Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Inflammation­based prognostic markers of metastatic pancreatic cancer using real­world data in Japan: The Tokushukai REAl­world Data (TREAD) project.

Inflammation-based prognostic markers based on a combination of blood-based parameters, including the modified Glasgow prognostic score (mGPS), have been associated with clinical outcomes in patients with various types of cancer. The present study aimed to evaluate and compare the accuracy of these previously reported markers in patients with metastatic pancreatic cancer receiving first-line chemotherapy. A total of 846 patients were identified between April 2010 and March 2020 as part of a nationwide real-world study from 46 Tokushukai medical group hospitals in Japan. Blood laboratory data collected within 14 days of starting first-line chemotherapy assessed 17 inflammation-based prognostic markers. Information from patients with no missing data was used to compare the accuracy and performance of the inflammation-based prognostic markers. A total of 487 patients were eligible for this supplemental analysis. The 17 inflammation-based markers demonstrated significant prognostic value. Among them, the concordance rate with overall survival (OS) was highest for mGPS. The median OS time of patients with mGPS 0, 1 and 2 was 8.2, 6.0 and 2.9 months, respectively. Compared with mGPS 0, mGPS 1 and 2 showed hazard ratios of 1.39 (95% confidence interval, 1.07-1.81) and 2.63 (2.00-3.45), respectively. The present real-world data analysis showed that various previously reported inflammation-based markers had significant prognostic value in patients with metastatic pancreatic cancer. Among these markers, the mGPS demonstrated the highest level of accuracy. This trial has been registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000050590 on April 1, 2023.

Contribution of radioactive particles to the post-explosion exposure of atomic bomb survivors implied from their stable chromosome aberration rates.

Even today when nearly 80 years have passed after the atomic bomb (A-bomb) was dropped, there are still debates about the exact doses received by the A-bomb survivors. While initial airborne kerma radiation (or energy spectrum of emitted radiation) can be measured with sufficient accuracy to assess the radiation dose to A-bomb survivors, it is not easy to accurately assess the neutron dose including appropriate weighting of neutron absorbed dose. Particularly, possible post-explosion exposure due to the radioactive particles generated through neutron activation have been almost neglected so far, mainly because of a large uncertainty associated to the behavior of those particles. However, it has been supposed that contribution of such non-initial radiation exposure from the neutron-induced radioactive particles could be significant, according to the findings that the stable chromosomal aberration rates which indicate average whole-body radiation doses were found to be more than 30% higher for those exposed indoors than for those outdoors even at the same initial dose estimated for the Life Span Study. In this Mini Review article, the authors explain that such apparently controversial observations can be reasonably explained by assuming a higher production rate of neutron-induced radioactive particles in the indoor environment near the hypocenter.

Real­world treatment outcomes among patients with metastatic pancreatic cancer in Japan: The Tokushukai real­world data project.

The present study aimed to investigate temporal trends in treatment patterns and prognostic factors for overall survival (OS) among patients with metastatic pancreatic cancer. From the Tokushukai REAl-world Data project, 1,093 patients with metastatic pancreatic cancer treated with gemcitabine, tegafur/gimeracil/oteracil (S-1), gemcitabine plus S-1, gemcitabine plus nab-paclitaxel, or fluorouracil, folic acid, oxaliplatin and irinotecan (FOLFIRINOX) between April 2010 and March 2020 were identified. Stratified/conventional Cox regression analyses were conducted to examine associations between patient- and tumor-related factors, study period, hospital volume, hospital type and first-line chemotherapy regimens. Overall, 846 patients were selected (503 male patients; median age, 70 years) after excluding ineligible patients. Over a median follow-up of 5.4 months, the median OS was 6.8 months (95% confidence interval, 6.3-7.4). The median OS for gemcitabine, S-1, gemcitabine plus S-1, gemcitabine plus nab-paclitaxel and FOLFIRINOX regimens was 5.9, 5.3, 7.7, 9.0 and 9.5 months, respectively. The median OS for 2010-2013, 2014-2017 and 2017-2020 was 6.2, 7.1 and 7.8 months, respectively. Performance status, body mass index and first-line chemotherapy regimens were identified to be significant prognostic factors. In summary, the real-world data indicated that standard care, including chemotherapy, for metastatic pancreatic cancer was widely used in hospitals throughout Japan and verified the survival benefits of gemcitabine plus nab-paclitaxel and FOLFIRINOX observed in prior clinical trials. This trial has been registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000050590 on April 1, 2023.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

Real-World Outcomes of Systemic Therapy in Japanese Patients with Cancer (Tokushukai REAl-World Data Project: TREAD): Study Protocol for a Nationwide Cohort Study.

Cohort studies using large-scale databases have become increasingly important in recent years. The Tokushukai Medical Group is a leading medical group in Japan that includes 71 general hospitals nationwide from Hokkaido to Okinawa, with a total of 18,000 beds, and a unified electronic medical record system. This retrospective cohort study aims to evaluate the real-world outcomes of systemic therapy for Japanese patients with cancer using this merit of scale. All adult patients with cancer who received systemic therapy using a centrally registered chemotherapy protocol system at 46 hospitals from April 2010 to March 2020 will be identified (~48,850 patients). Key exclusion criteria include active double cancer and inadequate data extraction. Data will be obtained through electronic medical records, diagnosis procedure combination data, medical prescription data, and the national cancer registration system that includes sociodemographic variables, diagnostic and laboratory tests, concomitant drug prescriptions, cost, and overall survival. Kaplan-Meier estimates will be calculated for time-to-event analyses. Stratified/conventional Cox proportional hazards regression analyses will be conducted to examine the relationships between overall survival and related factors. Our findings provide important insights for future research directions, policy initiatives, medical guidelines, and clinical decision-making.

Microdistribution of internal radiation dose in biological tissues exposed to 56Mn dioxide microparticles.

Manganese-56 (56Mn) was one of the dominant neutron-activated radionuclides during the first hours following the atomic-bombing of Hiroshima and Nagasaki. The radiation spectrum of 56Mn and the radiation emission from excited levels of 56Fe following 56Mn beta-decay include gamma-quanta, beta-particles, Auger electrons and X-rays. The dispersion of neutron activated 56Mn in the air can lead to entering of radioactive microparticles into the lungs. The investigation of spatial microdistribution of an internal dose in biological tissue exposed to 56Mn is an important matter with regards to the possible elevated irradiation of the lung alveoli and alveolar ducts. The Monte Carlo code (MCNP-4C) was used for the calculation of absorbed doses in biological tissue around 56Mn dioxide microparticles. The estimated absorbed dose has a very essential gradient in the epithelium cells of lung alveoli and alveolar duct: from 61 mGy/decay on the surface of simple squamous cells of epithelium to 0.15 mGy/decay at distance of 0.3 µm, which is maximal cell thickness. It has been concluded that epithelial cells of these pulmonary microstructures are selectively irradiated by low-energy electrons: short-range component of beta-particles spectrum and Auger electrons. The data obtained are important for the interpretation of biological experiments implementing dispersed neutron-activated 56Mn dioxide powder.

Solid cancer mortality risk among a cohort of Hiroshima early entrants after the atomic bombing, 1970-2010: implications regarding health effects of residual radiation.

There are two types of exposure to atomic bomb (A-bomb) radiation: exposure to initial radiation released at the time of the detonation of the bomb, and exposure to residual radiation, which remains afterwards. Health hazards caused by exposure from residual radiation have not yet been clarified. The purpose of our study was to reveal the relationships between mortality risk from solid cancer and residual radiation based on data from the early entrants to Hiroshima. It is hard to identify the individual residual radiation doses. However, these are assumed to depend on the date of entry and the entrants' behavior. Individual behavior is thought to be closely related to gender and age at exposure. We investigated a cohort of 45 809 individuals who were living in Hiroshima Prefecture on 1 January 1970 and were registered on the Database of Atomic Bomb Survivors as entrants after the bombing. Poisson regression methods were used to estimate excess relative risks (ERR) with data cross-classified by sex, age at entry, and date of entry. In males in their 20s, 30s, and 40s at entry and in females less than 10 years old and in their 40s at entry, solid cancer mortality risks were significantly higher among persons who entered the city on the day of the bombing than those who entered three or more days later. With adjustments for the age-dependent sensitivities to radiation exposure, it was extrapolated that middle-aged people who entered the city on the day of the bombing were exposed to higher levels of residual radiation than younger people.

Effects of internal exposure to neutron-activated 56MnO2 powder on locomotor activity in rats.

At the detonation of the atomic bombing in Hiroshima and Nagasaki, a significant amount of radionuclides was produced by the neutron induced activation. The residual radiation from the explosion is crucial to the health risk of the people who entered these cities after the bombing and might have inhaled these radioactive materials. Because 56Mn is one of the major radionuclides produced in soil and have not been studied until now, we had conducted a series of experiments using rats to investigate the biological impacts of exposure of 56MnO2 particles. In these experiments, the rats' spontaneous locomotor activity was also assessed to examine the possible effects of 56Mn on their behavior. However, the locomotor activity data obtained from an individual experiment failed to identify radiation effects due to the large variation among animals and the small sample size. In the present study, all available data from our previous studies on 56MnO2 exposure (0.02-0.15 Gy of whole-body doses) as well as 60Co-γ exposure (at 2-5 Gy of whole-body doses) were pooled. Our statistical method, which takes into account individual differences and daily fluctuations, successfully identified a decrease in locomotor activity caused by 56MnO2 exposure, where the changes were gradual and reached the maximum reduction around 2 weeks after exposure. In contrast, exposure to 60Co-γ rays produced the highest decline of activity within one day. These results suggest that internal exposure to 56Mn at whole-body doses of even less than 0.15 Gy may have a long-lasting impact on locomotor activity.

Internal doses in experimental mice and rats following exposure to neutron-activated 56MnO2 powder: results of an international, multicenter study.

The experiment was performed in support of a Japanese initiative to investigate the biological effects of irradiation from residual neutron-activated radioactivity that resulted from the A-bombing. Radionuclide 56Mn (T1/2 = 2.58 h) is one of the main neutron-activated emitters during the first hours after neutron activation of soil dust particles. In our previous studies (2016-2017) related to irradiation of male Wistar rats after dispersion of 56MnO2 powder, the internal doses in rats were found to be very inhomogeneous: distribution of doses among different organs ranged from 1.3 Gy in small intestine to less than 0.0015 Gy in some of the other organs. Internal doses in the lungs ranged from 0.03 to 0.1 Gy. The essential pathological changes were found in lung tissue of rats despite a low level of irradiation. In the present study, the dosimetry investigations were extended: internal doses in experimental mice and rats were estimated for various activity levels of dispersed neutron-activated 56MnO2 powder. The following findings were noted: (a) internal radiation doses in mice were several times higher in comparison with rats under similar conditions of exposure to 56MnO2 powder. (b) When 2.74 × 108 Bq of 56MnO2 powder was dispersed over mice, doses of internal irradiation ranged from 0.81 to 4.5 Gy in the gastrointestinal tract (small intestine, stomach, large intestine), from 0.096 to 0.14 Gy in lungs, and doses in skin and eyes ranged from 0.29 to 0.42 Gy and from 0.12 to 0.16 Gy, respectively. Internal radiation doses in other organs of mice were much lower. (c) Internal radiation doses were significantly lower in organs of rats with the same activity of exposure to 56MnO2 powder (2.74 × 108 Bq): 0.09, 0.17, 0.29, and 0.025 Gy in stomach, small intestine, large intestine, and lungs, respectively. (d) Doses of internal irradiation in organs of rats and mice were two to four times higher when they were exposed to 8.0 × 108 Bq of 56MnO2 (in comparison with exposure to 2.74 × 108 Bq of 56MnO2). (e) Internal radiation doses in organs of mice were 7-14 times lower with the lowest 56MnO2 amount (8.0 × 107 Bq) in comparison with the highest amount, 8.0 × 108 Bq, of dispersed 56MnO2 powder. The data obtained will be used for interpretation of biological effects in experimental mice and rats that result from dispersion of various levels of neutron-activated 56MnO2 powder, which is the subject of separate studies.

Quantitative Analysis of Effects of a Single 60Co Gamma Ray Point Exposure on Time-Dependent Change in Locomotor Activity in Rats.

Investigating initial behavioral changes caused by irradiation of animals might provide important information to aid understanding of early health effects of radiation exposure and clinical features of radiation injury. Although previous studies in rodents suggested that radiation exposure leads to reduced activity, detailed properties of the effects were unrevealed due to a lack of proper statistical analysis, which is needed to better elucidate details of changes in locomotor activity. Ten-week-old male Wistar rats were subjected to single point external whole-body irradiation with 60Co gamma rays at 0, 2.0, 3.5, and 5.0 Gy (four rats per group). Infrared sensors were used to continuously record the locomotor activity of each rat. The cumulative number of movements during the night was defined as "activity" for each day. A non-linear mixed effects model accounting for individual differences and daily fluctuation of activity was applied to analyze the rats' longitudinal locomotor data. Our statistical method revealed characteristics of the changes in locomotor activity after radiation exposure, showing that (1) reduction in activity occurred immediately-and in a dose-dependent manner-after irradiation and (2) recovery to pre-irradiation levels required almost one week, with the same recovery rate in each dose group.

Haematological analysis of Japanese macaques (Macaca fuscata) in the area affected by the Fukushima Daiichi Nuclear Power Plant accident.

Several populations of wild Japanese macaques (Macaca fuscata) inhabit the area around Fukushima Daiichi Nuclear Power Plant (FNPP). To measure and control the size of these populations, macaques are captured annually. Between May 2013 and December 2014, we performed a haematological analysis of Japanese macaques captured within a 40-km radius of FNPP, the location of a nuclear disaster two years post-accident. The dose-rate of radiocaesium was estimated using the ERICA Tool. The median internal dose-rate was 7.6 µGy/day (ranging from 1.8 to 219 µGy/day) and the external dose-rate was 13.9 µGy/day (ranging from 6.7 to 35.1 µGy/day). We performed multiple regression analyses to estimate the dose-rate effects on haematological values in peripheral blood and bone marrow. The white blood cell and platelet counts showed an inverse correlation with the internal dose-rate in mature macaques. Furthermore, the myeloid cell, megakaryocyte, and haematopoietic cell counts were inversely correlated and the occupancy of adipose tissue was positively correlated with internal dose-rate in femoral bone marrow of mature macaques. These relationships suggest that persistent whole body exposure to low-dose-rate radiation affects haematopoiesis in Japanese macaques.

Advantages of high b-value diffusion-weighted imaging for preoperative differential diagnosis between embryonal and ependymal tumors at 3 T MRI.

PURPOSE: It is often difficult to distinguish between embryonal and ependymal tumors using conventional MR imaging. The apparent diffusion coefficient (ADC) calculated from diffusion-weighted images (DWI) has been widely used for diagnosis, but its usefulness for differential diagnosis between embryonal and ependymal tumors has not been determined yet. Both DWI properties and ADC values of these two types of tumor at regular and high b-values on a 3 T MR scanner were retrospectively reviewed. MATERIALS AND METHODS: DWI at 3 T was acquired for 16 patients with embryonal tumors (including medulloblastoma, CNS embryonal tumors (NOS), and atypical teratoid/rhabdoid tumor), and 7 patients with ependymal tumors (including ependymoma and anaplastic ependymoma). ADC was measured by manually placing multiple regions of interest (ROIs) on ADC maps corresponding to enhancing lesions on contrast-enhanced T1-weighted images, both on standard (b-1000) and high (b-4000) b-value DWI. The minimum ADC (ADC-MIN) was calculated from several ROIs placed on each tumor. The relationship between tumor cell density and ADC-MIN was also investigated. RESULTS: Both at b-1000 and b-4000, ADC-MIN was significantly lower in embryonal tumors than in ependymal tumors. Embryonal tumors could be completely discriminated from ependymal tumors using both b-values, but ADC-MIN at b-4000 (t-value = -8.312, p < 0.001) was better than ADC-MIN at b-1000. There was a stronger negative correlation between cell density and ADC-MIN at b-4000 (r2 = 0.50, p < 0.001) than with ADC-MIN at b-1000 (r2 = 0.41, p < 0.001). CONCLUSION: Evaluating ADC-MIN at b-4000 would be a useful tool for distinguishing embryonal from ependymal tumors.

Chromosome aberrations in Japanese fishermen exposed to fallout radiation 420-1200 km distant from the nuclear explosion test site at Bikini Atoll: report 60 years after the incident.

During the period from March to May, 1954, the USA conducted six nuclear weapon tests at the "Bravo" detonation sites at the Bikini and Enewetak Atolls, Marshall Islands. At that time, the crew of tuna fishing boats and cargo ships that were operating approximately 150-1200 km away from the test sites were exposed to radioactive fallout. The crew of the fishing boats and those on cargo ships except the "5th Fukuryu-maru" did not undergo any health examinations at the time of the incident. In the present study, chromosome aberrations in peripheral blood lymphocytes were examined in detail by the G-banding method in 17 crew members from 8 fishing boats and 2 from one cargo ship, 60 years after the tests. None of the subjects examined had suffered from cancer. The percentages of both stable-type aberrations such as translocation, inversion and deletion, and unstable-type aberrations such as dicentric and centric ring in the study group were significantly higher (1.4- and 2.3-fold, respectively) than those in nine age-matched controls. In the exposed and control groups, the percentages of stable-type aberrations were 3.35 % and 2.45 %, respectively, and the numbers of dicentric and centric ring chromosomes per 100 cells were 0.35 and 0.15, respectively. Small clones were observed in three members of the exposed group. These results suggest that the crews were exposed to slightly higher levels of fallout than had hitherto been assumed.

Osteoprotegerin Prevents Development of Abdominal Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture and subsequent high mortality. Establishment of medical therapies for the prevention of AAAs requires further understanding of the molecular pathogenesis of this condition. This report details the possible involvement of Osteoprotegerin (OPG) in the prevention of AAAs through inhibition of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In CaCl2-induced AAA models, both internal and external diameters were significantly increased with destruction of elastic fibers in the media in Opg knockout (KO) mice, as compared to wild-type mice. Moreover, up-regulation of TRAIL expression was observed in the media by immunohistochemical analyses. Using a culture system, both the TRAIL-induced expression of matrix metalloproteinase-9 in smooth muscle cells (SMCs) and the chemoattractive effect of TRAIL on SMCs were inhibited by OPG. These data suggest that Opg may play a preventive role in the development of AAA through its antagonistic effect on Trail.

High Excess Risk of Heart Disease Mortality among Hiroshima Atomic Bomb Male Survivors Exposed Near the Hypocenter.

Heart disease (HD) mortality is the second leading cause of death in Japan. The HD mortality risk among Atomic bomb survivors is slightly positive but shows a statistically significant dose-response relationship with initial radiation dose, as reported by the Radiation Effects Research Foundation. In that report, dosimetry was based on initial radiation only, with the effect of indirect radiation dose not taken into consideration. The atomic bomb radiation, however, consisted of both initial and residual radiation. We reevaluated the dose-response relationship for HD mortality using exposure distance (ground distance between the location where exposed and the hypocenter) as a surrogate indicator of radiation dose. At Hiroshima University, a cohort study has been conducted with Hiroshima Atomic Bomb Survivors (ABS) since 1970. We selected 29605 subjects from the ABS who were exposed at 3.5 km or less from the hypocenter and alive on January 1, 1970. These subjects, referred to as "Hiroshima hibakusha" in this paper, were followed until December 31, 2010. We stratified the cohort data with respect to sex and age at the time of bombing (ATB) into 10-year age groups. For each stratum, by applying an extended Cox regression model with time-dependent covariates, we analyzed the risk of HD mortality using either initial radiation dose or exposure distance as an explanatory variable. The results indicate a high excess risk in males and older age ATB females who were exposed near the hypocenter. This difference may be explained by the effect of female sex hormone on the circulatory system among young age ATB females. Some unknown risk factor related to exposure distance was also implicated in the elevated risk of HD among the Hiroshima hibakusha, especially in males. This necessitates further study.

High Initial-dose Dependency of Cerebrovascular Disease Mortality among Female Survivors of the Hiroshima Atomic Bomb Exposed in Teens: A Cohort Study, 1970-2010.

Several studies have been conducted on cerebrovascular disease mortality in Atomic bomb survivors. Previous studies have investigated the relationship between mortality and initial radiation dose after adjusting for the effects of sex and age at the time of the bombing (ATB), and detected a weak (but statistically significant) dose-response relationship was detected. The objective of the present study was to examine whether the sex- and age ATB-specific cerebrovascular disease mortality among Hiroshima atomic bomb survivors can be explained by the initial radiation dose. At Hiroshima University, a cohort study has been conducted with Hiroshima Atomic Bomb Survivors (ABS) since 1970. We selected 30,378 subjects from the ABS who were exposed at 3.5 km or less from the hypocenter and still alive on January 1, 1970. These subjects were followed up until December 31, 2010. The cohort data were stratified with respect to sex and age ATB into 10-year age groups. For each stratum, using Cox regression, we performed survival analyses of the risk of cerebrovascular mortality using the initial radiation dose and the exposure distance (the ground distance between the exposure location and the hypocenter) as explanatory variables. The results indicated that the risks to females exposed at 10 to 19 years old were highly dependent on the initial radiation dose (hazard ratio: 1.51, p < 0.001), while the risks to males were not. There might exist some radiation exposure effects limited to women who were in their teens at the time of exposure. However, the background mechanisms remain unclear, necessitating further study.

Diffusion-weighted imaging and the apparent diffusion coefficient on 3T MR imaging in the differentiation of craniopharyngiomas and germ cell tumors.

The apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) plays an important role in diagnosing intracranial tumors and predicting the histopathological grade of the tumor. However, the differences in the ADC values between craniopharyngiomas and germ cell tumors (GCTs) have not been clarified. We therefore evaluated the DWI and ADC values at b = 1000 and b = 4000 s/mm(2) on 3T magnetic resonance (MR) imaging and assessed the possibility of differentiating between craniopharyngiomas and GCTs. We retrospectively reviewed 19 patients with craniopharyngioma and 24 patients with GCT who underwent surgery and received a histopathological diagnosis. Thirty-four patients underwent DWI with b = 1000 and b = 4000 s/mm(2) and nine patients underwent periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) DWI with b = 1000 s/mm(2). The ADC was determined by manually placing regions of interests (ROIs) in the respective tumor regions on the ADC maps and is expressed as the minimum (ADC(MIN)), mean (ADC(MEAN)), and maximum (ADC(MAX)) absolute values. The craniopharyngiomas showed lower intensity on DWI at b = 1000 and b = 4000 s/mm(2) than the GCTs. Furthermore, the craniopharyngiomas demonstrated significantly high ADC values (ADC(MIN), ADC(MEAN), and ADC(MAX)) in comparison with the GCTs on DWI at b = 1000 and b = 4000 s/mm(2). The logistic discriminant analysis clarified the advantage of ADC(MIN) at b = 4000 s/mm(2) in differentiating between craniopharyngiomas and GCTs compared with the other ADC values. DWI and the ADC values may help clinicians to differentiate between craniopharyngiomas and GCTs. The ADC(MIN) at b = 4000 s/mm(2) is particularly useful for differentiation.

Workshop Report on Atomic Bomb Dosimetry--Review of Dose Related Factors for the Evaluation of Exposures to Residual Radiation at Hiroshima and Nagasaki.

Groups of Japanese and American scientists, supported by international collaborators, have worked for many years to ensure the accuracy of the radiation dosimetry used in studies of health effects in the Japanese atomic bomb survivors. Reliable dosimetric models and systems are especially critical to epidemiologic studies of this population because of their importance in the development of worldwide radiation protection standards. While dosimetry systems, such as Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02), have improved, the research groups that developed them were unable to propose or confirm an additional contribution by residual radiation to the survivor's total body dose. In recognition of the need for an up-to-date review of residual radiation exposures in Hiroshima and Nagasaki, a half-day technical session was held for reports on newer studies at the 59 th Annual HPS Meeting in 2014 in Baltimore, MD. A day-and-a-half workshop was also held to provide time for detailed discussion of the newer studies and to evaluate their potential use in clarifying the residual radiation exposure to atomic bomb survivors at Hiroshima and Nagasaki. The process also involved a re-examination of very early surveys of radioisotope emissions from ground surfaces at Hiroshima and Nagasaki and early reports of health effects. New insights were reported on the potential contribution to residual radiation from neutron-activated radionuclides in the airburst's dust stem and pedestal and in unlofted soil, as well as from fission products and weapon debris from the nuclear cloud. However, disparate views remain concerning the actual residual radiation doses received by the atomic bomb survivors at different distances from the hypocenter. The workshop discussion indicated that measurements made using thermal luminescence and optically stimulated luminescence, like earlier measurements, especially in very thin layers of the samples, could be expanded to detect possible radiation exposures to beta particles and to determine their significance plus the extent of the various residual radiation areas at Hiroshima and Nagasaki. Other suggestions for future residual radiation studies are included in this workshop report.

A two-phase Poisson process model and its application to analysis of cancer mortality among A-bomb survivors.

We consider a two-phase Poisson process model where only early successive transitions are assumed to be sensitive to exposure. In the case where intensity transitions are low, we derive analytically an approximate formula for the distribution of time to event for the excess hazard ratio (EHR) due to a single point exposure. The formula for EHR is a polynomial in exposure dose. Since the formula for EHR contains no unknown parameters except for the number of total stages, number of exposure-sensitive stages, and a coefficient of exposure effect, it is applicable easily under a variety of situations where there exists a possible latency time from a single point exposure to occurrence of event. Based on the multistage hypothesis of cancer, we formulate a radiation carcinogenesis model in which only some early consecutive stages of the process are sensitive to exposure, whereas later stages are not affected. An illustrative analysis using the proposed model is given for cancer mortality among A-bomb survivors.