Shuji Yonehara

Long‐term trend of thyroid cancer risk among Japanese atomic‐bomb survivors: 60 years after exposure

Thyroid cancer risk following exposure to ionizing radiation in childhood and adolescence is a topic of public concern. To characterize the long‐term temporal trend and age‐at‐exposure variation in the radiation‐induced risk of thyroid cancer, we analyzed thyroid cancer incidence data for the period from 1958 through 2005 among 105,401 members of the Life Span Study cohort of Japanese atomic‐bomb survivors. During the follow‐up period, 371 thyroid cancer cases (excluding those with microcarcinoma with a diameter <10 mm) were identified as a first primary among the eligible subjects. Using a linear dose–response model, the excess relative risk of thyroid cancer at 1 Gy of radiation exposure was estimated as 1.28 (95% confidence interval: 0.59–2.70) at age 60 after acute exposure at age 10. The risk decreased sharply with increasing age‐at‐exposure and there was little evidence of increased thyroid cancer rates for those exposed after age 20. About 36% of the thyroid cancer cases among those exposed before age 20 were estimated to be attributable to radiation exposure. While the magnitude of the excess risk has decreased with increasing attained age or time since exposure, the excess thyroid cancer risk associated with childhood exposure has persisted for >50 years after exposure.

Duodenal gangliocytic paraganglioma with lymph node metastasis in a 17-year-old boy

A case of duodenal gangliocytic paraganglioma (DGP) in a 17‐year‐old boy is presented. In this case a lymph node in the peripancreatic region was involved by a metastatic tumor. A review of the literature on DGP indicates that this case represents the youngest patient and is the second case of DGP with metastasis. Immunohistochemical staining for neuron‐specific enolase (NSE), neurofilament (NF), pancreatic polypeptide, and somatostatin showed positive results for epithelioid and ganglion‐like cells, whereas spindle cells showed immunoreactivities for S‐100 protein, NSE, and NF. The histogenesis of DGP is discussed.

Radiation and smoking effects on lung cancer incidence among atomic-bomb survivors

Abstract While radiation increases the risk of lung cancer among members of the Life Span Study (LSS) cohort of atomic bomb survivors, there are still important questions about the nature of its interaction with smoking, the predominant cause of lung cancer. Among 105,404 LSS subjects, 1,803 primary lung cancer incident cases were identified for the period 1958–1999. Individual smoking history information and the latest radiation dose estimates were used to investigate the joint effects of radiation and smoking on lung cancer rates using Poisson grouped survival regression methods. Relative to never-smokers, lung cancer risks increased with the amount and duration of smoking and decreased with time since quitting smoking at any level of radiation exposure. Models assuming generalized interactions of smoking and radiation fit markedly better than simple additive or multiplicative interaction models. The joint effect appeared to be super-multiplicative for light/moderate smokers, with a rapid increase in excess risk with smoking intensity up to about 10 cigarettes per day, but additive or sub-additive for heavy smokers smoking a pack or more per day, with little indication of any radiation-associated excess risk. The gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 (95% confidence interval: 0.31–1.00) for nonsmokers with a female : male ratio of 3.1. About one-third of the lung cancer cases in this cohort were estimated to be attributable to smoking while about 7% were associated with radiation. The joint effect of smoking and radiation on lung cancer in the LSS is dependent on smoking intensity and is best described by the generalized interaction model rather than a simple additive or multiplicative model.

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.

Role of Point Mutation of the K‐ras Gene in Tumorigenesis of B6C3F1 Mouse Lung Lesions Induced by Urethane

In order to elucidate the role of point mutation of the K‐ras gene in the tumorigenetic process of lung tumors, an experimental model of lung lesions in mice induced by the administration of urethane was used. A total of 135 B6C3F1 male mice, 6 weeks old, were given urethane in the drinking water at 0, 6, 60, 600 or 1200 ppm, and were then killed after varying periods of time. The lung lesions were histologically characterized as hyperplasia, adenoma and adenocarcinoma. Point mutations in codons 12 and 61 of the K‐ras gene were detected by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and confirmed by using dideoxy sequencing analysis. K‐ras gene mutation was identified in 9 (23.7%) of 38 lesions classified as hyperplasia, 31 (46.3%) of 67 adenomas, and 3 (50%) of 6 adenocarcinomas. The most frequent mutation was an AT‐to‐TA transversion at the second base of codon 61 and this pattern accounted for 65% of the three mutant forms observed. These results suggest that the point mutation of K‐ras gene is involved in all stages of mouse lung tumorigenesis, i.e., activation of this gene can also influence the later stages of lung lesions.

Alteration in length of telomeric repeats in lung cancer

We investigated the relationship between telomere length and various characteristics of tumor cells in 46 lung cancer specimens (40 primary lesions and six metastatic lesions). Three variant patterns of telomere length were observed in 16 cases (34.8%): reduction in 13 cases, elongation in two cases, and convergence in one case. These variant patterns were frequently observed in small cell carcinomas, in metastatic lesions, and in cases which possessed the S-type allele of the L-myc gene. All three cases with telomere elongation or convergence were associated with a poor prognosis. This is compatible with the previous report suggesting that telomerase activity may be an indicator of immortality in vitro. In adenocarcinoma, telomere reduction or elongation was also observed in the early stages with a low percentage of cells in the S-phase, while in cases with other histologic types, these changes were observed only in late stage, in metastatic lesions, or in cancerous tissues with a high percentage of cells in the S-phase. Although the reduction of telomere length in these tissues may be a result of many cell divisions, it may represent another stage of carcinogenesis in early-stage adenocarcinoma.

Histologic characteristics of skin cancer in Hiroshima and Nagasaki: Background incidence and radiation effects

Skin cancers, though rare in Japan, have reportedly been on the rise, but little else is known about epidemiologic features of different histologic types of skin cancer. The Life Span Study cohort, which consists of 93,700 atomic‐bomb survivors, many of whom were exposed to negligibly low radiation doses, and 26,600 people not exposed to radiation, enables a population‐based study of spontaneous as well as radiation‐related cancer risk. Skin tumor incident cases diagnosed between 1958 and 1987 were ascertained by linkage to the Hiroshima and Nagasaki tumor registries augmented by searches of other data sources. Study pathologists reviewed tumor specimens and pathology reports and classified tumors using the World Health Organization classification scheme. They identified 274 primary incident skin cancers, of which 106 were basal cell carcinoma (BCC), 81 were squamous cell carcinoma (SCC), and 14 were malignant melanomas. Background incidence rates and radiation effects were assessed by Poisson regression models allowing for the effects of demographic and other covariates. BCC and SCC background incidence rates were both about 3 per 100,000 per year. BCCs were mainly on the head/neck (81%), whereas SCCs occurred most frequently on the arms/legs (45%) and head/neck (29%), consistent with the presumed role played by solar UV exposure in skin cancer. The BCC rates increased significantly between 1958 and 1987, whereas the SCC rates remained unchanged. The excess absolute risk of BCC per unit skin surface area related to atomic‐bomb radiation exposure did not differ between UV‐exposed and shielded parts of the body, suggesting the additivity of the radiation‐related and background BCC risks.

EARLY CANCER AND RELATED LESIONS IN THE BRONCHIAL EPITHELIUM IN FORMER WORKERS OF MUSTARD GAS FACTORY

The bronchial epithelium in stepwise transverse sections was examined histologically in 66 male autopsy cases, composed of the groups of 19 mustard gas (MG) ex‐workers with lung cancer, 17 MG ex‐workers with non‐lung cancer, 10 non‐MG lung cancer cases, and 20 non‐MG non‐lung cancer cases. Foci of moderate or severe atypical cellular lesion or dysplasia, or of carcinoma in situ (CIS) in total slides of each group, were counted as 146 in 3,485, 72 in 2, 226, 70 in 3,797, and 18 in 4,611, respectively. The relative frequency of moderate or severe dysplasia and CIS in MG exposed non‐lung cancer cases resembled that found in lung cancer cases of both MG and non‐MG exposed. Seven CIS lesions were detected from among all MG‐exposed cases and one CIS was found in a non‐MG lung cancer case. Six out of eight CIS examples were adjoined by dysplasia. A multi‐variate analysis revealed a significant correlation between the incidence of atypical lesions and MG exposure, though the incidence of atypical lesions was also influenced significantly by age, smoking, and chronic bronchitis. The incidence of atypical lesions was significantly higher in cases of squamous cell lung cancer than those of other histological types, particularly small cell cancer.

Radiation and Smoking Effects on Lung Cancer Incidence by Histological Types Among Atomic Bomb Survivors

While the risk of lung cancer associated separately with smoking and radiation exposure has been widely reported, it is not clear how smoking and radiation together contribute to the risk of specific lung cancer histological types. With individual smoking histories and radiation dose estimates, we characterized the joint effects of radiation and smoking on type-specific lung cancer rates among the Life Span Study cohort of Japanese atomic bomb survivors. Among 105,404 cohort subjects followed between 1958 and 1999, 1,803 first primary lung cancer incident cases were diagnosed and classified by histological type. Poisson regression methods were used to estimate excess relative risks under several interaction models. Adenocarcinoma (636 cases), squamous-cell carcinoma (330) and small-cell carcinoma (194) made up 90% of the cases with known histology. Both smoking and radiation exposure significantly increased the risk of each major lung cancer histological type. Smoking-associated excess relative risks were significantly larger for small-cell and squamous-cell carcinomas than for adenocarcinoma. The gender-averaged excess relative risks per 1 Gy of radiation (for never-smokers at age 70 after radiation exposure at age 30) were estimated as 1.49 (95% confidence interval 0.1–4.6) for small-cell carcinoma, 0.75 (0.3–1.3) for adenocarcinoma, and 0.27 (0–1.5) for squamous-cell carcinoma. Under a model allowing radiation effects to vary with levels of smoking, the nature of the joint effect of smoking and radiation showed a similar pattern for different histological types in which the radiation-associated excess relative risk tended to be larger for moderate smokers than for heavy smokers. However, in contrast to analyses of all lung cancers as a group, such complicated interactions did not describe the data significantly better than either simple additive or multiplicative interaction models for any of the type-specific analyses.

Skin Cancer Incidence among Atomic Bomb Survivors from 1958 to 1996

The radiation risk of skin cancer by histological types has been evaluated in the atomic bomb survivors. We examined 80,158 of the 120,321 cohort members who had their radiation dose estimated by the latest dosimetry system (DS02). Potential skin tumors diagnosed from 1958 to 1996 were reviewed by a panel of pathologists, and radiation risk of the first primary skin cancer was analyzed by histological types using a Poisson regression model. A significant excess relative risk (ERR) of basal cell carcinoma (BCC) (n = 123) was estimated at 1 Gy (0.74, 95% confidence interval (CI): 0.26, 1.6) for those age 30 at exposure and age 70 at observation based on a linear-threshold model with a threshold dose of 0.63 Gy (95% CI: 0.32, 0.89) and a slope of 2.0 (95% CI: 0.69, 4.3). The estimated risks were 15, 5.7, 1.3 and 0.9 for age at exposure of 0–9, 10–19, 20–39, over 40 years, respectively, and the risk increased 11% with each one-year decrease in age at exposure. The ERR for squamous cell carcinoma (SCC) in situ (n = 64) using a linear model was estimated as 0.71 (95% CI: 0.063, 1.9). However, there were no significant dose responses for malignant melanoma (n = 10), SCC (n = 114), Paget disease (n = 10) or other skin cancers (n = 15). The significant linear radiation risk for BCC with a threshold at 0.63 Gy suggested that the basal cells of the epidermis had a threshold sensitivity to ionizing radiation, especially for young persons at the time of exposure.