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Background: Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan., Methods: We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years])., Results: The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population., Conclusion: To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer)., (© 2024. The Author(s).)

Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group ( n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group ( n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants ( P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors ( β = -0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy., Competing Interests: Electrodes for intraepidermal electrical stimulation were supplied by Nihon Kohden Corp, Tokyo, Japan. All authors report no disclosures relevant to the manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Epstein‒Barr virus (EBV) infection is a primary oncogenic factor of nasopharyngeal carcinoma (NPC) that elicits epithelial-mesenchymal transition (EMT). Although diabetic patients are more susceptible to various infectious diseases, the pathological association with virus-related NPC has not yet been clarified. Herein, we evaluated the influence of diabetes on the clinicopathological changes of 70 patients with NPC. Disease-specific survival (DSS) modified by viral infection was also analysed. The proportion of NPC patients with diabetes was 32.9% (23/70 cases), and 91.3% (21/23 cases) were infected with EBV detected by EBER-I in situ hybridisation. NPC with diabetes showed an effect on EMT evaluated by immunostaining for E-cadherin and vimentin, which was correlated with HbA1c levels. Receiver operating characteristic (ROC) curve analysis determined a HbA1c level of 6.5% as the cut-off value for primary disease death at 2 years [area under the curve (AUC) 0.76; sensitivity 0.64; and specificity 0.81]. High HbA1c levels (≥6.5%) significantly increased the number of lymph node metastases in NPC compared to low HbA1c levels (<6.5%, p<0.01). Diabetic NPC patients had a significantly poorer prognosis than all non-diabetic patients (DSS, 72 months vs not reached, p<0.05). Diabetic EBV-positive NPC patients had a significantly poorer prognosis than non-diabetic EBV-positive patients (DSS, 35 months vs not reached, p<0.01). Multivariate analysis using the Cox proportional hazards model also suggested that HbA1c ≥6.5% was a significant factor in poor prognosis, with a hazard ratio of 6.84 (p<0.05). Collectively, our results revealed for the first time a high prevalence of EBV infection, poor prognosis and the importance of proper glycaemic control in diabetic NPC patients., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Despite recent advances in the range of therapies available for the treatment of multiple myeloma (MM), there are limited data surrounding survival outcomes and baseline characteristics influencing survival in general clinical practice in Japan. The aim of this study was to use electronic medical records (EMRs) to examine overall survival (OS) and prognostic factors in Japanese patients with MM. We extracted EMRs in the Real World Data (RWD) database of patients with a confirmed diagnosis of MM and treatment history with bortezomib, thalidomide, and/or lenalidomide. OS and prognostic factors for OS were analyzed using a univariate analysis and decision tree model. Of the 6509 patients in the database with a diagnosis of MM, 1565 were eligible. Patients had a median (range) age of 72 (23-92) years, a median OS of 53.5 months, and a 5-year OS rate of 45.6%. In alignment with previous studies, International Staging System stage and age were prognostic of OS. In addition, platelet and erythrocyte counts, chloride, total protein, C-reactive protein, and lactate dehydrogenase levels were identified as important prognostic factors for OS and were used to pilot a simple prognostic tool. In conclusion, we found that the survival outcomes extracted from EMRs in the RWD of Japanese patients with MM aligned with a previous retrospective study from Japan. Baseline laboratory parameters prognostic for OS were explored with additional factors to International Staging System and age identified. These might be used to optimize treatment selection, although further investigation using additional data sources is required., Competing Interests: S.U. and S.M. are employees of Bristol Myers Squibb K.K. and stockholders of Bristol Myers Squibb. K.I. and D.I. are employees of SUSMED Inc. These do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. T.I. reports study funding from Bristol Myers Squibb K.K. and honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Chugai, CSL Behring, Novartis, Sanofi, and Takeda. J.K. reports grants or contracts from Asahi Kasei, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eizai, Fujimoto Pharmaceutical, Kyowa Kirin, Nippon Shinyaku, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Shionogi, Sumitomo Pharmaceutical, Takeda Pharmaceutical, and Taiho Pharmaceutical; consulting fees from Bristol Myers Squibb and Janssen Pharmaceutical; and payments or honoraria from Bristol Myers Squibb, Janssen Pharmaceutical, Ono Pharmaceutical, and Sanofi. K.S. reports honoraria from Abbvie, Amgen, Bristol Myers Squibb, Janssen, Novartis, ONO, Sanofi, and Takeda; consulting fees from Amgen, Bristol Myers Squibb and Takeda; and research funding from Bristol Myers Squibb., (Copyright: © 2023 Uno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Overdiagnosis of thyroid cancer has become a major global medical issue. Ultrasound-based thyroid cancer screening has promoted overdiagnosis, and recently international recommendations state that it should not be conducted, even after a nuclear accident. The Fukushima thyroid cancer screening program was initiated in 2011 as a health policy after the nuclear accident. The risk of radiation-induced thyroid cancer was unlikely given the low radiation levels, but the thyroid cancer screening program has continued at 2-year intervals with a relatively high participation rate and is now in its fifth round. It is therefore crucial to clarify whether those targeted for screening understand the disadvantages of screening, and to identify factors that influenced their decision to participate., Methods: We conducted an anonymous mail-based questionnaire among young people from Fukushima Prefecture (subjects) and a neighboring prefecture that was not targeted for screening (non-subjects). We asked them about the significance of the thyroid cancer screening in Fukushima Prefecture, their reasons for accepting or refusing screening, their perception of the harms of screening, and their opinions on thyroid examination at school. We compared the results of the questionnaire between subjects and non-subjects and between examinees (who were screened) and non-examinees (who declined screening)., Results: Only 16.5% of respondents were aware of the harms associated with thyroid cancer screening, with most perceiving that the benefits outweighed the harms. Comparison of subjects' and non-subjects' responses showed there were no significant differences between the two groups. Among subjects, there were also no differences in responses between examinees and non-examinees. The most common reason for participation in screening was that the screening was conducted in schools and perceived as obligatory., Conclusions: These results highlighted a serious ethical issue in that school-based screening leads to making young people think that it is mandatory screening in an opt-out and default setting manner, with a lack of knowledge about the disadvantages of screening. Based on the autonomy of the subjects and the ethical principle of the post-disaster, surveys after a nuclear disaster should be conducted in an opt-in style without an opt-out style such as school-based screening., (© 2022. The Author(s).)

Various studies have investigated radiation risk perceptions after the accident at the Fukushima Daiichi Nuclear Power Station. However, student surveys are limited. This study aimed to investigate the perception of radiation risk among students aged 18-20 years who were in the 5th and 6th grades of elementary school at the time of the accident. We surveyed students in the Fukushima Prefecture and outside the prefecture. Out of all the data, 59% of the respondents were living in the Fukushima Prefecture at the time of the accident and 41% outside the prefecture. Trajectory analysis showed that changes in anxiety levels over time since 2011 could be divided into five classes: (a) the anxiety was the highest, and this tendency persisted. (b) High at the beginning, but decreased more quickly than class 1. (c) High at the beginning, but it diminished quickly. (d) Not high, but did not diminish easily in later years. (e) Low from the beginning, and persisted. Multinomial logistic analysis showed that among students living outside the prefecture at the time of the accident, a significantly higher proportion was in groups 4 and 5 than in group 2. A significant proportion of boys were present in groups 3, 4 and 5. A significant proportion of students whose current educational institutions were inside the prefecture were present in group 3. The level of anxiety was associated with the academic course, but not with subjective knowledge of radiation. In contrast, in the qualitative analysis of the free text, 31% considered 'knowledge about radiation' as the reason for the reduction in anxiety level. At the time of the investigation, most young people were not anxious about radiation. However, approximately 20% still had strong anxiety. We established that continuous risk communication is necessary. Furthermore, that stabilization and support related to life in general is important., (© 2021 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Many radiation protection actions carry a multitude of direct and indirect consequences that can impact on the welfare of affected populations. Health surveillance raises ethical challenges linked to privacy and data protection, as well as questions about the net benefit of screening. The SHAMISEN project recognized these issues and developed specific recommendations to highlight ethical challenges. Following a brief overview of ethical issues related to accident management, this paper presents the SHAMISEN recommendations: R1 The fundamental ethical principle of doing more good than harm should be central to accident management; and R4 Ensure that health surveillance respects the autonomy and dignity of affected populations, and is sensitive to any inequity in the distribution of risks and impacts. While a holistic approach to accident management means that decisions will be complicated by different values, perceptions and uncertainties about outcomes, addressing ethical issues could help ensure that the assumptions and potential conflicts behind eventual decisions are as transparent as possible., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The complex disaster of the Great East Japan Earthquake and the Fukushima nuclear accident caused concern about their various health impacts. Many types of intervention are desired as a countermeasure, depending on the phase of the disaster cycle. The importance of developing and applying codes of conduct has recently been emphasized for post-disaster investigations. Thyroid examination as a type of cancer screening survey was launched from October 2011 after the Fukushima nuclear accident as part of the Fukushima Health Management Survey. In this article, we reviewed the results of three rounds of thyroid examination from 2011 to 2018, and summarized the points to consider in the health survey conducted after the Fukushima nuclear accident. Large-scale mass screening by ultrasound thyroid examination resulted in many cancer diagnoses, >200 cases from a large reservoir of thyroid cancer that goes mainly unnoticed without screening. To prevent the harms of such over-diagnosis, we should be aware of the disadvantage of mass-screening based on the expected natural history of thyroid cancer. A change in strategy from mass-screening to individual monitoring is urgently needed according to international recommendations that are opposed to thyroid ultrasound cancer screening even after a nuclear disaster. To guarantee autonomy and informed choice on post-disaster disease monitoring for residents in a disaster-zone, it is important to set protocol participation and on a voluntary code of conduct basis., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

Background: After the Fukushima Daiichi Nuclear Power Plant accident, a preliminary ultrasound-based screening for thyroid cancer was conducted to establish a baseline for subsequent evaluations. In this survey, we assessed the relationship between the proportion of non-examinees and characteristics of the target populations., Methods: After summarizing a regional difference of non-examinees among the population of 359,200 (primary evaluation) and 2,246 (confirmatory testing) individuals who were living in Fukushima Prefecture on March 11, 2011, we estimated odds ratios (ORs) for each characteristic, including age, sex, area of residence, and moving after the accident, based on the proportion of non-examinees for the primary examination and the confirmatory testing, using a multivariate logistic regression model., Results: The dataset included 64,117 non-examinees (primary evaluation) and 194 (confirmatory testing). The logistic regression result indicated that girls were not likely to be non-examinees compared to boys, with adjusted OR of 0.80 (95% confidence interval [CI], 0.78-0.81) for the primary evaluation. Odds were lowest for children 6-10 years old (OR 0.26; 95% CI, 0.25-0.27), and higher for those 11-15 years old (OR 1.28; 95% CI, 1.25-1.32) and over 16 years old (OR 5.30; 95% CI, 5.16-5.43) when compared to children 0-5 years old. Individuals residing in the western part of the prefecture showed higher ORs. There was a higher proportion of non-examinees among those who moved after the accident compared to those who did not in the primary evaluation (OR 1.72; 95% CI, 1.64-1.79)., Conclusions: In addition to demographic characteristics, a change of residence could be a potential factor that influenced the proportion of non-examinees. Our results will help proper interpretation of reports and prospective management of the survey.

Since Fukushima nuclear accident in 2011, thyroid ultrasound examinations have been conducted. The first full-scale examination detected 71 thyroid-cancer cases. This study examined whether radiation exposure was associated with thyroid-cancer incidence.Subjects were participants in the baseline screening and newborns during the 2011 fiscal year. Under nested matched case-control study design, 10 controls per each case were selected by matching the age, sex, baseline screening results, and interval between examinations. With 3 dose levels of external radiation: 1.3 + mSv (upper), 0.8 to 1.3 (middle), and 0.0 to 0.8 (reference), we applied 2 logistic models adjusting for 3 participation-proportions (primary, secondary, and fine-needle aspiratory cytology), overweight, and the B-result of baseline screening (Model 1), and past medical history, family history of thyroid cancer, and frequencies of eating seafood and seaweed in addition to the parameters in Model 1 (Model 2). We examined each model in 3 ways: (a) excluding subjects with a missing radiation exposure dose; and substituting (b1) median or (b2) mean dose of the municipality with missing dose.Odds ratios (ORs) of middle-dose exposure were (a) 1.35 (0.46-3.94), (b1) 1.55 (0.61-3.96), and (b2) 1.23 (0.50-3.03) for Model 1, and (a) 1.18 (0.39-3.57), (b1) 1.31 (0.49-3.49), and (b2) 1.02 (0.40-2.59) for Model 2. For upper-dose exposure, similar results were obtained. Past medical history was significantly associated (odds ratio  = 2.04-2.08) with both (b1) and (b2) in Model 2.No significant associations were obtained between the external radiation exposure and thyroid-cancer incidence.

The purpose of this study was to evaluate the kinetic parameters that determine the uptake rate of radioiodide in the thyroid over 24 h after administration and to estimate thyroid volumes/masses of present-day Japanese. Methods: We determined the thyroid uptake rate of I in healthy male Japanese after oral administration (4.5-8.0 MBq) without iodine restriction. Masses of thyroid glands were collected in 2012-2016 during autopsies of 7,651 male and 3,331 female subjects. Volumes of thyroid glands were estimated by ultrasonography and magnetic resonance imaging in 52 male subjects. Results: The thyroid uptake rate of I for 24 h was 16.1 ± 5.4%. Kinetic model analysis was conducted to obtain the clearances (L h) for thyroid uptake and urinary excretion of I (0.499 ± 0.258 and 2.10 ± 0.39 L h, respectively). The masses of thyroid glands were on average 19.8 g (95% confidence interval of 18.3-19.5 g) and 15.5 g (95% confidence interval of 14.7-16.2 g) in male and female subjects aged 19-52 y, respectively. Volumes of thyroid glands estimated by ultrasonography and magnetic resonance imaging were 17.5 ± 5.2 and 14.2 ± 5.3 mL, respectively. In healthy Japanese, there has been no significant change for at least 50 y in the thyroid uptake of radioiodide over 24 h or in its kinetic parameters. These Japanese-specific kinetic parameters will allow quantitative estimation of the radiation exposure from the Fukushima accident and its variance during the individual's evacuation from or stay in Fukushima.

Patients with indolent non-Hodgkin lymphoma (iNHL) typically respond to first-line immunochemotherapy, but relapse is common. Treatment options for relapsed iNHL include chemotherapy ± rituximab and rituximab monotherapy. Lenalidomide plus rituximab (R 2 ) is an immunomodulatory regimen that enhances rituximab-mediated cytotoxicity and improves clinical activity in iNHL. AUGMENT was a double-blind phase III randomized trial of R 2 vs. rituximab + placebo (R-placebo) in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma who were not refractory to rituximab. The primary endpoint was progression-free survival (PFS). Data reported here focus on Japanese patients from AUGMENT and reflect 36 patients (n = 18, each group). PFS was superior in the R 2 group, HR = 0.32 (95% CI 0.11-0.96). Median PFS was not reached (95% CI 19.7-NE) in the R 2 group vs. 16.5 months (95% CI 11.3-30.6) in the R-placebo group. Grade 3/4 adverse events were more frequent in patients treated with R 2 (67%) than with R-placebo (22%), primarily attributable to increased neutropenia (50% vs 17%). R 2 resulted in significantly longer median PFS than R-placebo in Japanese patients with R/R iNHL, and the efficacy and the safety profile of R 2 were similar to those reported in the global population.

Background: The 2011 Great East Japan Earthquake led to a nuclear accident at Fukushima Daiichi Nuclear Power Plant. This study examines the associations of radiation dose and lifestyle factors with incidence of thyroid cancer in Fukushima., Methods: We designed a prospective study with 300,473 participants aged 18 years or younger, who underwent thyroid examinations from October 2011. Follow-up surveys were conducted through June 2017, and 245,530 participants (123,480 men and 122,050 women, 82% follow-up) received follow-up examinations. Fukushima Prefecture was divided into five areas based on individual external radiation dose. We calculated relative risks and 95% confidence intervals (CIs) for thyroid cancer in each area, with area of lowest dose as reference, using age-adjusted Poisson regression models. We also calculated risks associated with overweight and obesity., Results: The incidence per 100,000 for Groups A (highest dose), B, C, D, and E (lowest dose) were 13.5, 19.2, 17.3, 9.0, and 8.3, respectively. Compared with Group E, the age-adjusted risks (95% CIs) were 1.62 (0.59, 4.47) for group A, 2.32 (0.86, 6.24) for group B, 2.21 (0.82, 5.94) for group C, and 1.02 (0.36, 2.86) for group D. Obesity was positively associated with thyroid cancer incidence; the multivariable-adjusted risk of thyroid cancer was 2.23 (1.01, 4.90) for obese individuals compared with nonobese individuals., Conclusion: Regional differences in radiation dose were not associated with increased risk of thyroid cancer among children in Fukushima within 4 to 6 years after the nuclear power plant accident. Obesity may be an important factor for further follow-up in Fukushima.

Importance: Ultrasonographic (US) screening for thyroid cancer was performed in the Fukushima Health Management Survey after the 2011 Fukushima Daiichi nuclear power station accident. Clinical characteristics of thyroid cancers screened by US among children and young adults during the first 5 years after the accident were analyzed., Objectives: To evaluate the number of detected thyroid cancers by age group within 5 years of the Fukushima Daiichi nuclear power station accident and to compare the basic clinical characteristics and demographic patterns in first- and second-round examinations., Design, Setting, and Participants: In this observational study, 324 301 individuals 18 years or younger at the time of accident were included. Patients received a cytologic diagnosis of malignant or suspected malignant thyroid cancer during the first (fiscal years 2011-2013) or second round (fiscal years 2014-2015) of screening. Number of detected cases of cancer was evaluated, correcting for the number of examinees by age group at the time of the accident and for the incidence of detected cancers according to age group at the time of the screening (age groups were divided into 3-year intervals). Results were compared using the age-specific incidence of unscreened cancers from a national cancer registry., Main Outcomes and Measures: Clinical baseline characteristics of the patients and the age-specific number and incidence of thyroid cancers detected during the second round., Results: Among 299 905 individuals screened in the first round (50.5% male; mean [SD] age at screening, 14.9 [2.6] years), malignant or suspected thyroid cancer was diagnosed in 116. Among 271 083 individuals screened in the second round (50.4% male; age at screening, 12.6 [3.2] years), malignant or suspected thyroid cancer was diagnosed in 71. The most common pathologic diagnosis in surgical cases was papillary thyroid cancer (149 of 152 [98.0%]). The distribution pattern by age group at the time of the accident, where the number of detected thyroid cancer cases was corrected by the number of examinees, increased with older age in both screening rounds. This demographic pattern was similar between the first and second examinations. The distribution pattern of the incidence rate by age group at the time of screening in the second round also increased with older age. The incidence rate detected by screening was 29 cases per 100 000 person-years for those aged 15 to 17 years, 48 cases per 100 000 person-years for those aged 18 to 20 years, and 64 cases per 100 000 person-years for those aged 21 to 22 years., Conclusions and Relevance: Large-scale mass US screening of young people resulted in the diagnosis of a number of thyroid cancers, with no major changes in overall characteristics within 5 years of the 2011 Fukushima nuclear power station accident. These results suggest that US screening can identify many detectable cancers from a large pool of nonclinical and subclinical thyroid cancers among individuals of a relatively young age, in an age-dependent manner.

Following the Fukushima Daiichi Nuclear Power Plant (FNPP) accident on 11 March 2011, there have been concerns regarding the health impacts of the ensuing radioactive environmental contamination, which was spatially heterogeneous. This study aimed to assess the geographical variability of thyroid cancer prevalence among children and adolescents in Fukushima Prefecture. We computed the sex- and age-standardised prevalence ratio using 115 diagnosed or suspected thyroid cancer cases among approximately 300,000 examinees at the first-round ultrasound examination during 2011-2015 from 59 municipalities in the prefecture, under the Fukushima Health Management Survey. We applied flexibly shaped spatial scan statistics and the maximised excess events test on the dataset to detect locally anomalous high-prevalence regions. We also conducted Poisson regression with selected regional indicators. Furthermore, approximately 200 examinees showed positive ultrasound examination results but did not undergo confirmatory testing; thus, we employed simulation-based sensitivity tests to evaluate the possible effect of such undiagnosed cases in the statistical analysis. In conclusion, this study found no significant spatial anomalies/clusters or geographic trends of thyroid cancer prevalence among the ultrasound examinees, indicating that the thyroid cancer cases detected are unlikely to be attributable to regional factors, including radiation exposure resulting from the FNPP accident.

Herein we report that a preferable inhibition of the nucleation phase of Aβ42, related to the formation of toxic oligomers, by triterpenoids from medicinal herbs originates from a salt bridge of their carboxy groups with Lys16 and 28 in Aβ42. Such a direct interaction targeting the monomer, dimer, and trimer suppressed further oligomerization. In contrast, the corresponding congeners without carboxy groups failed to do so.

Work-related mental health impairment is recognized as a real problem in the context of helping responders, including health professionals, due to adverse health outcomes after a severe disaster. The Great East-Japan Earthquake, which occurred on 11 March 2011, was an unprecedented complex disaster that caused a nuclear accident at the Fukushima Daiichi Nuclear Power Plant (NPP). In addition to disaster stress and daily work, medical and health-care professionals, particularly nurses, provided counseling services to residents concerned about radiation health risks or mental health issues. This review focuses on the psychological aspects of the complex nuclear disaster, which was a combined artificial nuclear accident and natural disaster, and we investigated the psychological effects on hospital nurses associated with their experiences during the disaster. We looked at several investigations into the mental health of nurses after a nuclear disaster and in other situations. It was shown that mental health of nurses is impacted, not only after nuclear disasters but also in other circumstances. Furthermore, we noted the effects of extended periods of a heavy workload and daily life. Regarding anxiety about radiation exposure, nurses who had more knowledge of radiation tended to have better mental health, suggesting that education about the health risks of radiation exposure is important for health-care professionals. In summary, it is essential that nurses are provided with education about radiation exposure and its associated health risks, and also that there is a comprehensive approach to mental health care for nurses during the chronic phase of a disaster.

Context: Childhood thyroid cancer is of great concern after the Fukushima nuclear power plant accident. Baseline analytical data on thyroid ultrasound examination (TUE) in children are important for future studies., Objective: We analyzed the age and sex distribution of findings from the TUEs of children and adolescents in the Fukushima Health Management Survey (FHMS)., Design, Setting, and Participants: From October 2011 through March 2014, 294,905 participants aged 18 years or younger at the time of the earthquake voluntarily had TUEs in the first round of the FHMS. A secondary confirmatory examination was performed in 2032 subjects. Age- and sex-dependent prevalence and size of thyroid cysts, nodules, and cancers were analyzed., Main Outcome Measures: Age, sex, and size distribution of findings were analyzed., Results: Thyroid cysts, nodules, and cytologically suspected cancers were detected in 68,009, 1415, and 38 male subjects and in 73,014, 2455, and 74 female subjects, respectively. There was an age-dependent increase in the detection rate of thyroid nodules and cancer, but that of cysts reached a peak at 11 to 12 years. Sex affected the prevalence of thyroid nodules and cancers after the onset of puberty, but only a small difference was exhibited in that of cysts., Conclusions: The thyroid cancer detection rate in Fukushima was clarified, and the proportion of individuals with thyroid nodules and cysts varied substantially by age. The results of this study will contribute to future epidemiological research on nodular thyroid diseases in children and adolescents.

Importance: Thyroid cancer generally grows at a very slow rate in adults, and overdiagnosis is a global issue. However, the detection of early-stage thyroid cancer by screening is not well described in young patients. To prevent overdiagnosis, it is essential to understand the natural course of thyroid cancer growth detection by ultrasonography screening in young patients., Objective: To evaluate the natural progression of thyroid cancer in young patients., Design, Setting, and Participants: An observational study evaluated changes in the diameter of malignant or suspected malignant thyroid tumors on 2 occasions. Changes in malignant thyroid tumor diameter were estimated during the observation period between the screening and confirmatory examinations in the first-round thyroid ultrasonography examination of the Fukushima Health Management Survey in patients younger than 21 years after a nuclear accident at a power plant in Fukushima, Japan. In total, 116 patients cytologically diagnosed with or suspected to have thyroid cancer were classified into 3 groups based on a greater than 10% reduction, a change of -10% to +10% in diameter, and a greater than 10% increase in tumor diameter. The association between tumor growth rate and tumor diameter was analyzed. The study was conducted from March 1, 2016, to August 6, 2017., Main Outcomes and Measures: Tumor volume changes, the coefficient of growth of thyroid cancer in young patients, and the association between the observation period or tumor diameter and them., Results: Of 116 patients, 77 were female; the mean age was 16.9 years (median, 17.5 years). The mean observation period was 0.488 (range, 0.077-1.632) years. No significant differences in age, sex, tumor diameter, observation period, or serum levels of thyrotropin and thyroglobulin were observed among the groups. Whereas tumor volume changes were not linearly correlated with the observation period (Pearson R = 0.121; 95% CI, -0.062 to 0.297), the coefficient of growth was significantly and negatively correlated with the tumor diameter in the screening examination (Spearman ρ = -0.183; 95% CI, -0.354 to -0.001), suggesting growth arrest after the initial proliferation phase., Conclusions and Relevance: Ultrasonography screening could reveal asymptomatic thyroid cancer that is falling into a growth arrest pattern in many young patients. Considering the long life expectancy, prevention of overdiagnosis necessitates careful long-term monitoring without immediate diagnosis for suspected noninvasive thyroid cancer.

During the 4 years following the nuclear power plant accident of 2011, 39 males and 77 females were diagnosed with or suspected of having cancer based on the first-round thyroid examination of the Fukushima Health Management Survey (FHMS) targeting residents aged <19 years in Fukushima. Prior comparisons between the observed data and Japan's National Cancer Registry (NCR) data suggested that this incidence might be excessive, but such comparisons are problematic because they need not only to adjust index unit (prevalence proportion vs incidence rate), but also examine characteristics (complete enumeration mass screening for the aged 0 to 18 years vs detections in clinical settings for all the residents) and sensitivity of the examinations. The purpose of this study is to build a common model applicable to any region in Japan under nonaccident conditions, and estimate the expected prevalence based on the numbers of subjects surveyed in the FHMS using a simulation of the sensitivity.The cancer-progression model is an extension of Day and Walter's, the parameters of which were estimated by minimizing the weighted root mean squared error between the average age-specific thyroid incident rates from 2001 to 2010 in the NCR and those determined by the model. We estimated expected detectable prevalent cases by the model with their examination-participation proportions and simulated several sensitivities.Median sojourn times were 34 years (males) and 30 years (females) by the model. Simulation results showed that the numbers of observed prevalent cases were within the 95% confidence intervals of the expected prevalent cases with several sensitivities in each gender.We successfully built a cancer-progression model of thyroid cancer based on Japan's NCR data under no accident conditions. It is a tool for comparing the observed prevalence data of examinations and the NCR data, which resolved 3 issues of index unit, the characteristics and sensitivity of the examinations. Simulation results imply that the number of observed thyroid cancer cases can be detected by the FHMS first-round thyroid screening at several sensitivities under no accident conditions.

Objective: The CHOKAI and STONE scores are prediction models for ureteral stones. The aims of the present study were to evaluate the diagnostic performance, to examine the optimal cut-off value, and to compare the diagnostic performance of each model., Methods: Patients who presented to our emergency department with renal colic were considered for this prospective study. We analyzed the predictive performance of both STONE and CHOKAI scores at their optimal cut-off values, using receiver operating characteristic (ROC) curve and area under the curve (AUC), as well as sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) at the optimal cut-off value., Results: Of the 96 patients who met the inclusion criteria, 79 were definitively diagnosed with ureteral stones. All patients were of Japanese descent. The AUC of the CHOKAI score was 0.971 at an optimal cut-off value of 6, showing a sensitivity of 0.911, specificity of 0.941, LR+ of 15.49, and LR- of 0.094. The AUC of the STONE score was 0.873 at an optimal cut-off value of 8, showing a sensitivity of 0.823, specificity of 0.824, LR+ of 4.662, and LR- of 0.215. The AUC of the CHOKAI score was significantly higher than that of the STONE score (p=0.010). Of the 73 patients with a CHOKAI score of ≥6, 98.6% had ureteral stones, and of the 68 patients with a STONE score of ≥8, 95.6% had ureteral stones., Conclusions: The simplified CHOKAI score is a useful tool to screen for ureteral stones in patients with renal colic., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Thyroid hemiagenesis is a rare congenital variant characterized by the lack of development of one thyroid lobe with no clinical manifestations., Methods: This study was performed to determine the prevalence and characteristics of thyroid hemiagenesis in a normal Japanese population. This cross-sectional study was performed from October 9, 2011, to April 30, 2015. In total, 299,908 children and young adults in the Fukushima Health Management Survey were examined to determine the presence of thyroid agenesis or hemiagenesis. Thyroid width, thickness, and length were measured in 292,452 of these subjects., Results: Thyroid agenesis was diagnosed in 13 subjects, and hemiagenesis was detected in 67 subjects (0.02%; 22.3/100,000 individuals). Although there was no significant sex-related difference (p = 0.067), the female:male ratio was 1.67:1.00. Females were significantly dominant in right hemiagenesis, while there was no difference in left hemiagenesis between males and females. The thyroid volumes at the 2.5th and 97.5th percentiles for age and body surface area were determined for each sex. Multivariate regression analysis showed that a large hemithyroid volume was independently associated with the presence of contralateral hemiagenesis (p < 0.001)., Conclusion: The prevalence of thyroid hemiagenesis in the present study is in agreement with that reported in other countries. The prevalence of right hemiagenesis was higher in females, and the larger contralateral lobe in patients with rather than without hemiagenesis may have been caused by a compensatory feedback mechanism to prevent hypothyroidism. In addition, the prevalence of hemiagenesis, especially right hemiagenesis, may be affected by sex-related factors similar to those in patients with an ectopic thyroid gland.

The mental health of hospital nurses is a key health issue in public health promotion during the recovery phase following the Fukushima disaster. In this study, conducted 4 years after the disaster, we analyzed the overall mental health, knowledge, risk perception of radiation, and work and daily life burdens of nurses working at medical institutions in the Fukushima Prefecture (collection rate = 89.6%; response number = 730). Overall mental health status was estimated using the 12-item version of the General Health Questionnaire, and 333 respondents (45.6%) scored above the 12-item General Health Questionnaire threshold point (≥4), indicating probable emotional distress compared with the general population under normal circumstances. Multivariate logistic analysis suggested that the ability to cope with daily life and work-related stressors were more important than risk perception and acquisition of knowledge regarding radiation and its control methods for supporting the mental health of nurses following the Fukushima disaster.

A thyroid ultrasound examination program has been conducted in the aftermath of the Fukushima Daiichi Nuclear Power Plant accident to address concerns about the increased risk of thyroid cancer similar to those experienced by local residents after the 1986 Chernobyl accident. This is the second-largest thyroid cancer screening in younger age ever, following only that conducted after Chernobyl. As the natural history of thyroid cancer in younger populations is not well characterized, large-scale screening using thyroid ultrasound could result in overdiagnosis, even with careful planning, as has been experienced in South Korea. Awareness regarding the thyroid gland is generally low among residents, who tend to directly associate examination results with radiation exposure and are likely to develop newfound anxiety and feelings of self-condemnation and guilt. We reviewed the dilemma surrounding cancer screening and particularly underscored the need to address psychosocial issues associated with possible overdiagnosis. We modified our approach to address individual and social anxiety induced by results of screening conducted after the Fukushima accident. These findings and our experiences regarding the psychosocial issues related to thyroid examination should assist residents in their lifelong decision making and help them prepare for future disasters.

In a Japanese phase II study (MM-025), the efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) were confirmed at a median follow-up of 14.2 months in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem cell transplantation. In the present report, we analyzed the follow-up data from the abovementioned study. Treatment was stopped for all 26 patients after a median follow-up of 31.3 months, and the median treatment duration was approximately 25 months. The overall response rate was 87.5%, and the complete response rate was 20.8%. The median duration of response and progression-free survival were 30.7 and 31.6 months, respectively. The median overall survival has not yet been reached. At least one grade 3/4 adverse event was experienced by 23 patients (88.5%), and 18 patients (69.2%) experienced serious adverse events. There were no treatment-related deaths. Therefore, the efficacy and safety of Rd were confirmed in transplant-ineligible Japanese patients with newly diagnosed multiple myeloma at the present follow-up period.

Purpose Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL. Patients and Methods Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25 mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival. Results Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥ 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible. Conclusion Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted.

Oligomers of the 42-mer amyloid-β protein (Aβ42), rather than fibrils, cause synaptic dysfunction in the pathology of Alzheimer's disease (AD). The nucleation phase in a nucleation-dependent aggregation model of Aβ42 is related to the formation of oligomers. Uncaria rhynchophylla is one component of "Yokukansan", a Kampo medicine, which is widely used for treating AD symptoms. Previously, an extract of U. rhynchophylla was found to reduce the aggregation of Aβ42, but its active principles have yet to be identified. In the present work, uncarinic acid C (3) was identified as an inhibitor of Aβ42 aggregation that is present in U. rhynchophylla. Moreover, compound 3 acted as a specific inhibitor of the nucleation phase of Aβ42 aggregation. Compound 3 was synthesized from saponin A (10), an abundant byproduct of rutin purified from Uncaria elliptica. Comprehensive structure-activity studies on 3 suggest that both a C-27 ferulate and a C-28 carboxylic acid group are required for its inhibitory activity. These findings may aid the development of oligomer-specific inhibitors for AD therapy.

We report a rare case of primary pituitary lymphoma in a 75-year-old immunocompetent woman. The patient was blind in the right eye and presented with visual disturbance in the left eye that started 2 months previously. She also exhibited right third and fifth cranial nerve palsy. Magnetic resonance imaging(MRI)revealed an intrasellar mass lesion with right cavernous sinus invasion and suprasellar extension with compression of the optic chiasm. The mass lesion was isointense on both T1WI and T2WI, and showed less enhancement than a normal pituitary gland on gadolinium-enhanced T1WI. We therefore suspected the tumor to be a nonfunctioning pituitary adenoma. The patient underwent endoscopic endonasal transsphenoidal surgery. The tumor was firm and grayish, and had an ill-defined border along the normal pituitary gland. Histological examination revealed a malignant CD5-positive diffuse large B-cell lymphoma. After surgery, the patient received both chemotherapy and radiotherapy. Although the visual acuity of the right eye did not improved, other symptoms improved. At the 34-month follow-up, no recurrence was detected on serial MRI. Patients with primary pituitary lymphoma often exhibit ophthalmoplegia and/or panhypopituitarism more frequently than expected from radiological findings. In cases of pituitary tumors with atypical symptoms, a biopsy and general physical examination should be performed immediately to determine the diagnosis and perform adjuvant therapy even when the tumor is assumed as nonfunctioning pituitary adenoma from the image findings.

After the Fukushima Daiichi nuclear accident in 2011 and thyroid examinations of children in Fukushima, the Radiation Medical Science Center began "Explanatory meetings on thyroid examination" as a method of communication with residents such as the subjects themselves and their guardians. Through questionnaires, we examined the relationship between anxiety (regarding the effects of radiation on the thyroid) before the meetings and individual attributes including attitudes on radiation, and then verified the effects of the meetings using measures of anxiety, comprehension, and satisfaction, as the outcomes. Of the meetings in 2014-2015, 799 people attended 30 sessions in Kenchu, Kenpoku, Iwaki, Soso, and outside of Fukushima Prefecture, and 594 people responded the questionnaires before and after the meetings on the same day. Level of anxiety before the meetings varied depending on individual attributes (including attitudes regarding collection information on radiation, advisors on radiation, and levels of subjective understanding), highlighting the importance of presenting information about radiation in a manner that is easy to understand, as well as providing opportunities for the exchange of opinions. Participation in meetings reduced anxiety. This was largely attributed to explanations about general characteristics of cancer and objective facts, including doses; status of the Chernobyl accident; and comparison in results of thyroid examinations with other prefectures in Japan. An opportunity for a question-and-answer session also contributed to increased overall satisfaction. The lower number of meeting participants was associated with anxiety reduction and higher subjective comprehension. The present findings obtained will be useful to facilitate evidence-based risk communication.

The 2011 Great East Japan Earthquake led to a subsequent nuclear accident at the Fukushima Daiichi Nuclear Power Plant. In its wake, we sought to examine the association between external radiation dose and thyroid cancer in Fukushima Prefecture. We applied a cross-sectional study design with 300,476 participants aged 18 years and younger who underwent thyroid examinations between October 2011 and June 2015. Areas within Fukushima Prefecture were divided into three groups based on individual external doses (≥1% of 5 mSv, <99% of 1 mSv/y, and the other). The odds ratios (ORs) and 95% confidence intervals of thyroid cancer for all areas, with the lowest dose area as reference, were calculated using logistic regression models adjusted for age and sex. Furthermore, the ORs of thyroid cancer for individual external doses of 1 mSv or more and 2 mSv or more, with the external dose less than 1 mSv as reference, were calculated. Prevalence of thyroid cancer for the location groups were 48/100,000 for the highest dose area, 36/100,000 for the middle dose area, and 41/100,000 for the lowest dose area. Compared with the lowest dose area, age-, and sex-adjusted ORs (95% confidence intervals) for the highest-dose and middle-dose areas were 1.49 (0.36-6.23) and 1.00 (0.67-1.50), respectively. The duration between accident and thyroid examination was not associated with thyroid cancer prevalence. There were no significant associations between individual external doses and prevalence of thyroid cancer. External radiation dose was not associated with thyroid cancer prevalence among Fukushima children within the first 4 years after the nuclear accident., Competing Interests: The authors have no conflicts of interest to declare.

Adrenocortical carcinoma (ACC) is a rare, highly malignant neoplasm harboring marked histologic heterogeneity. The Ki-67 labeling index (LI) is one of the most effective diagnostic and prognostic markers in ACC. However, its assessment has by no means been standardized. Therefore, in this study, we analyzed the Ki-67 LI in 18 ACC cases both by seven pathologists using microscopes (MA; manual analysis) and with digital image analysis (DIA) and also compared the Ki-67 LI obtained by selecting "hot spots" and formulating the "average" reading of the whole tumor specimen. In addition, we performed statistical analysis of the association between Ki-67 LI and the clinical and pathologic features of individual cases. The DIA was significantly correlated with MA in hot spots but not in the average fields. The Ki-67 LI in hot spots was significantly and consistently higher than that in average areas by both MA and DIA, indicating intratumoral heterogeneity. The Ki-67 LI was significantly correlated with the Weiss criteria (eosinophilic cytoplasm, nuclear atypia, atypical mitoses, and sinusoidal invasion) by any mode of evaluation. The clinical outcome was significantly better in the patients with a Ki-67 < 10% than in those with a Ki-67 > 10% by MA in hot spots. The Ki-67 LI in hot spots measured by MA best reflected the clinical and pathologic features of ACC. Employment of DIA to obtain the Ki-67 LI in ACC requires further improvement, including correction of its overestimation of the value by counting non-tumorous cells and nuclear segmentation in areas of high cell density., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Thyroid nodules and cancers are rare in children compared with adults. However, after the 1986 Chernobyl Nuclear Power Plant accident, a rapid increase in childhood thyroid cancer was observed. To avoid any confusion and misunderstanding of data obtained in Fukushima after the 2011 nuclear accident, baseline prevalence of thyroid nodules and cancers should be carefully assessed with standardized criteria systematically, and comprehensively applied to the population perceived to be at risk., Aims: Under the official framework of the Fukushima Health Management Survey, the thyroids of children in Fukushima were examined using ultrasound, and the results collected in the first four years after the nuclear accident were analyzed in order to establish a baseline prevalence of childhood thyroid abnormalities, especially cancer., Subjects and Methods: Of 367,685 people aged 18 years or younger as of April 1, 2011, who were living in Fukushima Prefecture at the time of the accident, 300,476 underwent thyroid ultrasound screening. Of those, 2108 subjects with thyroid nodules were further examined using an advanced ultrasound instrument, with standardized criteria applied to determine the need for fine-needle aspiration cytology (FNAC). FNAC results determined the need for surgery and histological confirmation of the cytological diagnosis., Results: Of the 2108 rescreened subjects, 543 underwent FNAC, of whom 113 were diagnosed with malignancy or suspected malignancy. Subsequently, 99 patients underwent surgical resection, revealing 95 cases of papillary thyroid cancer, three poorly differentiated cancers, and one benign nodule. The overall prevalence of childhood thyroid cancer in Fukushima was determined to be 37.3 per 100,000 with no significant differences between evacuated and non-evacuated areas. Thyroid cancer patients had external exposure estimates of <2.2 mSv during the first four months., Conclusions: The high prevalence of childhood thyroid cancer detected in this four-year study in Fukushima can be attributed to mass screening. It clearly exceeds what is found incidentally anywhere else. Direct comparisons with any other results, even those from cancer registries, are not meaningful because of differences in methodology.

In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Serum thyroid hormone concentration is regulated through the hypothalamic-pituitary-thyroid axis. This study aimed to clarify the relationships between thyroid hormone regulation and ultrasonographic findings in subjects with thyroid nodules detected during thyroid ultrasound examination for the Fukushima Health Management Survey., Methods: As of October 31, 2014, a total of 296,253 subjects, who had been living in Fukushima Prefecture at the time of the Fukushima nuclear power plant accident and were aged ≤18 years on March 11, 2011, participated in two concurrent screening programs. In the primary screening, thyroid nodules were detected in 2241 subjects. A secondary confirmatory thyroid ultrasound examination and blood sampling for thyroid function tests were performed on 2004 subjects. The subjects were reassessed and classified into disease-free subjects (Group 1), subjects with cysts only (Group 2), subjects with nodules (Group 3), and subjects with malignancy or suspected malignancy (Group 4). Serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4), thyrotropin (TSH), thyroglobulin, and the fT3/fT4 ratio were classified according to the diagnoses., Results: Inverse relationships between age and log TSH values (Spearman's correlation r = -0.311, p = 0.015), serum fT3 concentration (r = -0.688, p < 0.001), and the fT3/fT4 ratio (r = -0.520, p < 0.001) were observed in Group 1. When analysis of covariance with Bonferroni post hoc comparisons was used in the four groups, the log TSH values were significantly lower in both Group 3 and Group 4 compared with Group 1 and Group 2 after correcting for age (p < 0.001; Group 1 vs. Group 3, p = 0.016; Group 1 vs. Group 4, p = 0.022; Group 2 vs. Group 3, p = 0.001; Group 2 vs. Group 4, p = 0.008). However, no significant differences were observed between the four groups regarding levels of fT3, fT4, fT3/fT4 ratio, and thyroglobulin (p = 0.304, 0.340, 0.208, and 0.583, respectively)., Conclusion: TSH suppression can be present in response to illness, including thyroid nodules, in young subjects. Low TSH levels may be associated with the finding of papillary thyroid cancer as well as with thyroid nodules in children and adolescents.

Background: Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas., Methods: In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0-2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1-21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298., Findings: We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient., Interpretation: We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study., Funding: Celgene Corporation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

As a response to the health effects associated with the Fukushima Daiichi Nuclear Power Plant accident that occurred after the Great East Japan Earthquake, the Thyroid Ultrasound Examination program as a part of the Fukushima Health Management Survey was started on Oct. 9th, 2011. Since this project required a large-scale cohort comprising all residents aged ≤ 18 years living in Fukushima when the earthquake happened, the nurturing of many ultrasound examiners was a matter of great urgency. Moreover, the standardization of examination procedures and skills of examiners were also important issues. Therefore, educational projects were established to develop ultrasound skills for medical doctors and technicians in Fukushima Prefecture. Marked efforts for this project resulted in increases in ultrasound examiners and institutions taking part in the Thyroid Ultrasound Examination project. Medical technicians specialized in ultrasound examinations are actively involved in these educational projects. We report the details of human resource development projects from the point of view of such medical technicians.

We herein present the findings of a 42-year-old woman with either adrenal pheochromocytoma or intraadrenal paraganglioma that simultaneously secreted somatostatin, thus mimicking insulin-dependent diabetes mellitus. Pheochromocytoma was clinically diagnosed based on scintigraphy, elevated catecholamine levels, and finally a histopathological analysis of resected specimens. The patient had diabetic ketosis, requiring 40 U insulin for treatment. Following laparoscopic adrenalectomy, insulin therapy was discontinued and the urinary c-peptide levels changed from 5.5-9.0 to 81.3-87.0 μg/day. Histologically, somatostatin immunoreactivity was detected and the somatostatin levels were elevated in the serum-like fluid obtained from the tumor. Clinicians should be aware of the possible occurrence of simultaneous ectopic hormone secretion in patients with pheochromocytoma.

Unlabelled: After the Fukushima nuclear power plant accident on March 11, 2011, the public of Japan became particularly concerned about the possibility of an increased risk of childhood thyroid cancer, similar to what was observed after the Chernobyl's accident. Due to serious public health perception, there was an urgency to evaluate the baseline levels of childhood thyroid status in Fukushima prefecture. Therefore we have commenced a thyroid ultrasound examination (TUE) survey of the approximately 360,000 pediatric inhabitants (0 to 18 years of age) who lived in Fukushima at the time of the accident in October 2011. The subjects were divided into three categories according to the standardized diagnostic criteria of ultrasound findings. Category A contained the subjects whose TUE findings were intact or benign. Category B were recommended a confirmatory TUE. Category C was recommended an immediate confirmatory TUE., Results: The survey of 40,302 subjects in the first year was completed in March, 2013. There were 40,097 (99.5%), 205 (0.50%) and 0 subjects in categories A, B and C, respectively. Of the 82 category B subjects who underwent fine needle aspiration cytology (FNAC), 12 were diagnosed with a malignant tumor or were suspected to have malignancy. The 12 subjects received thyroid surgery and 11 thyroid cancers and one benign nodule were confirmed histologically after surgery. This is the first large-scaled TUE survey to employ sophisticated ultrasound screening and aim to evaluate the baseline frequency of childhood thyroid nodules and cysts. The results will become the golden standard of future comparative TUE in Fukushima, Japan.

This phase 1, open-label, dose-escalation study investigated the tolerated dose (recommended dose), safety, efficacy, and pharmacokinetics of pomalidomide alone or pomalidomide plus low-dose dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma. Twelve patients were enrolled. Patients received pomalidomide 2 mg (Cohort 1) or 4 mg (Cohort 2) orally on day 1 and days 3-21 of a 28-day cycle. The tolerated dose of pomalidomide was determined to be 4 mg given on days 1-21 of a 28-day cycle. Efficacy outcomes with pomalidomide plus low-dose dexamethasone were consistent with those of previous studies. Responses (partial response or better) were achieved by three patients (25%; 1 [17%] in Cohort 1 and 2 [33%] in Cohort 2), and the median time to response was 6.4 months overall (9.0 months for Cohort 1 and 4.2 months for Cohort 2). The median progression-free survival was 5.5 months overall (5.1 months for Cohort 1 and not reached for Cohort 2). The most frequently occurring grade ≥3 adverse events were neutropenia (67%), anemia (25%), lymphopenia (25%), and pneumonia (25%), consistent with previous studies of pomalidomide plus low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Further investigation of pomalidomide is recommended for Japanese patients with refractory or relapsed and refractory multiple myeloma. This study was registered with ClinicalTrials.gov (NCT01568294)., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

We report an extremely rare case of familial breast cancer with deleterious germline mutations in both BRCA1 and BRCA2 genes, of which, to date, no such case has been reported among Japanese breast/ovarian cancer patients. Genetic testing of the family members indicated that the same double heterozygosity for BRCA1 and BRCA2 genes was transmitted to the paternal cousin, and the same BRCA2 mutation to the younger sister with bilateral breast cancer, younger brother with stomach cancer, and proband's son and daughter without cancer. Immunohistochemical analysis of BRCA protein expression was performed using breast cancer tissues from the proband with double heterozygosity for BRCA1 and BRCA2 genes and from her sibling without BRCA1 mutation but with BRCA2 mutation. There was no staining of either BRCA in the proband and no staining of BRCA2 in the sibling.

Past nuclear disasters, such as the atomic bombings in 1945 and major accidents at nuclear power plants, have highlighted similarities in potential public health effects of radiation in both circumstances, including health issues unrelated to radiation exposure. Although the rarity of nuclear disasters limits opportunities to undertake rigorous research of evidence-based interventions and strategies, identification of lessons learned and development of an effective plan to protect the public, minimise negative effects, and protect emergency workers from exposure to high-dose radiation is important. Additionally, research is needed to help decision makers to avoid premature deaths among patients already in hospitals and other vulnerable groups during evacuation. Since nuclear disasters can affect hundreds of thousands of people, a substantial number of people are at risk of physical and mental harm in each disaster. During the recovery period after a nuclear disaster, physicians might need to screen for psychological burdens and provide general physical and mental health care for many affected residents who might experience long-term displacement. Reliable communication of personalised risks has emerged as a challenge for health-care professionals beyond the need to explain radiation protection. To overcome difficulties of risk communication and provide decision aids to protect workers, vulnerable people, and residents after a nuclear disaster, physicians should receive training in nuclear disaster response. This training should include evidence-based interventions, support decisions to balance potential harms and benefits, and take account of scientific uncertainty in provision of community health care. An open and joint learning process is essential to prepare for, and minimise the effects of, future nuclear disasters., (Copyright © 2015 Elsevier Ltd. All rights reserved.)