evidence from the present data that exposure as a child may increase risks of cancer of the body of the uterus. Elevated risks were seen for all of the five broadly classified histological groups considered, including squamous cell carcinoma, adenocarcinoma, other epithelial cancers, sarcomas and other non-epithelial cancers. Although the data were limited, there was a significant radiation-associated increase in the risk of cancer occurring in adolescence and young adulthood. In view of the persisting increase in solid cancer risks, the LSS should continue to provide important new information on radiation exposure and solid cancer risks for at least another 15 to 20 years.

Radiation-Related Heart Disease: Current Knowledge and Future Prospects

INTRODUCTIONIt has been recognized since the 1960s that the heart may bedamaged by substantial doses of radiation [>30 Gray (Gy)],such as used to occur during mantle radiotherapy for Hodg-kin lymphoma. During the last few years, however, evidencethat radiation-related heart disease (RRHD) can occur fol-lowing doses below 20 Gy has emerged from several inde-pendent sources. Those sources include studies of breastcancer patients who received mean cardiac doses of 3 to 17Gy when given radiotherapy following surgery and studiesof survivors of the atomic bombings of Japan who receiveddoses of up to 4 Gy.At doses above 30 Gy, an increased risk of RRHD can be-comes apparent within a year or two of exposure, and the riskincreases with higher radiotherapy dose, younger age at irra-diation, and the presence of conventional risk factors. Atlower doses, the typical latency period is much longer andis often more than a decade. The nature and magnitude ofthe risk following lower doses is not well characterized,and it is not yet clear whether there is a threshold dose belowwhich there is no risk.The evidence regarding RRHD comes from several differ-ent disciplines. The present review brings together informa-tion from pathology, radiobiology, cardiology, radiationoncology, and epidemiology; it summarizes current knowl-edge, identifies gaps in that knowledge, and outlines somepotential strategies for filling them.CURRENT KNOWLEDGEPathologyThe pathological expressions of RRHD documented fol-lowing therapeutic irradiation can be broadly reduced tofour conditions: pericarditis, pericardial fibrosis, diffusemyocardial fibrosis, and coronary artery disease (CAD)(1, 2). Radiation may also cause valvular disease, althoughtheevidence for this isnotasstrong.None of these conditionsis specific to radiation.Radiation-related pericarditis is characterized by an exu-date of a variable amount of protein-rich fluid within thepericardial sac (pericardial effusion). Rapid accumulationof this fluid can, in rare cases, cause potentially fatal cardiactamponade. Almost invariably, fibrin accumulates on the

A pooled analysis of case–control studies of thyroid cancer: cigarette smoking and consumption of alcohol, coffee, and tea

Objective: To analyze the role of smoking, alcohol, coffee and tea in relation to thyroid cancer, we conducted a pooled analysis of 14 case–control studies conducted in the United States, Europe, and Asia. Methods: The sample consisted of 2725 thyroid cancer cases (2247 females, 478 males) and 4776 controls (3699 females, 1077 males). Conditional logistic regression with stratification on study, age at diagnosis, and gender was used to compute odds ratios and 95% confidence intervals. Results: Thyroid cancer risk was reduced in persons who had ever smoked. The relationship was more pronounced in current smokers (OR = 0.6, 95% CI = 0.6–0.7) than former smokers (OR = 0.9, 95% CI = 0.8–1.1). There were significant trends of reduced risk with greater duration and frequency of smoking. For consumption of wine and beer, there was a significant trend of decreasing thyroid cancer risk (p = 0.02) that was not maintained after adjustment for current smoking (p = 0.12). Thyroid cancer risk was not associated with consumption of coffee or tea. These findings were consistent in both gender-specific and histology-specific (papillary and follicular) analyses. Conclusions: Pooled analyses of these geographically diverse case–control data indicate a reduced thyroid cancer risk associated with current smoking. A reduced risk associated with alcohol was eliminated after adjustment for smoking, and caffeinated beverages did not alter thyroid cancer risk.

ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer.

In their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian‐American cohort that was exposed to iodine‐131 (131I) from the Chernobyl accident, the authors identified RET/PTC rearrangements and other driver mutations in 60% of tumors.

Dose response and temporal patterns of radiation-associated solid cancer risks.

Abstract— Findings of the Life Span Study (LSS) cohort of atomic-bomb survivors are a primary source for quantitative risk estimates that underlie radiation protection. Because of the size and length of follow-up, the LSS provides considerable information on both the nature of the dose response and on how radiation-associated excess risks vary with age, age at exposure, sex, and other factors. Our current analyses extend the mortality follow-up by 7 y (through 1997) and add 8 y (through 1995) to the incidence follow-up. During the follow-up periods there have been a total of about 9,300 solid cancer deaths and almost 12,200 incident cases. As outlined in this presentation, while discussing issues related to the shape of the dose response and low dose risks in some detail, the new reports consider temporal patterns in greater detail than has been done previously. As we have reported, the LSS solid cancer dose response is well described by simple linear dose response over the 0 to 2 Sv range (with some leveling off at higher estimated doses). This remains the case with the extended follow-up. Although LSS is often referred to as a high dose study, about 75% of the 50,000 cohort members with doses in excess of 5 mSv have dose estimates in a range of direct interest for radiation protection (0–200 mSv). Analyses of data limited to this low dose range provide direct evidence of a significant solid cancer dose response with a risk per unit dose that is consistent with that seen for the full dose range. Previous LSS reports have focused on descriptions of the solid cancer excess risks in which the excess relative risk varies with age at exposure and sex. In addition to the age at exposure effects, our current analyses suggest excess relative risks also vary with age (at death or diagnosis). Excess relative risks are higher for those exposed earlier in life, with attained age-specific risks changing by about 20% per decade, but tend to decrease with increasing attained age, roughly in proportion to (1/attained-age)1.5, for any age at exposure. Despite the decreasing relative risk, excess rates have increased rapidly throughout the study period with some indication, especially for the incidence data, that attained-age-specific rates are higher for those exposed at younger ages. Simple comparisons of site-specific excess risks are used to illustrate how the interpretation of age-at-exposure effects on excess relative risks or excess rates is complicated by changes in baseline rates with birth cohort or time period.

RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics†

Childhood exposure to iodine‐131 from the 1986 nuclear accident in Chernobyl, Ukraine, led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited.

Clinical and epidemiologic characteristics of first primary tumors of the central nervous system and related organs among atomic bomb survivors in Hiroshima and Nagasaki, 1958–1995†

Analysis conducted in the Life Span Study (LSS) cohort of atomic bomb survivors in Hiroshima and Nagasaki found a significant dose‐related excess of tumors of the central nervous system (CNS) and the pituitary gland. The objective of the current study was to evaluate clinical and epidemiologic characteristics of first primary tumors of the CNS and the pituitary gland in this cohort and to compare them with characteristics among other populations.

Squamous cell and basal cell carcinoma of the skin in relation to radiation therapy and potential modification of risk by sun exposure.

Background: Epidemiologic studies consistently find enhanced risk of basal cell carcinoma of the skin among individuals exposed to ionizing radiation, but it is unclear whether the radiation effect occurs for squamous cell carcinoma. It is also not known whether subgroups of individuals are at greater risk, eg, those with radiation sensitivity or high ultraviolet radiation exposure. Methods: We analyzed data from a case-control study of keratinocyte cancers in New Hampshire. Incident cases diagnosed in 1993–1995 and 1997–2000 were identified through a state-wide skin cancer surveillance system, and controls were identified through the Department of Transportation and Center for Medicare and Medicaid Service Files (n = 1121 basal cell carcinoma cases, 854 squamous cell carcinoma cases, and 1049 controls). Results: We found an association between history of radiation treatment and basal cell carcinoma. The association was especially strong for basal cell carcinomas arising within the radiation treatment field (odds ratio = 2.6; 95% confidence interval = 1.5–4.3), and among those treated with radiation therapy before age 20 (3.4; 1.8–6.4), those whose basal cell carcinomas occurred 40 or more years after radiation treatment (3.2; 1.8–5.8), and those treated with radiation for acne (11; 2.7–49). Similar age and time patterns of risk were observed for squamous cell carcinoma, although generally with smaller odds ratios. For basal cell carcinoma, early exposure to radiation treatment was a risk factor largely among those without a history of severe sunburns, whereas for squamous cell carcinoma, radiation treatment was a risk factor primarily among those with a sun-sensitive skin type (ie, a tendency to sunburn). Conclusions: Radiation treatment, particularly if experienced before age 20, seems to increase the long-term risk of both basal and squamous cell carcinomas of the skin. These risks may differ by sun exposure or host response to sunlight exposure.

Incidence of haematopoietic malignancies in US radiologic technologists

Background: There are limited data on risks of haematopoietic malignancies associated with protracted low-to-moderate dose radiation. Aims: To contribute the first incidence risk estimates for haematopoietic malignancies in relation to work history, procedures, practices, and protective measures in a large population of mostly female medical radiation workers. Methods: The investigators followed up 71 894 (77.9% female) US radiologic technologists, first certified during 1926–80, from completion of a baseline questionnaire (1983–89) to return of a second questionnaire (1994–98), diagnosis of a first cancer, death, or 31 August 1998 (731 306 person-years), whichever occurred first. Cox proportional hazards regression was used to compute risks. Results: Relative risks (RR) for leukaemias other than chronic lymphocytic leukaemia (non-CLL, 41 cases) were increased among technologists working five or more years before 1950 (RRu200a=u200a6.6, 95% CI 1.0 to 41.9, based on seven cases) or holding patients 50 or more times for x ray examination (RRu200a=u200a2.6, 95% CI 1.3 to 5.4). Risks of non-CLL leukaemias were not significantly related to the number of years subjects worked in more recent periods, the year or age first worked, the total years worked, specific procedures or equipment used, or personal radiotherapy. Working as a radiologic technologist was not significantly linked with risk of multiple myeloma (28 cases), non-Hodgkin’s lymphoma (118 cases), Hodgkin’s lymphoma (31 cases), or chronic lymphocytic leukaemia (23 cases). Conclusion: Similar to results for single acute dose and fractionated high dose radiation exposures, there was increased risk for non-CLL leukaemias decades after initial protracted radiation exposure that likely cumulated to low-to-moderate doses.

Retrospective Biodosimetry among United States Radiologic Technologists

Abstract Parveen, B., Preston, D. L., Doody, M. M., Hauptmann, M., Kampa, D., Alexander, B. H., Petibone, D., Simon, S. L., Weinstock, R. M., Bouville, A., Yong, L. C., Freedman, D. M., Mabuchi, K., Linet, M. S., Edwards, A. A., Tucker, J. D. and Sigurdson, A. J. Retrospective Biodosimetry among United States Radiologic Technologists. Radiat. Res. 167, 727–734 (2007). Measurement of chromosome translocations in peripheral blood lymphocytes has been used to quantify prior exposure to ionizing radiation, including for workers exposed to low, chronic doses. We assessed translocation frequencies in a subset of U.S. radiologic technologists to substantiate ionizing radiation dose estimates developed for 110,418 technologists who worked between 1916 and 1984. From 3,441 cohort members known to have begun working before 1950, we selected a sample of 152, stratified by estimated cumulative dose, oversampling from higher-dose categories and excluding persons with a prior cancer diagnosis, a personal or family history of chromosomal instability disorders, or a current history of smoking. Estimates of film-badge dose ranged from less than 10 cSv to more than 30 cSv. Blood samples, obtained in 2004, were analyzed by fluorescence in situ hybridization (FISH) whole chromosome painting by simultaneously labeling chromosomes 1, 2 and 4 in red and 3, 5 and 6 in green. Translocations were scored in 1800 well-spread metaphase cells and expressed per 100 cell equivalents (CE) per person. Linear Poisson regression models with allowance for overdispersion were used to assess the relationship between estimated occupational red bone marrow absorbed dose in cGy and translocation frequency, adjusted for age, gender and estimated red bone marrow absorbed dose score from personal diagnostic procedures. We observed 0.09 excess translocations per 100 CE per cGy red bone marrow dose (95% CI: −0.01, 0.2; P = 0.07), which is similar to the expected estimate based on previous cytogenetic studies (0.05 excess translocations per 100 CE per cGy). Despite uncertainty in the estimates of occupational red bone marrow absorbed doses, we found good general agreement between the doses and translocation frequencies, lending support to the credibility of the dose assessment for this large cohort of U.S. radiologic technologists.