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.

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.

[Surgical Treatment of Thyroid Cancer].

The strategy for surgical treatment of thyroid cancer differs depending on the histopathological type. In papillary thyroid cancer, which accounts for most cases of thyroid cancer, total thyroidectomy is recommended in high-risk cases with tumors of more than 5 cm or with N1, EX2, or M1 tumors in Japan. On the other hand, ipsilateral lobectomy is performed for low-risk cases with T1N0M0. Our department has also added a treatment policy for the prognostic factor, age. Prophylactic lymph node dissection is performed in the central neck region but is not recommended in the lateral neck region. In follicular thyroid cancer, total thyroidectomy is recommended for widely invasive cancer, and hemithyroidectomy or ipsilateral lobectomy is performed for minimally invasive cancer. When widely invasive cancer is diagnosed after lobectomy, completion thyroidectomy is recommended. Whether minimally invasive follicular cancer with vascular invasion requires completion thyroidectomy is controversial. I also handle medullary thyroid cancer, poorly differentiated thyroid cancer, undifferentiated thyroid cancer, and thyroid malignant lymphoma with a different policy. It is important to balance a surgical treatment strategy with a molecular targeted therapy and radioactive iodine treatment.

Electrohydraulic musculoskeletal robotic leg for agile, adaptive, yet energy-efficient locomotion.

Robotic locomotion in unstructured terrain demands an agile, adaptive, and energy-efficient architecture. To traverse such terrains, legged robots use rigid electromagnetic motors and sensorized drivetrains to adapt to the environment actively. These systems struggle to compete with animals that excel through their agile and effortless motion in natural environments. We propose a bio-inspired musculoskeletal leg architecture driven by antagonistic pairs of electrohydraulic artificial muscles. Our leg is mounted on a boom arm and can adaptively hop on varying terrain in an energy-efficient yet agile manner. It can also detect obstacles through capacitive self-sensing. The leg performs powerful and agile gait motions beyond 5 Hz and high jumps up to 40 % of the leg height. Our leg's tunable stiffness and inherent adaptability allow it to hop over grass, sand, gravel, pebbles, and large rocks using only open-loop force control. The electrohydraulic leg features a low cost of transport (0.73), and while squatting, it consumes only a fraction of the energy (1.2 %) compared to its conventional electromagnetic counterpart. Its agile, adaptive, and energy-efficient properties would open a roadmap toward a new class of musculoskeletal robots for versatile locomotion and operation in unstructured natural environments.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1. DESIGN/PATIENTS: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed. MEASUREMENTS: Clinical and genetic features of Japanese patients with MEN1 were examined. RESULTS: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient. CONCLUSIONS: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan.

More than 50% of patients with multiple endocrine neoplasia type 1 (MEN1) develop gastroenteropancreatic neuroendocrine tumors (GEPNETs), and insulinoma is the second most common functioning GEPNET. Compared to other functioning and nonfunctioning GEPNETs in MEN1, insulinoma is considered to develop at a younger age. To clarify the clinical features of insulinoma developed in Japanese patients with MEN1, a recently constructed database of Japanese MEN1 patients was analyzed. Among 560 registered cases, insulinoma was seen in 69 patients and information on age at diagnosis was available for 54 patients. Tumors predominantly occurred in the body and tail of the pancreas. The mean age at diagnosis of insulinoma (34.8 ± 16.7 yrs) was significantly younger than that of gastrinoma (50.6 ± 14.3 yrs) and nonfunctioning tumor (44.7 ± 13.3 yrs) in patients with MEN1. Patients diagnosed as having insulinoma during middle-age (30 - 49 yrs) tended to have a long period from appearance of hypoglycemic symptoms to diagnosis of the tumor. Of note, 13 patients (24%) were diagnosed as having insulinoma before 20 yrs of age. Such young onset was not seen in other GEPNETs. Since the development of GEPNETs during adolescence is quite rare, insulinoma diagnosed before 20 yrs strongly suggests the presence of MEN1 and warrants further investigation, including MEN1 genetic testing. Also, clinicians should be aware that insulinoma can often be missed in middle-aged patients.

Active pole bending effect in pole support phase.

In pole vaulting, model analysis is one of the key methods to increase vaulting height. To date, the effects of athletes' motions during 'pole support phase' have been measured and modelled to improve and set new world records. The motions were extracted based on the context of pole bending interaction and parameters to improve vaulting height were investigated. However, due to experimental, mechanical, and sensing restrictions, ranges and interactions of the parameters were poorly addressed. To investigate further, a parameter space must be globally explored. Here, we show parameter sensitivities and interactive effects between initial velocity, pole length, bending amplitude and switching time. From the simulation studies, we found that active pole bending enabled successful pole vaulting with lower initial velocity and longer poles. Vaulting height had a local maximum point at a specific initial velocity and positive bending could control conditions to deliver the local maximum height. Positive bending controls the rising-up speed of the pole and contributes to the verticalisation of the vaulting angle. Negative bending increases the vaulting speed and contributes to the robustness of the vaulting angle. Our results demonstrate how these parameters affect the vaulting performances and suggest how athletes should activate their bodies.

Inertial Tail Effects during Righting of Squirrels in Unexpected Falls: From Behavior to Robotics.

Arboreal mammals navigate a highly three dimensional and discontinuous habitat. Among arboreal mammals, squirrels demonstrate impressive agility. In a recent "viral" YouTube video, unsuspecting squirrels were mechanically catapulted off of a track, inducing an initially uncontrolled rotation of the body. Interestingly, they skillfully stabilized themselves using tail motion, which ultimately allowed the squirrels to land successfully. Here we analyze the mechanism by which the squirrels recover from large body angular rates. We analyzed from the video that squirrels first use their tail to help stabilizing their head to visually fix a landing site. Then the tail starts to rotate to help stabilizing the body, preparing themselves for landing. To analyze further the mechanism of this tail use during mid-air, we built a multibody squirrel model and showed the righting strategy based on body inertia moment changes and active angular momentum transfer between axes. To validate the hypothesized strategy, we made a squirrel-like robot and demonstrated a fall-stabilizing experiment. Our results demonstrate that a squirrel's long tail, despite comprising just 3% of body mass, can inertially stabilize a rapidly rotating body. This research contributes to better understanding the importance of long tails for righting mechanisms in animals living in complex environments such as trees.

Donor site of follicular unit excision hair transplantation: the relationship between appearance and actual hair density, and hair diameter.

Donor site morbidity is an important consideration for follicular unit excision (FUE). We examined 103 male patients with adult androgenic alopecia. Patients were divided into three groups (Good, Fair, and Poor) based on visual assessment of the donor site. Hair density and hair diameter were measured using digital photography. A total of 72, 21 and 10 patients were classified into the Good, Fair and Poor appearance groups. The average hair density of each group was 127.8 ± 22.6 hair/cm2, 114.8 ± 23.1 hair/cm2 and 94.9 ± 25.4 hair/cm2. The hair density of the Good group was significantly higher than that of the Poor group (p = 0.003). The average hair diameter of each group was 0.0968 ± 0.0267 mm, 0.0754 ± 0.0299 mm and 0.0473 ± 0.0158 mm. The hair diameter of the Good group was significantly higher than that of the Poor group (p = 0.001). Thirty-three of 72 patients whose hair density was >130 hair/cm2 belonged to the Good group. Seven of 10 patients whose hair density was <105.0 hair/cm2 belonged to the Poor group, while 31 of 72 patients whose hair diameter was <0.101 mm were included in the Good group. Eight of 10 patients whose hair diameter was less than 0.070 mm were in the Poor group. Donor sites rated Good on appearance had both high hair density and thick hair diameter. To maintain a good appearance after FUE, donor site hair density should not be less than 105.0 hair/cm2.

The Clinicopathological Results of Thyroid Cancer With BRAFV600E Mutation in the Young Population of Fukushima.

BACKGROUND: Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features. METHODS: We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC). RESULTS: The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ±â€…6.8 mm) than in wild-type BRAF cases (20.9 ±â€…10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis. CONCLUSIONS: The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima.

A Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi-Tyrosine Kinase Inhibitor Lenvatinib.

Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor α, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib.

Findings of Thyroid Ultrasound Examination Within 3 Years After the Fukushima Nuclear Power Plant Accident: The Fukushima Health Management Survey.

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.

[Strategy for the surgical treatment of the well-differentiated thyroid carcinoma in our hospital].

Well differentiated thyroid carcinoma (WDTC) consists of papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Although both cancers are excellent prognosis, there are different in carcinogenesis by some genes, criteria of pathological diagnosis and transforming pattern between PTC and FTC. So the strategy for surgical treatment of them should be discussed separately. The patient with PTC less than 45 years old whose tumor is localized in a unilateral lobe without extra thyroidal invasion, lymph node metastasis and distant metastasis should be performed a unilateral lobectomy with central node dissection (D1). PTC patient over 45 years old except micro PTC case (T1a N0, M0) is recommended total thyroidectomy with modified radical neck dissection (D2 or D3). Encapsulated FTC is not necessary prophylactic lymph node dissection and only preformed unilateral lobectomy. If this patient has vascular invasion after lobectomy, completion thyroidectomy will be recommended for monitoring by serum Tg and whole body 123I scan.

Prevalence and Characterization of Thyroid Hemiagenesis in Japan: The Fukushima Health Management Survey.

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.

Identification of Three Novel Fusion Oncogenes, SQSTM1/NTRK3, AFAP1L2/RET, and PPFIBP2/RET, in Thyroid Cancers of Young Patients in Fukushima.

BACKGROUND: The BRAFV600E mutation is the most frequent genetic abnormality in adult papillary thyroid carcinomas (PTCs). On the other hand, various chromosomal rearrangements are more prevalent in childhood and adolescent PTCs. The aim of the present study was to identify novel rearrangements in PTCs from young patients. METHODS: Among 63 postoperative specimens of childhood and adolescent PTCs, which had been discovered by the thyroid ultrasound screening program in Fukushima, nine samples without prevalent known oncogenes, BRAFV600E, RAS, RET/PTC1, RET/PTC3, and ETV6/NTRK3, were analyzed in the current study by quantitative real-time reverse transcription polymerase chain reaction to screen for novel fusion genes by comparing transcript expression between extracellular and kinase domains of ALK, NTRK1, NTRK3, and RET. RESULTS: Of the above nine samples, five samples were suspected to harbor a fusion, and using subsequent 5' rapid amplification of cDNA end (RACE), two already reported fusion oncogenes, STRN/ALK and TPR/NTRK1, and three novel fusions, SQSTM1/NTRK3, AFAP1L2/RET, and PPFIBP2/RET, were identified. Functional analyses of these three chimeric genes were performed, and their transforming abilities were confirmed through the activation of mitogen-activated protein kinase (MAPK). CONCLUSIONS: Three novel fusion oncogenes have been identified in young PTC patients in Fukushima, suggesting that rare fusions may be present among the cases negative for known oncogenes in this age group and that such rearrangements can play a significant role in thyroid carcinogenesis.

Comparison of childhood thyroid cancer prevalence among 3 areas based on external radiation dose after the Fukushima Daiichi nuclear power plant accident: The Fukushima health management survey.

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.

Inappropriate Suppression of Thyrotropin Concentrations in Young Patients with Thyroid Nodules Including Thyroid Cancer: The Fukushima Health Management Survey.

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.

Comprehensive Survey Results of Childhood Thyroid Ultrasound Examinations in Fukushima in the First Four Years After the Fukushima Daiichi Nuclear Power Plant Accident.

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.

BRAF mutations in papillary carcinomas of the thyroid.

BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway. Recent studies have reported that mutations of the BRAF gene were detected with varying frequencies in several cancers, notably more than 60% in melanoma. We analysed mutations of BRAF and RAS genes in 100 cases of thyroid carcinoma to investigate genetic aberrations in the RAS/RAF/MEK/MAP kinase pathway. BRAF mutations were detected exclusively in papillary carcinomas (40 in 76 cases: 53%), and were exclusively V599E, a mutation frequently observed in other carcinomas. NRAS mutation was observed in six cases (6%), all in histological types other than papillary carcinoma, and was exclusively Q61R. No mutations were found in KRAS or HRAS. Our results suggest that BRAF mutations may play a critical role in the carcinogenesis of papillary carcinoma of the thyroid.

Roles of RAS and BRAF mutations in thyroid carcinogenesis.

Papillary carcinoma and follicular carcinoma are types of differentiated thyroid carcinomas, develop from the same thyroid follicular epithelial cells and show distinct biological behavior. Although several studies have demonstrated differences in the biological characteristics of these carcinomas, little is known about the genetic backgrounds that underlie these differences. The clarification of the genetic background can lead to the understanding of thyroid carcinogenesis, proper therapeutic strategies, and development of the molecular targeting drugs. Recently, aberrant activation of RAS-RAF-MEK-MAP kinase signaling pathway is frequently found in thyroid carcinoma. The pathway transmits a mitogenic signal to the nucleus, and constitutive activation of the pathway is thought to promote uncontrolled cell division. In our series, BRAF mutation was detected exclusively in papillary carcinoma (54%), and was exclusively V599E (a single nucleotide change of A-T at nucleotide 1796). NRAS mutation was observed in follicular carcinoma (50%) and in anaplastic carcinoma (28%), and was exclusively Q61R (a single nucleotide change of A-G at nucleotide 182). No mutations were found in KRAS or HRAS. In this chapter, we explain the role of RAS-RAF-MEK-MAP kinase pathway in carcinogenesis of the thyroid and its clinical implication based on our study. In addition, we review the current knowledge in this field.