Young people's perspectives of thyroid cancer screening and its harms after the nuclear accident in Fukushima Prefecture: a questionnaire survey indicating opt-out screening strategy of the thyroid examination as an ethical issue.

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.

Trajectory and factors of radiation risk perception of students aged 10-12 years at the time of the Fukushima Daiichi Nuclear Power Station accident.

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.

Factors Influencing the Proportion of Non-examinees in the Fukushima Health Management Survey for Childhood and Adolescent Thyroid Cancer: Results From the Baseline Survey.

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.

A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11ß-hydroxylase inhibitor, in Japanese patients with endogenous Cushing's syndrome other than Cushing's disease.

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11ß-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.

External Radiation Dose, Obesity, and Risk of Childhood Thyroid Cancer After the Fukushima Daiichi Nuclear Power Plant Accident: The Fukushima Health Management Survey.

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.

Nuclear disasters and health: lessons learned, challenges, and proposals.

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.

The protocol and preliminary baseline survey results of the thyroid ultrasound examination in Fukushima [Rapid Communication].

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.

Explanatory Meetings on Thyroid Examination for the "Fukushima Health Management Survey" after the Great East Japan Earthquake: Reduction of Anxiety and Improvement of Comprehension.

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.

[Primary Pituitary Malignant Lymphoma that was Difficult to Differentiate from Nonfunctioning Pituitary Adenoma:A Case Report].

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.

[Human Resource Development for Thyroid Ultrasound Examination Program in Fukushima].

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.

Systematic determination of thyroid volume by ultrasound examination from infancy to adolescence in Japan: the Fukushima Health Management Survey.

Although several reports have defined normal thyroid volume depending on either age or body surface, there are no sequential reference values on childhood thyroid volume evaluated by using ultrasonography and epidemiological analysis in Japan. The aim of the present study was to establish updated reference values for thyroid volume by ultrasound examination and epidemiological analysis in 0-19 year-old Japanese children. It is based on a cross-sectional study conducted from October 9, 2011 to March 31, 2012. The subjects were 38,063 children who were examined by ultrasonography as the initial preliminary survey of the Fukushima Health Management Survey in October 9, 2011 to March 31, 2012. The width, thickness, and height of each lobe were measured and the volume of each lobe was calculated by the mean of the elliptical shape volume formula. The values of thyroid volume at the 2.5 and 97.5 percentiles of age and body surface area for each gender group were obtained from 0-19 year-old children. Positive correlation was observed between thyroid volume and either age or body surface. The right lobe was significantly larger than the left lobe. The thyroid volume in females was larger than that in males after adjusting body surface area. The reference values of childhood thyroid for each age or body surface area were obtained by this extensive survey using ultrasound. These reference values may be used to define the normal size of thyroid gland by echosonography in Japanese children, although thyroid volume may be affected by dimorphic factors such as sex hormones.

Plasma free metanephrines in the diagnosis of pheochromocytoma: diagnostic accuracy and strategies for Japanese patients.

Measuring the levels of the plasma free metanephrines (PFMs) represents a recently developed and promising test for the diagnosis of pheochromocytoma in the United States and Europe. As this test has not yet been evaluated in Japan, it is necessary to evaluate the diagnostic efficacy of measuring the levels of PFMs compared with the standard measurement of the urinary excretion of metanephrines (uMNs) whose reliability is well established to detect of pheochromocytoma. A total of 101 Japanese subjects clinically suspected of having pheochromocytoma in were included in this study. Subsequently, we prospectively measured the PFMs levels in all patients, compared with those of biochemical markers of the catecholamine secretion and metabolisms in the plasma and urine. All subjects with adrenal tumors underwent tumor excision. Data were available for 84 of the 101 patients, 47 of whom had histopathologically proven pheochromocytoma and 37 were finally diagnosed with non-pheochromocytoma. The results of comparisons in the accuracy of measurement for diagnosis of pheochromocytoma between PFMs and the urinary excretion of metanephrines (uMNs) were 0.980 VS 0.951 for AUC of receiver operatorating characteristic (ROC) curve, 0.957 VS 0.894 for sensitivity, and 0.973 VS 0.946 for specificity, respectively. Although the differences were small, the results of our study definitely demonstrated that measurement of PFMs was not inferior to standard urinary metanephrines (uMNs) measurement, which is established to be the most reliable biochemical method to detect pheochromocytoma. This study clearly shows measuring the PFMs levels to be a reliable and efficient method for diagnosing pheochromocytoma in Japanese patients, as demonstrated in previous reports.

Activating transcription factor 3 (ATF3) in the human adrenal cortex: its possible involvement in aldosterone biosynthesis.

The activating transcription factor 3 (ATF3) is a member of the cAMP-responsive element-binding (CREB) protein family of transcription factors. ATF3 is expressed in H295R human adrenocortical carcinoma cells and considered a rapid-responder gene to angiotensin-II stimulation. However, the functions of ATF3 in human adrenocortical tissues have remained unknown. In this study, we analyzed the localization and possible regulatory mechanisms of ATF3 in human adrenocortical cells and tissues. The expression levels of ATF3 mRNA were analyzed in 66 aldosterone-producing adenomas (APA) and 14 cortisol-producing adenomas (CPA) using real-time RT-PCR. To localize the ATF3 protein, we performed immunohistochemical analysis in 20 non-pathological adrenal glands, 9 adrenal glands with idiopathic hyperaldosteronism (IHA), 20 APA, and 5 CPA using a mouse monoclonal antibody against human ATF3. We showed that ATF3 mRNA levels were higher in APA compared to CPA (P = 0.0053). ATF3 was immunolocalized to the zona glomerulosa of non-pathological adrenal glands and adrenal glands with IHA, and diffusely detected in the tumor cells of APA and CPA. Subsequently, H295R cells were treated for 6 h with each inhibitor of Src kinase (SRC), PKC, JAK2, and calcium-dependent calmodulin kinase-II (CaMKII) in the presence or absence of angiotensin-II. The expression levels of ATF3 mRNA were increased by angiotensin-II (about 3.5-fold induction), but the magnitude of the induction was significantly decreased in the presence of an inhibitor for SRC (PP2) or CaMKII (KN93). These results suggest that ATF3 is a downstream target of SRC and CaMKII signaling, and may be involved in adrenocortical aldosterone synthesis.

Ultrasonographic thyroid nodular findings in Japanese children.

PURPOSE: The Fukushima Health Management Survey conducted after the accident at the Fukushima Nuclear Power Plant included thyroid ultrasound examinations for children aged ≤18 years at the time of the accident. The purpose of this study was to investigate the frequency of thyroid nodular lesions detected using high-quality ultrasonography in a general population of Japanese children, in whom such data have not been previously characterized. METHODS: The current study investigated 4,365 free-living children aged between 3 and 18 years in three Japanese prefectures (Aomori, Yamanashi and Nagasaki). The same ultrasonography equipment as that used in the Fukushima Survey was employed to observe thyroid nodular lesions. The following categories of findings were used-'A', further examinations are not necessary; 'B', the presence of thyroid nodules with a diameter of ≥5.1 mm or thyroid cysts with a diameter of ≥20.1 mm; and 'C', immediate further examinations are required. As a sub-category of 'A', 'A1' was defined as the absence of nodules or cysts, and 'A2' was defined as the presence of thyroid nodules with a diameter of ≤5.0 mm or thyroid cysts with a diameter of ≤20.0 mm. RESULTS: Overall, 4,321 (99 %) of the total participants were classified with a status of 'A' and 44 (1 %) were classified with a status of 'B'. No participants were classified with a status of 'C'. A total of 56.5 % of the total participants was classified with a status of 'A2'. Thyroid nodules were identified in 1.6 % of the total participants and thyroid cysts were identified in 56.9 % of the participants. CONCLUSION: The current study provides data regarding the actual frequency of ultrasonographically detected thyroid nodular lesions among the Japanese children. These results would be useful for evaluating thyroid findings in Japanese children, although careful interpretation is required.

Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma.

OBJECTIVE: Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects. PATIENTS AND METHODS: For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls. RESULTS: Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation. CONCLUSION: This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies.