Ikuno Takahashi

Risk Factors for Hepatocellular Carcinoma in a Japanese Population: A Nested Case-Control Study

Background: Epidemiologic studies have shown effects of lifestyle-related factors on risk for hepatocellular carcinoma. However, few cohort studies have incorporated, in a strict and in-depth manner, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections or investigated synergism between such factors. Methods: We conducted a nested case-control study using sera stored before hepatocellular carcinoma diagnosis in the longitudinal cohort of atomic bomb survivors. The study included 224 hepatocellular carcinoma cases and 644 controls that were matched to the cases on gender, age, city, time of serum storage, and method of serum storage, and countermatched on radiation dose. Results: Univariate analysis showed that HBV and HCV infections, alcohol consumption, smoking habit, body mass index (BMI), and diabetes mellitus were associated with increased hepatocellular carcinoma risk, whereas coffee drinking was associated with decreased hepatocellular carcinoma risk. Multivariate relative risks of hepatocellular carcinoma (95% confidence interval) were 45.8 (15.2-138), 101 (38.7-263), 70.7 (8.3-601), 4.36 (1.48-13.0), and 4.57 (1.85-11.3), for HBV infection alone, HCV infection alone, both HBV and HCV infections, alcohol consumption of ≥40 g of ethanol per day, and BMI of >25.0 kg/m2 10 years before diagnosis, respectively. HBV and HCV infection and BMI of >25.0 kg/m2 remained independent risk factors even after adjusting for severity of liver fibrosis. Among HCV-infected individuals, the relative risk of hepatocellular carcinoma for a 1 kg/m2 increase in BMI was 1.39 (P = 0.003). Conclusions: To limit the risk for hepatocellular carcinoma, control of excess weight may be crucial for individuals with chronic liver disease, especially those with chronic hepatitis C. (Cancer Epidemiol Biomarkers Prev 2008;17(4):846–54)

A prospective follow-up study of the association of radiation exposure with fatal and non-fatal stroke among atomic bomb survivors in Hiroshima and Nagasaki (1980–2003)

Objective Use of medical radiotherapy has increased markedly in recent decades. Whether the consequence includes an increased risk of cardiovascular disease remains to be determined. The purpose of this study was to examine the association between radiation exposure and the incidence of stroke among Japanese atomic bomb survivors. Design A prospective follow-up study. Setting and participants Radiation exposure from the atomic bombing was assessed in 9515 subjects (34.8% men) with 24-year follow-up from 1980. Subjects were free of prevalent stroke when follow-up began. Outcome measures Stroke events and the underlying cause of death were reviewed to confirm the first-ever stroke. Subtypes (ischaemic and haemorrhagic events) were categorised based on established criteria according to the definitions of typical/atypical stroke symptoms. Results Overall mean radiation dose (±SD) in units of gray (Gy) was 0.38±0.58 (range: 0–3.5). During the study period, 235 haemorrhagic and 607 ischaemic events were identified. For men, after adjusting for age and concomitant risk factors, the risk of haemorrhagic stroke rose consistently from 11.6 to 29.1 per 10 000 person-years as doses increased from <0.05 to ≥2 Gy (p=0.009). Incidence also rose within the dose range <1 Gy (p=0.004) with no dose threshold. In women, the risk of haemorrhagic stroke rose with increasing radiation exposure but not until doses reached a threshold of 1.3 Gy (95% CI 0.5 to 2.3). Among women, for doses <1.3 Gy, differences in stroke risk were modest (13.5 per 10 000 person-years), while it increased to 20.3 per 10 000 person-years for doses that ranged from 1.3 to <2.2 Gy and to 48.6 per 10 000 person-years for doses that were higher (p=0.002). In both sexes, dose was unrelated to ischaemic stroke. Conclusion While the risk of haemorrhagic stroke increases with rising radiation exposure for both sexes, effects in women are less apparent until doses exceed a threshold at 1.3 Gy.

Comparison between oscillometric- and Doppler-ABI in elderly individuals.

Peripheral arterial disease (PAD) generally remains under-recognized, mainly due to the specialized technical skills required to detect the low values of the ankle-brachial index (ABI). As a simpler and faster alternative to the standard method using continuous-wave Doppler ultrasound, we evaluated automated oscillometric ABI measurement by VP-2000 with an elderly cohort of 113 subjects (age range, 61 to 88 years). The standard deviation in ABIs measured by the Doppler method was statistically greater than that measured by the oscillometric method for each of the two legs (P < 0.001). Correlations in ABIs between the two methods were 0.46 for the left leg and 0.61 for the right leg; this result appears to have been caused by interobserver variation in the Doppler ABI measurements. While the trend showing greater differences between average oscillometric- and Doppler-ABIs was significant at the lower ABI ranges, there was little indication of differences in measurements having an average ABI > 1.1. The difference between the methods was suggestively larger in subjects who were smokers than in non-smokers (P = 0.09), but the difference was not affected by other potential atherosclerotic risk factors, including age at examination (P > 0.50). A larger difference at lower ABIs led to better PAD detection by the Doppler method compared to the oscillometric method (sensitivity = 50%, specificity = 100%), although the overall agreement was not small (Cohen’s Kappa = 0.65). Our findings indicate that oscillometric devices can provide more accurate estimation of the prevalence of PAD in elderly individuals than the conventional Doppler method.

Risk of death among children of atomic bomb survivors after 62 years of follow-up: a cohort study

BACKGROUND No clear epidemiological hereditary effects of radiation exposure in human beings have been reported. However, no previous studies have investigated mortality into middle age in a population whose parents were exposed to substantial amounts of radiation before conception. We assessed mortality in children of the atomic bomb survivors after 62 years of follow-up. METHODS In this prospective cohort study, we assessed 75 327 singleton children of atomic bomb survivors in Hiroshima and Nagasaki and unexposed controls, born between 1946 and 1984, and followed up to Dec 31, 2009. Parental gonadal doses of radiation from the atomic bombings were the primary exposures. The primary endpoint was death due to cancer or non-cancer disease, based on death certificates. FINDINGS Median follow-up was 54·3 years (IQR 45·4-59·3). 5183 participants died from disease. The mean age of the 68 689 surviving children at the end of follow-up was 53·1 years (SD 7·9) with 15 623 (23%) older than age 60 years. For parents who were exposed to a non-zero gonadal dose of radiation, the mean dose was 264 mGy (SD 463). We detected no association between maternal gonadal radiation exposure and risk of death caused by cancer (hazard ratio [HR] for 1 Gy change in exposure 0·891 [95% CI 0·693-1·145]; p=0·36) or risk of death caused by non-cancer diseases (0·973 [0·849-1·115]; p=0·69). Likewise, paternal exposure had no effect on deaths caused by cancer (0·815 [0·614-1·083]; p=0·14) or deaths caused by non-cancer disease (1·103 [0·979-1·241]; p=0·12). Age or time between parental exposure and delivery had no effect on risk of death. INTERPRETATION Late effects of ionising radiation exposure include increased mortality risks, and models of the transgenerational effects of radiation exposure predict more genetic disease in the children of people exposed to radiation. However, children of people exposed to the atomic bombs in Hiroshima and Nagasaki had no indications of deleterious health effects after 62 years. Epidemiological studies complemented by sensitive molecular techniques are needed to understand the overall effects of preconception exposure to ionising radiation on human beings.

Prevalence of Adult-Onset Multifactorial Disease among Offspring of Atomic Bomb Survivors

Abstract Fujiwara, S., Suyama, A., Cologne, J. B., Akahoshi, M., Yamada, Y., Suzuki, G., Koyama, K., Takahashi, N., Kasagi, F., Grant, E. J., Lagarde, F., Hsu, W. L., Furukawa, K., Ohishi, W., Tatsukawa, Y. , Neriishi, K., Takahashi, I., Ashizawa, K., Hida, A., Imaizumi, M., Nagano, J., Cullings, H. M., Katayama, H., Ross, N. P., Kodama, K. and Shore, R. E. Prevalence of Adult-Onset Multifactorial Disease among Offspring of Atomic Bomb Survivors. Radiat. Res. 170, 451–457 (2008). The first study to examine whether parental radiation exposure leads to increased heritable risk of common adult-onset multifactorial diseases (i.e., hypertension, diabetes mellitus, hypercholesterolemia, ischemic heart disease, and stroke) was conducted among 11,951 participants in the clinical examination program out of a potential of 24,673 mail survey subjects who were offspring of survivors born from May 1946 through December 1984. Logistic regression analyses demonstrated no evidence of an association between the prevalence of multifactorial diseases in the offspring and parental radiation exposure, after adjusting for age, city, gender and various risk factors. The odds ratio (OR) for a paternal dose of 1 Gy was 0.91 [95% confidence interval (CI) 0.81–1.01, P = 0.08], and that for a maternal dose of 1 Gy was 0.98 (95% CI 0.86–1.10, P = 0.71). There was no apparent effect of parental age at exposure or of elapsed time between parental exposure and birth, but male offspring had a low odds ratio (OR = 0.76 at 1 Gy) for paternal exposure, but cautious interpretation is needed for this finding. The clinical assessment of nearly 12,000 offspring of A-bomb survivors who have reached a median age of about 50 years provided no evidence for an increased prevalence of adult-onset multifactorial diseases in relation to parental radiation exposure.

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

IMPORTANCE Few studies have evaluated the association of radiation dose with thyroid nodules among adults exposed to radiation in childhood. OBJECTIVE To evaluate radiation dose responses on the prevalence of thyroid nodules in atomic bomb survivors exposed in childhood. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOMES AND MEASURES 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. RESULTS 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. CONCLUSIONS AND RELEVANCE 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.

Lifetime risk of stroke and impact of hypertension: estimates from the adult health study in Hiroshima and Nagasaki

Very few reports have been published on lifetime risk (LTR) of stroke by blood pressure (BP) group. This study included participants in the Radiation Effects Research Foundation Adult Health Study who have been followed up by biennial health examinations since 1958. We calculated the LTR of stroke for various BP-based groups among 7847 subjects who had not been diagnosed with stroke before the index age of 55 years using cumulative incidence analysis adjusting for competing risks. By 2003, 868 subjects had suffered stroke (512 (58.9%) were women and 542 (62.4%) experienced ischemic stroke). BP was a significant factor in determining risk of stroke for men and women, with distributions of cumulative risk for stroke significantly different across BP groups. The LTR of all-stroke for normotension (systolic BP/diastolic BP <120/80 mm Hg), prehypertension (120–139/80–89 mm Hg), stage1 hypertension (140–159/90–99 mm Hg) and stage 2 hypertension (>160/100 mm Hg) were 13.8–16.9–25.8–25.8% in men and 16.0–19.9–24.0–30.5% in women, respectively (P<0.001 among BP groups in both sexes). The estimates did not differ significantly (P=0.16) between normotensive and prehypertensive subjects. One in five Japanese atomic bomb survivor subjects experienced stroke over their lifetime from the age of 55 years. Long-term stroke risks were elevated in those with hypertension (>140/90 mm Hg) at any of the index ages of 45, 55, 65 and 75 years.

Is the association between smoking and the retinal venular diameter reversible following smoking cessation

PURPOSE Wider retinal venular caliber is shown to be associated with an increased risk of stroke, and smoking is associated with a wider retinal venular caliber. However, the impact of smoking cessation on the retinal vessels has not been previously reported. We examined this issue in an adult cohort of atomic bomb survivors. METHODS In the Adult Health Study of Japanese atomic bomb survivors, 1664 subjects had retinal photographs taken from 2006 to 2008. The central retinal artery and vein equivalents (CRAE and CRVE) were calculated using a semiautomated software program. Multiple surveys have assessed the effects of smoking since 1963. The associations between smoking, the time since cessation, and the retinal vessel caliber were determined using linear mixed effects models. RESULTS The CRVE was associated with an increased number of cigarettes smoked per day among women after adjusting for potential confounding factors (age, sex, blood pressure, hypertensive medications, white blood cell count, diabetes, body mass index, lipids, and radiation dose). Females who smoked 10 cigarettes per day had a 6.9-μm wider mean CRVE (P = 0.001) than nonsmokers. Females who had stopped smoking for 10 or more years had a mean CRVE similar to those who had never smoked (191.8 vs. 194.4 μm; P = 0.23). These associations were not observed in males or for CRAE. CONCLUSIONS Wider retinal venular caliber is associated with smoking in Japanese females; however, this association becomes nonsignificant after 10 or more years of smoking cessation, suggesting that the impact of smoking on retinal venular dilation is reversible following long-term smoking cessation.

Radiation-related risks of non-cancer outcomes in the atomic bomb survivors

Risks of non-cancer outcomes after exposure to atomic bomb (A-bomb) radiation have been evaluated among the Life Span Study (LSS) cohort and its subcohort, the Adult Health Study (AHS). Information regarding non-cancer outcomes in the LSS is obtained from death certificates. In the AHS, members undergo clinical examinations biennially to determine their health status. Many AHS studies have been limited to participants attending the clinic over a limited period, and therefore have varying degrees of inferential utility; as such, care is required for comparison with the LSS results. Disease structure of non-cancer diseases in Japan has changed over the long follow-up period since the end of World War II. The health status of the A-bomb survivors may be associated with the hardships of living in a devastated city and impoverished country following the prolonged war effort, in addition to the direct effects of radiation exposure. Radiation-related risk of cardiovascular disease may have increased due to radiation-related increased risk of hypertension and other secondary associations, and the risk of atherosclerotic disorders has also been reported recently. These results should be interpreted with caution because of changes in disease definitions over the follow-up period. The radiation-related risk of non-cancer respiratory diseases also appears to have increased over the follow-up period, but the shapes of the dose–response curves have shown little consistency.

A Report from the 2013 International Workshop: Radiation and Cardiovascular Disease, Hiroshima, Japan

Two longitudinal cohort studies of Japanese atomic bomb survivors-the life span study (LSS) and the adult health study (AHS)-from the Radiation Effects Research Foundation (RERF) indicate that total body irradiation doses less than 1 Gy are associated with an increased risk of cardiovascular disease (CVD), but several questions about this association remain.In particular, the diversity of heart disease subtypes and the high prevalence of other risk factors complicate the estimates of radiation effects. Subtype-specific analyses with more reliable diagnostic criteria and measurement techniques are needed. The radiation effects on CVD risk are probably tissue-reaction (deterministic) effects, so the dose-response relationships for various subtypes of CVD may be nonlinear and therefore should be explored with several types of statistical models.Subpopulations at high risk need to be identified because effects at lower radiation doses may occur primarily in these susceptible subpopulations. Whether other CVD risk factors modify radiation effects also needs to be determined. Finally, background rates for various subtypes of CVD have historically differed substantially between Japanese and Western populations, so the generalisability to other populations needs to be examined.Cardiovascular disease mechanisms and manifestations may differ between high-dose local irradiation and low-dose total body irradiation (TBI)-microvascular damage and altered metabolism from low-dose TBI, but coronary artery atherosclerosis and thrombotic myocardial infarcts at high localised doses. For TBI, doses to organs other than the heart may be important in pathogenesis of CVD, so data on renal and liver disorders, plaque instability, microvascular damage, metabolic disorders, hypertension and various CVD biomarkers and risk factors are needed. Epidemiological, clinical and experimental studies at doses of less than 1 Gy are necessary to clarify the effects of radiation on CVD risk.