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Ikuno Takahashi,1,3 Kyoji Furukawa,2 Waka Ohishi,1 Tetsuya Takahashi,3 Masayasu Matsumoto,3 Saeko Fujiwara11Department of Clinical Studies, 2Department of Statistics, Radiation Effects Research Foundation (RERF), Hiroshima, Japan; 3Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, JapanAbstract: 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.Keywords: ankle-brachial index, oscillometry, Doppler, peripheral arterial disease

Background: This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC)., Methods: 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens., Results: In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group; in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (ρ = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (ρ = -0.4, p < 0.01)., Conclusion: Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment., Competing Interests: Declarations. Conflict of interest: Authors declare no conflicts of interest for this article., (© 2024. The Author(s).)

Context: In recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation, however, no studies have examined low-to- moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors., Objectives: To examine the association between radiation dose and markers of inflammation and insulin resistance., Methods: This study investigated 3,152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance., Results: Radiation dose was significantly and positively associated with levels of CRP, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and HDL cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance., Conclusions: Insulin resistance might be a possible factor in the radiation related diabetes incidence in the A-bomb survivors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Studies in many populations have reported associations between circulating cytokine levels and various physiological or pathological conditions. However, the reliability of cytokine measurements in population studies, which measure cytokines in multiple assays over a prolonged period, has not been adequately examined; nor has stability during sample storage or intra-individual variation been assessed., Methods: We assessed (1) analytical reliability in short- and long-term repeated measurements; (2) stability and analytical reliability during long-term sample storage, and (3) variability within individuals over seasons, of four cytokines-osteopontin (OPN), osteoprotegerin (OPG), vascular endothelial growth factor-A (VEGF-A), and interleukin-17A (IL-17A). Measurements in plasma or serum samples were made with commercial kits according to standard procedures. Estimation was performed by fitting a random or mixed effects linear model on the log scale., Results: In repeated assays over a short period, OPN, OPG, and VEGF-A had acceptable reliability, with intra- and inter-assay coefficients of variation (CV) less than 0.11. Reliability of IL-17A was poor, with inter- and intra-assay CV 0.85 and 0.43, respectively. During long-term storage, OPG significantly decayed (- 33% per year; 95% confidence interval [- 54, - 3.7]), but not OPN or VEGF-A (- 0.3% or - 6.3% per year, respectively). Intra- and inter-assay CV over a long period were comparable to that in a short period except for a slight increase in inter-assay CV of VEGF-A. Within-individual variation was small for OPN and VEGF-A, with intra-class correlations (ICC) 0.68 and 0.83, respectively, but large for OPG (ICC 0.11)., Conclusions: We conclude that OPN and VEGF-A can be reliably measured in a large population, that IL-17A is suitable only for small experiments, and that OPG should be assessed with caution due to degradation during storage and intra-individual variation. The overall results of our study illustrate the need for validation under relevant conditions when measuring circulating cytokines in population studies., (© 2024. The Author(s).)

The numbers of naive T cells that react to novel pathogens not yet encountered by an immune system, decrease during aging, mainly due to age-associated involution of the thymus. CD45RA+ naive CD4 T cells consist of heterogeneous populations, including highly CXCR3-expressing cells that appear during the homeostatic proliferation of naive T cells and exhibit enhanced type-1 inflammatory phenotypes. Based on previous evidence of radiation-associated reductions in thymic function and peripheral blood naive CD4 T cells, we hypothesized that the homeostatic proliferation of naive CD4 T cells compensates for deficits in peripheral T-cell populations after radiation injury, which may increase the proportion of CXCR3high cells in naive CD4 T cells and enhance inflammation. The statistical models employed in this study revealed positive associations between the number of CXCR3high naive CD4 T cells and age as well as radiation dose among 580 Hiroshima atomic bomb survivors. In addition, the CXCR3high cells in these survivors increased not only with the levels of homeostatic cytokines, IL6 and IL7, but also with those of inflammatory indicators, CXCL10 and CRP. These results suggest that thymic T-cell production deficiency due to radiation and aging results in enhanced homeostatic proliferation that drives the appearance of CXCR3high naive CD4 T cells poised for an inflammatory response. Molecular mechanisms and clinical relevance of increasing CXCR3high cells in naive CD4 T populations should be further investigated in the context of inflammatory disease development long after radiation exposure., (© 2024 by Radiation Research Society.)

Background: Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma., Methods: Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample (n = 51) and tumor tissue (n, baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood., Results: Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies., Conclusions: Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma., (© 2023. Springer Nature Limited.)

Reactive oxygen species (ROS) play an important role in immune responses; however, their excessive production and accumulation increases the risk of inflammation-related diseases. Although irradiation is known to accelerate immunological aging, the underlying mechanism is still unclear. To determine the possible involvement of ROS in this mechanism, we examined 10,023 samples obtained from 3752 atomic-bomb survivors in Hiroshima and Nagasaki, who participated in repeated biennial examinations from 2008 to 2016, for the effects of aging and radiation exposure on intracellular ROS (H 2 O 2 and O 2 •- ) levels, percentages of T-cell subsets, and the effects of radiation exposure on the relationship between cell percentages and intracellular ROS levels in T-cell subsets. The cell percentages and intracellular ROS levels in T-cell subsets were measured using flow cytometry, with both fluorescently labeled antibodies and the fluorescent reagents, carboxy-DCFDA and hydroethidine. The percentages of naïve CD4 + and CD8 + T cells decreased with increasing age and radiation dose, while the intracellular O 2 •- levels in central and effector memory CD8 + T cells increased. Additionally, when divided into three groups based on the percentages of naïve CD4 + T cells, intracellular O 2 •- levels of central and effector memory CD8 + T cells were significantly elevated with the lowest radiation dose group in the naïve CD4 + T cells. Thus, the radiation exposure-induced decrease in the naïve CD4 + T cell pool size may reflect decreased immune function, resulting in increased intracellular ROS levels in central and effector memory CD8 + T cells, and increased intracellular oxidative stress., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Context: Recent epidemiological studies have shown increased risk of diabetes among childhood cancer survivors who received high therapeutic doses of radiation, particularly to the total body or to the abdomen. However, the effect of low-to-moderate dose radiation (<4 Gy) on the risk of diabetes is still unknown., Objectives: To investigate the radiation effect on diabetes incidence among atomic bomb (A-bomb) survivors, and whether the dose response is modified by other factors including city, sex, and age at time of bombing (ATB)., Methods: 9131 participants without diabetes at baseline were observed through biennial clinical exams from 1969 to 2015. A Cox proportional hazards model was used to estimate hazard ratios (HR) to evaluate the dose response for diabetes incidence., Results: During the study period, 1417 incident diabetes cases were identified. The overall crude incidence rate was 7.01/103 person-years. Radiation dose was significantly associated with diabetes incidence, with effect modification by city and age ATB. In Hiroshima, at ages 10 and 30 ATB, the HRs at 1 Gy of pancreatic radiation dose were 1.47 (95% CI, 1.31-1.66) and 1.13 (95% CI, 0.97-1.31), respectively. However, no significant radiation dose response was observed at these ages in Nagasaki. The HR for radiation dose was higher among those who were younger ATB and decreased 1% for each additional year of age., Conclusions: Among A-bomb survivors, a radiation association was suggested for incidence of diabetes. Results were inconsistent by city and age ATB, which could indicate potential confounding of the radiation association with diabetes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Although reactive oxygen species (ROS) play important roles in immune responses, excessive ROS production and accumulation might enhance the risk of inflammation-related diseases. Moreover, impaired immune function and the acceleration of pre-clinically persistent inflammation due to aging and radiation exposure have been observed in atomic bomb (A-bomb) survivors more than 60 years post-exposure. Meanwhile, the effects of aging and radiation exposure on ROS production in immune cells have not been characterized. This study investigated the relationship between intracellular ROS (H 2 O 2 and O 2 •- ) levels in blood cells or T cell subsets and serum iron, ferritin, and C-reactive protein (CRP) levels, as well as how these variables are affected by age and radiation exposure in A-bomb survivors. We examined 2495 Hiroshima A-bomb survivors. Multiple linear regression models adjusted for confounding factors indicated that intracellular O 2 •- levels in monocytes, granulocytes, and lymphocytes, and particularly in memory CD8 + T cells, including effector memory and terminally differentiated effector memory CD8 + T cells, increased with radiation dose. Additionally, serum iron, ferritin, and CRP levels affected intracellular ROS levels in specific blood cell types and T cell subsets. Serum CRP levels increased significantly with increasing age and radiation dose. Finally, when divided into three groups according to serum CRP levels, dose-dependent increases in the intracellular O 2 •- levels in blood cells and central memory and effector memory CD8 + T cells were most prominently observed in the high-CRP group. These results suggest that an increase in the levels of certain intracellular ROS, particularly after radiation exposure, might be linked to enhanced inflammatory status, including elevated serum CRP levels and reduced serum iron levels. This study reveals that aging and radiation exposure increase oxidative stress in blood cells, which is involved in impaired immune function and accelerated pre-clinically persistent inflammation in radiation-exposed individuals., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: 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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: K.M. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to declare., (Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY.)

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [- 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

The paper proposes an approach to causal mediation analysis in nested case-control study designs, often incorporated with countermatching schemes using conditional likelihood, and we compare the method's performance to that of mediation analysis using the Cox model for the full cohort with a continuous or dichotomous mediator. Simulation studies are conducted to assess our proposed method and investigate the efficiency relative to the cohort. We illustrate the method using actual data from two studies of potential mediation of radiation risk conducted within the Adult Health Study cohort of atomic-bomb survivors. The performance becomes comparable to that based on the full cohort, illustrating the potential for valid mediation analysis based on the reduced data obtained through the nested case-control design., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Exposure to high-doses of ionizing radiation has been reported to be associated with the risk of stroke. However, risks associated with lower dose exposures remain unclear, and there is little information available for the risk modification according to the dose-rate. There are few studies using animal models which might be able to provide complementary information on this association. In this study, the male stroke-prone spontaneously hypertensive rat (SHRSP) was used as a model animal. The rats were acutely irradiated with doses between 0 and 1.0 Gy or chronically irradiated with a cumulative dose of 0.5 or 1.0 Gy (at a dose rate of 0.05 or 0.1 Gy/day, respectively). The onset time of stroke related symptoms in SHRSP was used as an endpoint for evaluating the effects of low dose and the low dose-rate gamma-ray exposures. With respect to acute exposure, the time to the onset of stroke in the irradiated rats suggested the presence of a threshold around 0.1 Gy. For the low dose-rate chronically exposed, no significant increase in stroke symptom was observed. These findings are novel and demonstrate that the SHRSP system can be used to determine the association between the risk of stroke and radiation exposure with high sensitivity. Moreover, these studies provide important information regarding the association between the low dose and low dose-rate radiation exposure and circulatory diseases, especially stroke., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The findings from previously published studies have suggested that radiation exposure is associated with increased mortality and incidence of gastric cancer. However, few cohort studies have incorporated risk factors such as Helicobacter pylori (H. pylori) infection or chronic atrophic gastritis (CAG). The current study is aimed at evaluating the modifying effect of CAG on radiation risk of noncardia gastric cancer by histological type, by reanalyzing data from a nested case-control study conducted within the longitudinal clinical cohort of atomic bomb survivors. The analysis was restricted to 297 intestinal- or diffuse-type noncardia cases and 873 controls rematched to the cases on gender, age, city, and time and type of serum storage, and countermatched on radiation dose. Multivariable-adjusted relative risks [95% confidence interval (CI)] of noncardia gastric cancer were 3.9 (2.1-7.2) for H. pylori IgG seropositivity with cytotoxin-associated gene A (CagA) IgG low titer, 2.6 (1.9-3.6) for CAG, 1.9 (1.3-2.8) for current smoking, and 1.4 (1.1-1.9) for 1 Gy irradiation. Among subjects without CAG, the relative risk (95% CI) of noncardia gastric cancer at 1 Gy was 2.3 (1.4-3.7), whereas relative risk (95% CI) at 1 Gy was 1.1 (0.8-1.5) among subjects with CAG (for the overall interaction, P = 0.012). By histological type, the risk at 1 Gy was high for diffuse type without CAG, with adjusted relative risk (95% CI) of 3.8 (2.0-7.6), but was not high for diffuse type with CAG or for intestinal-type irrespective of CAG status. The results indicate that radiation exposure is associated with increased risk of diffuse-type noncardia gastric cancer without CAG, and this association exists despite adjustment for H. pylori infection and smoking habit., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

In this work, we utilized spontaneously hypertensive rats (SHR) and Wister Kyoto rats (WKY), from which the SHR was established, to evaluate the effects of whole-body acute radiation on the cardiovascular system at doses from 0 to 4 Gy. In the irradiated SHR, the systolic blood pressure (SBP) increased with increasing dose, while body weight gain decreased with increasing radiation dose. Furthermore, pathological observations of SHR demonstrated that the number of rats with cystic degeneration in the liver increased with increasing dose. The effects observed among SHR, such as increased SBP and retardation of body weight gain, appear very similar to those observed in Japanese atomic bomb survivors. In contrast, the SBP among WKY did not change relative to dose; the body weight, however, did change, as in the SHR. Therefore, the association between radiation exposure and SBP, but not between radiation exposure and retardation of body weight gain, may be affected by genetic background, as evident from strain difference. These results suggest that the SHR and WKY animal models may be useful for studying radiation effects on non-cancer diseases including circulatory diseases, chronic liver disease and developmental retardation., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients., Methods: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes., Results: Relative dose intensity (RDI) decreased significantly between weeks 1-2 and 3-4 ( p  < 0.001), and RDI during weeks 3-4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18-0.96, p  = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1-8.3, p  = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0-8.3, p  = 0.045) had higher risk of shorter PFS., Conclusion: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients., Competing Interests: Conflict of interest statement: Kazuaki Chayama has received research funding from Eizai. The funder had no role in the design of the study, collection, analysis, interpretation of data, writing of the manuscript or decision to publish the results., (© The Author(s), 2020.)

Epidemiological studies of people who were exposed to atomic bomb radiation and their children who were conceived after parental exposure to radiation (F 1 ) have investigated late health effects of atomic bomb radiation and its transgenerational effects. Those studies were initiated by the Atomic Bomb Casualty Commission (ABCC) in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF) in 1975, which continued the work of the ABCC. Follow-up of vital status and cause of death is performed for all RERF cohorts, including the atomic bomb survivors (the Life Span Study: LSS), in utero survivors, and the children of the survivors (F 1 ). Cancer incidence is investigated for accessible subpopulations of the cohorts. Health examinations for subcohorts of the LSS and in utero survivors are conducted as the Adult Health Study (AHS); a program of health examinations for a subcohort of the F 1 study is called the F 1 Offspring Clinical Study (FOCS). Participants of all clinical programs are asked to donate their blood and urine for storage and future biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors including those exposed in utero, and possible risks for some noncancer diseases. No increased risks due to parental exposure to radiation have been observed for malignancies or other diseases in F 1 , but continuing investigations are required.

We examined the relationship between glaucoma subtype and retinal vascular caliber as markers of ocular circulation. Subjects were Japanese atomic bomb survivors in Hiroshima and Nagasaki. After a screening examination, potential cases were subjected to further definitive examination. The diameters of central retinal artery and vein equivalents (CRAE and CRVE) on digitized retinal photographs were measured using an established method. Generalized linear regression analyses were used to examine the associations among vessel diameters, radiation exposure, and prevalence of glaucoma subtypes among the study subjects. We identified 196 cases of glaucoma (12%) based on optic disc appearance, perimetry results, and other ocular findings. The main subtypes were primary angle-closure glaucoma, primary open-angle glaucoma and normal-tension glaucoma (NTG). NTG was the dominant subtype (78%). NTG was negatively associated with CRAE and CRVE, and positively associated with radiation dose. CRVE was negatively associated with radiation dose and the association was unclear for CRAE. The smaller retinal vessel caliber in NTG patients than in subjects without glaucoma may indicate an association between ocular blood flow and the pathogenesis of NTG. However, significant relationships among vessel calibers, NTG and radiation exposure were not clear.

Enhanced inflammatory responses have been suggested decades after radiation exposure in atomic-bomb survivors, but cellular and molecular alterations related to prolonged inflammation remain unclear. This study, utilizing longitudinal haematological data over 50 years for 14 000 persons, investigated whether radiation exposure promoted the relative increase in peripheral myeloid cells, known as an aging-associated indicator of low-grade inflammation. Statistical modelling was performed with a linear mixed-effects model for leucocyte subsets, together with a proportional hazards regression model for all-cause mortality. We found that age trends in lymphocyte, neutrophil and monocyte percentages or counts differed before versus after age 60 years. Radiation dose was associated with monocyte percentages and counts, but not with the lymphoid-myeloid cell ratio. Radiation effects on monocytes were stronger after versus before age 60 years. Increases in monocyte percentages and counts were associated with higher risk of all-cause mortality. Studies of chromosomal aberrations have shown a clonal expansion of haematopoietic stem cells among atomic-bomb survivors. Therefore, radiation exposure might accelerate aging-associated clonal haematopoiesis, which could result in a long-lasting elevation of circulating monocytes., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups., Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models., Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function., Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background Past reports suggested that total-body irradiation at 0.5 to 1.0 Gy could be responsible for atherosclerosis. Peripheral artery disease ( PAD ) is a manifestation of systematic atherosclerosis. Whether the consequences of a low-to-moderate dose of radiation include increased risk of PAD remains to be determined. The purpose of this study was to examine the association between radiation exposure and prevalence of PAD among Japanese atomic bomb survivors. Methods and Results Radiation exposure from the atomic bombing was assessed in 3476 participants (41.1% men, mean age 74.8 years with SD 6.4 years) with a cross-sectional survey in 2010 to 2014. Left- and right-side ankle-brachial indexes and upstroke time ( UT ) were obtained using oscillometric VP -2000. PAD was defined as an ankle-brachial index of 1.0 or less or a prior history related to revascularization. UT was considered a sensitive marker of early-stage PAD . Association between radiation exposure and PAD or UT was assessed using multivariable regression analyses with adjustment for potential confounding factors. Of 3476 participants, 79 (2.3%) were identified as having prevalent PAD . Multivariate logistic regression analysis indicated that radiation dose was unrelated to PAD prevalence (odds ratio, 0.83; 95% confidence interval [0.57-1.21]). UT appeared to increase with radiation dose, but the increase was not statistically significant (1.09 ms/Gy; 95% confidence interval [-0.17 to 2.36]). Conclusions We found no clear association of radiation dose with PAD , but it remains to be determined whether UT is associated with radiation dose.

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.

Background: Cognitive function and physical function are important predictors of mortality., Aim: To investigate whether or not reaction time (RT) as a cognitive function and grip strength (GS) as a physical function were associated, alone or in combination, with mortality from heart disease or stroke., Methods: The subjects included 4901 Adult Health Study participants in Hiroshima who had undergone RT and GS measurements, were 35-74 years old at baseline (1970-1972) and were followed until the end of 2007., Results: After adjustment for other potential risk factors, RT was positively and GS was negatively associated with mortality from both heart disease and stroke. These associations were persistent in the model when adjusting simultaneously for RT, GS and other factors, but hazard ratios were attenuated. When we evaluated the associations by baseline age and gender, we found the greater hazard ratios for RT in the younger cohort, but no clear modification by age for GS. The interaction between RT and GS was statistically significant (P = 0.012) for stroke mortality. In the stratified analyses divided using the age-specific median value of RT or GS, the estimated hazard ratio of stroke mortality for RT was significant in participants with weak or strong GS but greater in the former, and for GS, it was only significant in participants with slow RT., Conclusion: RT and GS, alone and in combination, predicted heart disease and stroke mortalities. Interventions for both cognitive function and physical function may be beneficial for the prevention of cardiovascular disease mortality., (© 2018 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

The objective of this study was to evaluate effects of whole body radiation exposure early in life on influenza vaccination immune responses much later in life. A total of 292 volunteers recruited from the cohort members of ongoing Adult Health Study (AHS) of Japanese atomic bomb (A-bomb) survivors completed this observational study spanning two influenza seasons (2011-2012 and 2012-2013). Peripheral blood samples were collected prior to and three weeks after vaccination. Serum hemagglutination inhibition (HAI) antibody titers were measured as well as concentrations of 25 cytokines and chemokines in culture supernatant from peripheral blood mononuclear cells, with and without in vitro stimulation with influenza vaccine. We found that influenza vaccination modestly enhanced serum HAI titers in this unique cohort of elderly subjects, with seroprotection ranging from 18 to 48% for specific antigen/season combinations. Twelve percent of subjects were seroprotected against all three vaccine antigens post-vaccination. Males were generally more likely to be seroprotected for one or more antigens post-vaccination, with no differences in vaccine responses based on age at vaccination or radiation exposure in early life. These results show that early life exposure to ionizing radiation does not prevent responses of elderly A-bomb survivors to seasonal influenza vaccine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background/objectives: Few longitudinal studies have examined the association between diabetes risk and body composition in Asians. The aim of this prospective cohort study was to determine the role of body composition, estimated by whole-body dual-energy X-ray absorptiometry, in the development of diabetes and to examine the impact of body composition on diabetes risk in normal weight (body mass index (BMI) <23 kg/m 2 ) and overweight/obese groups (≥23 kg/m 2 )., Subjects/methods: We measured the body composition for 1532 diabetes-free subjects (463 men and 1069 women), aged 48-79 years, at the baseline examination period from 1994-96 and followed-up to detect new cases of diabetes over the next 15 years (median 13.4 years)., Results: After being adjusted for BMI and other potential confounding factors, body fat distribution was associated with diabetes risk. Percentage of trunk fat was positively associated with the development of diabetes (hazards ratio (HR) per 1 SD (95% confidential interval (CI)), 1.58 (1.10-2.28) in men, and 1.34 (0.99-1.83) in women), and percentage of leg fat was negatively associated with the development of diabetes (HR per 1 SD (95% CI), 0.68 (0.50-0.91) in men and 0.68 (0.55-0.85) in women). The estimated HRs of % trunk and leg fat on the development of diabetes differed little between normal weight and overweight/obese subjects. Appendicular lean mass was also negatively associated with diabetes risk only in normal weight men., Conclusions: Opposite associations of trunk fat and leg fat with diabetes risk were observed. Assessment of body composition might help in the evaluation of diabetes risk.

Purpose: Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE 2 )., Materials and Methods: A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis., Results and Conclusion: Radiation exposure, higher levels of bE 2 , testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE 2 level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE 2 was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE 2 levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.

Background: Although nucleoside/nucleotide analogue therapy is thought to suppress chronic hepatitis B (CHB) via regulation of inflammatory cytokines/chemokines, the mechanism is still unclear. In this study, serum cytokine/chemokine levels were measured in CHB patients treated with entecavir, and the association with antiviral response was analysed., Methods: A total of 78 Japanese patients with CHB were enrolled, and serum cytokine/chemokine levels were measured at baseline and at 12, 24 and 48 weeks of entecavir treatment using the MULTIPLEX kit., Results: Antiviral response to entecavir treatment was significantly associated with hepatitis B surface antigen (HBsAg) titre and serum interferon-gamma-inducible protein 10 (IP-10) level (12w; P=0.0002; OR=0.020 [95% CI 0.002, 0.156], P=0.003; OR=0.042 [95% CI 0.005, 0.336], respectively). HBe-positive patients whose serum macrophage-derived chemokine (MDC) level was lower (<582.83 pg/ml) and IP-10 level was higher (≥1,323.13 pg/ml) achieved hepatitis B e antigen (HBeAg) loss earlier than those who remained HBeAg-positive (P=0.044). HBsAg reduction by entecavir treatment was significantly associated with higher initial tumour necrosis factor-alpha (TNF-α) level (≥15.20 pg/ml) and higher alanine aminotransferase level (≥73 IU/l; P=0.009; OR=18.460 [95% CI 2.044, 166.709], P=0.022; OR=7.709 [95% CI 1.341, 44.327], respectively)., Conclusions: Results of the present study indicate that changes in cytokine/chemokine levels following entecavir therapy are associated with response to antiviral therapy in CHB patients. Monitoring of serum cytokine/chemokine levels could be useful for predicting reduction of HBV DNA and HBsAg and HBe seroconversion.