Nagasaki Atomic Bomb Survivors Research Articles

Radiation-induced hematopoietic disorders

Hematopoietic stem cells are one of the most sensitive tissues to radiation exposure. Epidemiological studies of atomic bomb survivors in Nagasaki and Hiroshima revealed a radiation dose-response relationship for acute myeloid leukemia, acute lymphoblastic leukemia, and Chronic myelogenous leukemia. In our study of myelodysplastic syndrome (MDS) in Nagasaki, the relative risk was higher in the proximal-exposed group. Additionally, the frequency of chromosome abnormalities associated with poor prognosis was higher in the proximal-exposed group than in the non-exposed group. However, no association between the exposure distance and prognosis was observed. We used next-generation sequencing to analyze the role of genetic abnormalities in the development of MDS. The results indicated that genetic mutations related to DNA methylation pathways, which are frequently observed in de novo MDS, were considerably less frequent in the proximal-exposed than in the distal-exposed group. These results suggest that the pathogenesis of MDS in atomic bomb survivors may be different from that of treatment-related and de novo MDS.

Relationship Between Radiation Exposure and Incident Atrial Fibrillation Among Atomic Bomb Survivors.

Background: Atrial fibrillation (AF) is a common arrhythmia. Although radiation exposure is associated with an elevated risk of cardiovascular disease, the effects of radiation on arrhythmia, especially AF, are unclear. We evaluated the relationship between radiation and AF in a cohort of atomic bomb survivors.Methods and Results: From a baseline enrollment period (1967–1969) to 2009, 7,379 Hiroshima and Nagasaki atomic bomb survivors (mean baseline age 50.6 years, 65.8% women, 72.9% from Hiroshima) without AF and who had been exposed to estimated radiation doses between 0 and 3.614 Gy were followed-up once every 2 years. AF was identified by 12-lead electrocardiograms and medical records. Treating age as the time scale, AF incidence was modeled with Cox proportional hazards models adjusting for demographics, AF risk factors, and radiation. We modeled radiation as both a continuous variable and categorized according to radiation dose (Control [<0.005 Gy] and 5 equal-sized groups based on radiation dose quintiles in the cohort). Over 4 decades of follow-up, we identified 276 AF cases in 176,687 person-years, for an incidence rate of 1.56 per 1,000 person-years. After adjusting for sex and city, neither categorized, linear, nor linear-quadratic models showed substantive evidence of radiation effects. Similar results were obtained after adjusting for AF risk factors.Conclusions: There were no clear positive associations between radiation dose and AF risk, rather null or non-significant inverse associations.

Chromosomal Analysis of Myelodysplastic Syndromes Among Atomic Bomb Survivors in Nagasaki

[Background] Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that develop de novo and also secondary to chemotherapy and / or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors in Nagasaki, Japan with significant correlation to radiation dose (Iwanaga et al. JCO 2011). The latest our study showed that MDS among proximally radiated survivors to the hypocenter had higher frequency of chromosomal aberrations, especially those related to poor prognosis such as complex karyotypes, however, survival and leukemia transformation did not show statistical difference by the distance from hypocenter (Matsuo et al. Caner Sci 2016).[Aim] In this study, we investigated chromosomal abnormalities of MDS among survivors to address (1) whether specific chromosomal aberration exists, and (2) why karyotype did not have strong impact on the survival and leukemia transformation.[Methods] We collected clinical information of MDS patients diagnosed from 1985 to 2013 registered in the Nagasaki-City MDS database. This database includes information from five hospitals in Nagasaki city. Patients were diagnosed according to the French-American-British (FAB) classification criteria. Patient risk was evaluated using the International Prognostic Scoring System (IPSS), and the revised IPSS (IPSS-R).[Results and Discussion] There were 133 MDS patients among A-bomb survivors, and 269 were unexposed. Among survivors, the number of cases according to distance from the hypocenter was 29 in the <1.5km group (Group I), 35 in the 1.5-2.99 km group (Group II) and 69 in the ≥3 km group (Group III). Abnormal karyotype frequency was significantly higher with more very poor karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocenter compared with unexposed cases. However, there was no difference in prognosis between exposed and unexposed cases. In the Group I, chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases (P=0.007, 0.01, and 0.001, respectively). These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy-related MDS. Detailed molecular study is warranted. DisclosuresMiyazaki:Nippon Shinyaku: Honoraria. Haase:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Association of human T-cell leukemia virus type 1 with prevalent rheumatoid arthritis among atomic bomb survivors: A cross-sectional study.

Previous studies have suggested that human T-cell leukemia virus type 1 (HTLV-1) might act as a pathogen in rheumatoid arthritis (RA), but epidemiological evidence of an association is scarce. We measured anti-HTLV-1 antibodies among Nagasaki atomic bomb survivors to determine whether HTLV-1 is related to RA and whether radiation exposure is associated with HTLV-1 and RA prevalence.This is a cross-sectional study among atomic bomb survivors who participated in biennial health examinations from 2006 to 2010. Serum levels of anti-HTLV-1 antibodies were measured using a chemiluminescent enzyme immunoassay and confirmed by Western blotting. Association between HTLV-1 and RA was analyzed by a logistic regression model.Of 2091 participants (women 61.5%; median age, 73 years), 215 (10.3%) had anti-HTLV-1 antibodies. HTLV-1 prevalence was higher among women (13.1% vs 5.8%; P < .001). Twenty-two participants (1.1%) were diagnosed with RA. HTLV-1 prevalence among RA participants was significantly higher than that among non-RA participants (27.3% vs 10.1%; P = .020). After adjustment for age, sex, and hepatitis C virus infection, HTLV-1 was significantly associated with prevalent RA (odds ratio, 2.89; 95% confidence interval, 1.06, 7.03). There was no association between radiation dose and either the prevalence of HTLV-1 or RA.This study, among a well-defined group of atomic bomb survivors, suggests that HTLV-1 is associated with RA.

In Memoriam: Mortimer L. Mendelsohn: (1 December, 1925-8 January, 2020).

In Memoriam: Mortimer L. Mendelsohn: (1 December, 1925-8 January, 2020).

Mary, Mothers, Lament, and Feminist Theology: The Dead Non-War Heroes of Nagasaki

In this essay, McClelland introduces some reflections of Nagasaki atomic bomb survivors about the loss of their mothers and some of their experiences of motherhood in the aftermath, utilizing a feminist lens to analyze the effects of the bomb. Japanese feminist Chizuko Ueno has written that those women who died might be signified as "non-war heroes" in an East Asian context where the "war-heroes" are traditionally male. The author draws on Kwok Pui-Lan's postcolonial theology of religious difference and Shelly Rambo's mixed terrain of remembering to discuss how and to what degree the violence and rupture of the atomic bombing is contested in the memory of the survivors. McClelland describes how the narratives of the Catholic survivors contain a common thread about Mary, whom they implicitly perceive as an expression of a "female face of God." The interviews considered here were collected between 2014 and 2016 as part of a larger historical project that employed a theological lens in describing the interpretation of Catholic memory of the atomic bombing of Nagasaki.

Mathematical modelling the pathway of genomic instability in lung cancer

Genomic instability plays a significant role in lung cancer. Although substantial research has been conducted using both clinical and theoretical studies, it is still a hotly debated issue to whether genomic instability is necessary or whether genomic instability precedes oncogenes activation and tumor suppressor genes inactivation for lung cancer. In response to this issue, we come up with a mathematical model incorporating effects of genomic instability to investigate the genomic instability pathway of human lung cancer. The presented model are applied to match the incidence rate data of lung cancer from the Life Span Study cohort of the atomic bomb survivors in Nagasaki and Hiroshima and the Surveillance Epidemiology and End Results registry in the United States. Model results suggest that genomic instability is necessary in the tumorigenesis of lung cancer, and genomic instability has no significant impact on the net proliferation rate of cells by statistical criteria. By comparing the results of the LSS data to those of the SEER data, we conclude that the genomic instability pathway exhibits a sensitivity to radiation exposure, more intensive in male patients.

Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki

Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. Our previous analyses demonstrated that MDS among these survivors had a significantly higher frequency of complex karyotypes and structural alterations of chromosomes 3, 8, and 11. However, there was no difference in the median survival time between MDS among survivors compared with those of de novo origin. This suggested that a different pathophysiology may underlie the causative genetic aberrations for those among survivors. In this study, we performed genome analyses of MDS among survivors and found that proximally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM were significantly more frequent in proximally exposed group with mutations identified on the remaining allele in 2 out of 5 cases. TP53, which is frequently mutated in therapy-related myeloid neoplasms, was equally affected between proximally and distally exposed patients. These results suggested that the genetic aberration profiles in MDS among atomic bomb survivors differed from those in therapy-related and de novo origin. Considering the role of ATM in DNA damage response after radiation exposure, further studies are warranted to elucidate how 11q deletion and aberrations of ATM contribute to the pathogenesis of MDS after radiation exposure.

EPR19-070: Incidence Pattern of Malignant Lymphoma by Cell-Lineage/Cell-Maturity Status in Nagasaki, Japan, 1985–2012: Preliminary Results

Background: Malignant lymphoma (ML) is a heterogeneous neoplasm with a wide range of etiological factors, pathological patterns, incidence rates, and outcomes. Most epidemiological studies have reported the incidence pattern of ML by simply dividing into 2 groups, Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). However, differences in the incidence pattern by cell-lineage or by cell-maturity have been rarely evaluated. The aim of this study was to characterize the incidence pattern of ML by cell-lineage and cell-maturity in Japanese population. Methods: This is a descriptive study based on regional cancer registry data. We obtained a dataset of anonymized 12,645 cases with ICD-O histology codes of ML diagnosed 1960–2012 from the Nagasaki Prefectural Cancer Registry. From those, we excluded 1,477 records because of codes other than ML, diagnosed before 1985, and possible relapse records of identical cases. Records based on ICD-O-1 or ICD-O-2 were substituted by the corresponding ICD-O-3 code. We also treated patients having multiple types of MLs at same diagnosis date as a single case of “composite/discordant lymphoma,” and patients having multiple types of MLs at different diagnosis date as a single case based on the first lymphoma. We finally confirmed 11,118 patients of ML that occurred in 1985–2012. The overall age-adjusted incidence rate (per 100,000 population) during 1985–2012 was already reported to be 20.5 for men and 12.9 for women. Then we divided them into the following cell-lineage/maturity groups: precursor B (B1), mature B (B2), other B (B3), precursor T (T1), mature T/NK (T2), undetermined cell-lineage NHL (U), HL (H), and other lymphomas (O). Results: The median age at diagnosis of all patients was 69.7 years (interquartile range, 59.4–78.0 years) and male sex were 5,980 (53.8%). The frequency of B-cell lineage, T/NK-cell lineage, and Hodgkin lymphoma were 5,196 (46.7%), 3,257 (29.3%), and 209 (1.9%), respectively, with a significant sex difference (P&lt;.0001). For B-cell maturity, B2 was predominant (84.8%), followed by B3 (14.4%) with a significant sex difference (P&lt;.0001). In T-cell, T2 was predominant (99.4%). Conclusion: This preliminary analysis suggests a significant sex difference in the cell-lineage and cell-maturity of ML. Additional analysis to elucidate whether there are any differences in the incidence pattern by cell-lineage and by cell-maturity of ML between general population and Nagasaki atomic bomb survivors are underway.

Genomic Analysis of Myelodysplastic Syndromes Among Nagasaki Atomic Bomb Survivors

Exposure to ionizing radiation is a well-established risk of cancer development. Atomic bomb (A-bomb) survivors were exposed to A-bomb radiation, then developed acute myeloid leukemia (AML), acute lymphoblastic leukemia, and chronic myeloid leukemia with the highest incidence around five to ten years after the bombing. On the other hand, the risk of myelodysplastic syndromes (MDS) were significantly high among the survivors even after 40 to 60 years from the bombing (Iwanaga et al. J Clin Oncol 2011), indicating a long-lasting influence of A-bomb radiation on human hematopoiesis. In general, genetic mutations are found in almost all MDS, however, the landscape of genetic alterations in MDS among A-bomb survivors remains to be elucidated.To study the role of A-bomb radiation on the pathogenesis of MDS and related conditions, we analyzed 32 patients with MDS and 3 cases diagnosed as idiopathic cytopenia of undetermined significance (ICUS) among A-bomb survivors using next generation sequencing technologies and SNP array karyotyping. Patients were categorized into two groups by the exposure distance; proximally exposed group (PE-group, 18 patients, < 2.7 km from the hypocenter) and distally exposed group (DE-group, 17 patients, directly exposed in 2.7-10 km, or those who entered the bombing area [inside of 2 km from the hypocenter] within two weeks after the bombing [no acute radiation syndromes]). Median exposure distance was 1.1 and 3.4 km in PE- and DE-group, respectively (P < .001). There was no significant difference in sex, subtype of MDS, and ages at bombing and the diagnosis, between the two groups, whereas frequencies of abnormal karyotype (78% vs. 59%, P = .29) and complex karyotype (33% vs. 12%, P = .23) were higher in PE-group without statistical significance.Whole genome sequencing of three patients in PE-group revealed that most frequent nucleotide substitution was cytosine-to-thymine (C to T), which is a hallmark of age-related mutational changes. Using whole exome sequencing and 154 genes-targeted capture sequencing (T-S), we identified significant differences in mutated genes between the two groups. No patients of PE-group had mutations in TET2 although it was most frequently affected in DE-group (29% [5 out of 17 patients], P = .019), and the frequency of gene mutations in DNA methylation pathway was 5.6% (1 out of 18 patients) and 41% (7 out of 17) in PE- and DE-group, respectively (P = .018). TP53 and the genes coding RNA splicing factors (SFs) were mutated equally in both groups (TP53, 11% and 12% [P = 1]; SFs, 33% and 35% [P = 1] in PE- and DE-group, respectively).Copy number alterations were analyzed using SNP-array and T-S data. We found that loss of long arm of chromosome 11 (11q loss) was significantly accumulated in PE-group (33% [6 out of 18 patients] vs. 0%, P = .019), whereas loss of chromosome 5q and chromosome 7 were almost equally identified in both groups (chromosome 5q, 22% and 12% [P = .66]; chromosome 7, 22% and 29% [P = .71] in PE- and DE-group, respectively). On the commonly affected region of 11q in this study, there were three genes recurrently altered in MDS and AML; ATM, KMT2A, and CBL. Copy number loss was found in these three genes, and the alteration of ATM was significantly increased in PE-group (28% [5 out of 18 patients] vs. 0%, P = .046) than DE-group. The remaining allele of ATM also possessed a mutation in two out of five patients in PE-group, indicating a deleterious effect on the function of ATM.In summary, we revealed two unique genetic features in MDS among A-bomb survivors who were proximally exposed to A-bomb radiation; significantly less frequent mutations in DNA methylation pathway and significant accumulation of 11q loss, suggesting a long-lasting effect of ionizing radiation and an important role of 11q loss in the initiation of MDS. DisclosuresNo relevant conflicts of interest to declare.

THYROID DISEASES AMONG ATOMIC BOMB SURVIVORS

Systematic epidemiological studies of Hiroshima and Nagasaki atomic bomb survivors have made substantial contributions to the understanding of radiation effects on human health. A recent study of atomic bomb survivors reported that an increased risk of thyroid cancer associated with childhood exposure might have persisted for more than 50 years after exposure. In analyses of non-cancer thyroid diseases, several cross-sectional studies, including the latest study focusing on survivors exposed in childhood, suggested that the risk of thyroid nodules increased, while risks of thyroid dysfunction and autoimmunity were not apparent several decades after radiation exposure. However, careful interpretations are needed because only limited data from cross-sectional studies are available. Further longitudinal studies are necessary to improve our understanding of the effect of radiation on the thyroid and its function.

Autoradiographic analysis of internal plutonium radiation exposure in Nagasaki atomic bomb victims

BackgroundRadiation doses received by Hiroshima and Nagasaki atomic bomb survivors has been evaluated from data related only to external exposure because there was no reliable evidence for internal exposure in atomic bomb victims. However, we assumed that the contribution of internal exposure cannot be ruled out. MethodsAutoradiography was carried out with the 70-year old paraffin-embedded specimens taken from Nagasaki atomic bomb victims who died within 5 months after the bombing. After exposure to photo emulsion for 6 months alpha-tracks were revealed in the specimens. We confirmed the alpha-tracks were emitted from deposited plutonium (Pu) in reference to the track length of the 8.787 MeV alpha-particle of thorium series from Polonium-212. Radioactivity concentration of Pu was obtained by counting alpha-tracks. The absorbed dose of each cell nucleus penetrated by an alpha-particle was estimated by calculating the absorbed energy from the particle. ResultsUsing old paraffin embedded sections processed about 70 years ago, we demonstrated for the first time that conditions in the aftermath of the bombing led to internal exposure to alpha-particles emitted from Pu, the fissile material of the Nagasaki atomic bomb. Dose rate of internal exposure was higher in the victims exposed outdoors than those indoors. Radioactivity concentration was relatively uniform among organs examined in a victim. ConclusionPu was deposited in the bodies of the Nagasaki A-bomb victims presumably via various routes. Organ dose from Pu of the Nagasaki A-bomb victims studied was during their surviving period, which is lower compared with external exposure. However, the impact to the individual cell nucleus by a single alpha-particle might not be negligible, It would be meaningful; to analyze the relationship of the impact of internal exposure at the cellular level and organ dose. The 70-year old pathological specimens utilized in our study are an invaluable source for understanding internal radiation exposure and are crucial in elucidating experimentally unreproducible phenomena.

Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki

The myelodysplastic syndromes (MDS) are clonal haematopoietic disorders that develop de novo and also secondary to chemotherapy and/or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors with significant correlation to radiation dose; however, the clinical characteristics of these survivors have not been well analysed. In this study, we investigated chromosomal abnormalities of MDS among survivors. The frequency of abnormal karyotypes was significantly higher, with more very poor risk karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocentre compared with unexposed cases. However, abnormal karyotype frequency did not reflect the prognosis of exposed cases with respect to distance from the hypocentre. In addition, there was no difference in prognosis between exposed and unexposed cases. Among proximally exposed cases (<1·5km from the hypocentre), chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases. These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy-related MDS. Detailed molecular study is warranted.

Cancer mortality in residents of the terrain-shielded area exposed to fallout from the Nagasaki atomic bombing.

The health effects of radiation exposure from the atomic bomb fallout remain unclear. The objective of the present study is to elucidate the association between low-dose radiation exposure from the atomic bomb fallout and cancer mortality among Nagasaki atomic bomb survivors. Of 77 884 members in the Nagasaki University Atomic Bomb Survivors Cohort, 610 residents in the terrain-shielded area with fallout were selected for this analysis; 1443 residents in the terrain-shielded area without fallout were selected as a control group; and 3194 residents in the direct exposure area were also selected for study. Fifty-two deaths due to cancer in the terrain-shielded fallout area were observed during the follow-up period from 1 January 1970 to 31 December 2012. The hazard ratio for cancer mortality in the terrain-shielded fallout area was 0.90 (95% confidence interval: 0.65–1.24). No increase in the risk of cancer mortality was observed, probably because the dose of the radiation exposure was low for residents in the terrain-shielded fallout areas of the Nagasaki atomic bomb, and also because the number of study subjects was small.

Thyroid Dysfunction and Autoimmune Thyroid Diseases Among Atomic Bomb Survivors Exposed in Childhood.

The risk of thyroid cancer increases and persists for decades among individuals exposed to ionizing radiation in childhood, although the long-term effects of childhood exposure to medium to low doses of radiation on thyroid dysfunction and autoimmune thyroid diseases have remained unclear. To evaluate radiation dose responses for the prevalence of thyroid dysfunction and autoimmune thyroid disease among atomic bomb survivors exposed in childhood. Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years old at exposure underwent thyroid examinations at the Radiation Effects Research Foundation between 2007 and 2011, which was 62 to 66 years after the bombing. Data from 2668 participants (mean age, 68.2 years; 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; dose range, 0 to 4.040 Gy) were analyzed. Dose-response relationships between atomic bomb radiation dose and the prevalence of hypothyroidism, hyperthyroidism (Graves' disease), and positive for antithyroid antibodies. Prevalences were determined for hypothyroidism (129 cases, 7.8%), hyperthyroidism (32 cases of Graves' disease, 1.2%), and positive for antithyroid antibodies (573 cases, 21.5%). None of these was associated with thyroid radiation dose. Neither thyroid antibody-positive nor -negative hypothyroidism was associated with thyroid radiation dose. Additional analyses using alternative definitions of hypothyroidism and hyperthyroidism found that radiation dose responses were not significant. Radiation effects on thyroid dysfunction and autoimmune thyroid diseases were not observed among atomic bomb survivors exposed in childhood, at 62 to 66 years earlier. The cross-sectional design and survival bias were limitations of this study.

Neutron relative biological effectiveness in Hiroshima and Nagasaki atomic bomb survivors: a critical review

The calculated risk of cancer in humans due to radiation exposure is based primarily on long-term follow-up studies, e.g. the life-span study (LSS) on atomic bomb (A-bomb) survivors in Hiroshima and Nagasaki. Since A-bomb radiation consists of a mixture of γ-rays and neutrons, it is essential that the relative biological effectiveness (RBE) of neutrons is adequately evaluated if a study is to serve as a reference for cancer risk. However, the relatively small neutron component hampered the direct estimation of RBE in LSS data. To circumvent this problem, several strategies have been attempted, including dose-independent constant RBE, dose-dependent variable RBE, and dependence on the degrees of dominance of intermingled γ-rays. By surveying the available literature, we tested the chromosomal RBE of neutrons as the biological endpoint for its equivalence to the microdosimetric quantities obtained using a tissue-equivalent proportional counter (TEPC) in various neutron fields. The radiation weighting factor, or quality factor, Qn, of neutrons as expressed in terms of the energy dependence of the maximum RBE, RBEm, was consistent with that predicted by the TEPC data, indicating that the chromosomally measured RBE was independent of the magnitude of coexisting γ-rays. The obtained neutron RBE, which varied with neutron dose, was confirmed to be the most adequate RBE system in terms of agreement with the cancer incidence in A-bomb survivors, using chromosome aberrations as surrogate markers. With this RBE system, the cancer risk in A-bomb survivors as expressed in unit dose of reference radiation is equally compatible with Hiroshima and Nagasaki cities, and may be potentially applicable in other cases of human radiation exposure.

Clinical features and prognosis of patients with myelodysplastic syndromes who were exposed to atomic bomb radiation in Nagasaki.

There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS in Nagasaki atomic bomb survivors using the International Prognostic Scoring System (IPSS) and the revised version (IPSS‐R). Subjects were 140 patients with primary MDS diagnosed between 1985 and 2011 and evaluable for IPSS, IPSS‐R, and exposure distance. Of those, 31 were exposed at <1.5 km, 35 at 1.5–2.99 km, and 74 at ≥3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at ≥3.0 km, those exposed at <1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate/poor IPSS, and intermediate/poor/very poor IPSS‐R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS‐R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to overt leukemia among atomic bomb survivors.

Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques.

Heart disease is an increasingly recognized, serious late effect of radiation exposure, most notably among breast cancer and Hodgkin's disease survivors, as well as the Hiroshima and Nagasaki atomic bomb survivors. The purpose of this study was to evaluate the late effects of total-body irradiation (TBI) on cardiac morphology, function and selected circulating biomarkers in a well-established nonhuman primate model. For this study we used male rhesus macaques that were exposed to a single total-body dose of ionizing gamma radiation (6.5-8.4 Gy) 5.6-9.7 years earlier at ages ranging from ∼3-10 years old and a cohort of nonirradiated controls. Transthoracic echocardiography was performed annually for 3 years on 20 irradiated and 11 control animals. Myocardium was examined grossly and histologically, and myocardial fibrosis/collagen was assessed microscopically and by morphometric analysis of Masson's trichrome-stained sections. Serum/plasma from 27 irradiated and 13 control animals was evaluated for circulating biomarkers of cardiac damage [N-terminal pro B-type natriuretic protein (nt-proBNP) and troponin-I], inflammation (CRP, IL-6, MCP-1, sICAM) and microbial translocation [LPS-binding protein (LBP) and sCD14]. A higher prevalence of histological myocardial fibrosis was observed in the hearts obtained from the irradiated animals (9/14) relative to controls (0/3) (P = 0.04, χ(2)). Echocardiographically determined left ventricular end diastolic and systolic diameters were significantly smaller in irradiated animals (repeated measures ANOVA, P < 0.001 and P < 0.008, respectively). Histomorphometric analysis of trichrome-stained sections of heart tissue demonstrated ∼14.9 ± 1.4% (mean ± SEM) of myocardial area staining for collagen in irradiated animals compared to 9.1 ± 0.9 % in control animals. Circulating levels of MCP-1 and LBP were significantly higher in irradiated animals (P < 0.05). A high incidence of diabetes in the irradiated animals was associated with higher plasma triglyceride and lower HDLc but did not appear to be associated with cardiovascular phenotypes. These results demonstrate that single total-body doses of 6.5-8.4 Gy produced long-term effects including a high incidence of myocardial fibrosis, reduced left ventricular diameter and elevated systemic inflammation. Additional prospective studies are required to define the time course and mechanisms underlying radiation-induced heart disease in this model.

Adjustment of lifetime risks of space radiation-induced cancer by the healthy worker effect and cancer misclassification.

Background. The healthy worker effect (HWE) is a source of bias in occupational studies of mortality among workers caused by use of comparative disease rates based on public data, which include mortality of unhealthy members of the public who are screened out of the workplace. For the US astronaut corp, the HWE is assumed to be strong due to the rigorous medical selection and surveillance. This investigation focused on the effect of correcting for HWE on projected lifetime risk estimates for radiation-induced cancer mortality and incidence.Methods. We performed radiation-induced cancer risk assessment using Poisson regression of cancer mortality and incidence rates among Hiroshima and Nagasaki atomic bomb survivors. Regression coefficients were used for generating risk coefficients for the excess absolute, transfer, and excess relative models. Excess lifetime risks (ELR) for radiation exposure and baseline lifetime risks (BLR) were adjusted for the HWE using standardized mortality ratios (SMR) for aviators and nuclear workers who were occupationally exposed to ionizing radiation. We also adjusted lifetime risks by cancer mortality misclassification among atomic bomb survivors.Results. For all cancers combined (“Nonleukemia”), the effect of adjusting the all-cause hazard rate by the simulated quantiles of the all-cause SMR resulted in a mean difference (not percent difference) in ELR of 0.65% and mean difference of 4% for mortality BLR, and mean change of 6.2% in BLR for incidence. The effect of adjusting the excess (radiation-induced) cancer rate or baseline cancer hazard rate by simulated quantiles of cancer-specific SMRs resulted in a mean difference of in the all-cancer mortality ELR and mean difference of in the mortality BLR. Whereas for incidence, the effect of adjusting by cancer-specific SMRs resulted in a mean change of for the all-cancer BLR. Only cancer mortality risks were adjusted by simulated quantiles for misclassification, and results indicate a mean change of 1.1% for all-cancer mortality ELR, while the mean change in the all-cancer PC was approximately 4% for males and 6% for females.Conclusions. The typical life table approach for projecting lifetime risk of radiation-induced cancer mortality and incidence for astronauts and radiation workers can be improved by adjusting for HWE while simulating the uncertainty of input rates, input excess risk coefficients, and bias correction factors during multiple Monte Carlo realizations of the life table.

Association of radiation dose with prevalence of thyroid nodules among atomic bomb survivors exposed in childhood (2007-2011).

Few studies have evaluated the association of radiation dose with thyroid nodules among adults exposed to radiation in childhood. To evaluate radiation dose responses on the prevalence of thyroid nodules in atomic bomb survivors exposed in childhood. This survey study investigated 3087 Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years at exposure and participated in the thyroid study of the Adult Health Study at the Radiation Effects Research Foundation. Thyroid examinations including thyroid ultrasonography were conducted between October 2007 and October 2011, and solid nodules underwent fine-needle aspiration biopsy. Data from 2668 participants (86.4% of the total participants; mean age, 68.2 years; 1213 men; and 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; median dose, 0.018 Gy; dose range, 0-4.040 Gy) were analyzed. The prevalence of all thyroid nodules having a diameter of 10 mm or more (consisting of solid nodules [malignant and benign] and cysts), prevalence of small thyroid nodules that were less than 10 mm in diameter detected by ultrasonography, and atomic bomb radiation dose-responses. Thyroid nodules with a diameter of 10 mm or more were identified in 470 participants (17.6%): solid nodules (427 cases [16.0%]), malignant tumors (47 cases [1.8%]), benign nodules (186 cases [7.0%]), and cysts (49 cases [1.8%]), and all were significantly associated with thyroid radiation dose. Excess odds ratios per gray unit were 1.65 (95% CI, 0.89-2.64) for all nodules, 1.72 (95% CI, 0.93-2.75) for solid nodules, 4.40 (95% CI, 1.75-9.97) for malignant tumors, 2.07 (95% CI, 1.16-3.39) for benign nodules, and 1.11 (95% CI, 0.15-3.12) for cysts. The interaction between age at exposure and the dose was significant for the prevalence of all nodules (P = .003) and solid nodules (P < .001), indicating that dose effects were significantly higher with earlier childhood exposure. No interactions were seen for sex, family history of thyroid disease, antithyroid antibodies, or seaweed intake. No dose-response relationships were observed for small (<10-mm diameter) thyroid nodules. Radiation effects on thyroid nodules exist in atomic bomb survivors 62 to 66 years after their exposure in childhood. However, radiation exposure is not associated with small thyroid nodules.