TERT promoter mutations increase tumor aggressiveness by altering TERT mRNA splicing in papillary thyroid carcinoma.

CONTEXT: Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis compared with TERT-p mutation-positive tumors. OBJECTIVE: TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. METHODS: We investigated the expression of two major variants, α deletion (dA) and ß deletion (dB), in a series of 207 PTCs operated between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. RESULTS: The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into three groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A + B/dB ratio in mut+/exp + was significantly higher than that in mut-/exp + PTCs. Analysis with clinicopathological data revealed that +A + B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor suppressive role. CONCLUSION: These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Radiation-Related Thyroid Cancer.

Radiation is an environmental factor that elevates the risk of developing thyroid cancer. Actual and possible scenarios of exposures to external and internal radiation are multiple and diverse. This article reviews radiation doses to the thyroid and corresponding cancer risks due to planned, existing, and emergency exposure situations, and medical, public, and occupational categories of exposures. Any exposure scenario may deliver a range of doses to the thyroid, and the risk for cancer is addressed along with modifying factors. The consequences of the Chornobyl and Fukushima nuclear power plant accidents are described, summarizing the information on thyroid cancer epidemiology, treatment, and prognosis, clinicopathological characteristics, and genetic alterations. The Chornobyl thyroid cancers have evolved in time: becoming less aggressive and driver shifting from fusions to point mutations. A comparison of thyroid cancers from the 2 areas reveals numerous differences that cumulatively suggest the low probability of the radiogenic nature of thyroid cancers in Fukushima. In view of continuing usage of different sources of radiation in various settings, the possible ways of reducing thyroid cancer risk from exposures are considered. For external exposures, reasonable measures are generally in line with the As Low As Reasonably Achievable principle, while for internal irradiation from radioactive iodine, thyroid blocking with stable iodine may be recommended in addition to other measures in case of anticipated exposures from a nuclear reactor accident. Finally, the perspectives of studies of radiation effects on the thyroid are discussed from the epidemiological, basic science, and clinical points of view.

Characteristics and immune checkpoint status of radioiodine-refractory recurrent papillary thyroid carcinomas from Ukrainian Chornobyl Tissue Bank donors.

Introduction: The radioiodine-refractory (RAI-R) recurrent papillary thyroid carcinomas (PTCs) are more frequent in elderly patients and have an unfavorable prognosis. Data on the prevalence and characteristics of RAI-R recurrent PTCs in patients of young and middle age with or without a history of radiation exposure in childhood are poorly described. The aim of the current study was: i) to determine the frequency of RAI-R recurrent PTCs among donors of the Chornobyl Tissue Bank (CTB) and analyze the clinicopathological features of primary tumors (PTs), primary metastases (PMTSs), recurrent metastases (RMTSs) and risk factors for RMTS, and ii) to determine the immune checkpoint status (ICS) of the RAI-R recurrent PTCs and to assess the factors associated with ICS positivity. Methods: Sixty RAI-R recurrent PTCs (46 exposed to radiation and 14 non-exposed, 2.5% of all cases registered with the CTB) from the Ukrainian patients aged up to 48 years were identified. Results: The clinicopathological characteristics of the PTs moderately to weakly resembled those of the PMTS and RMTS from the same patients while the metastatic tissues were highly similar. The multivariate model of RMTS included the dominant solid-trabecular growth pattern of the PT, cystic changes, N1b metastases, and the probability of a causation (POC) of PTC by radiation as risk factors. Among these factors, the lateral PMTS (N1b) had the strongest effect. The longer period of latency (a POC component) was the second statistically significant characteristic. ICS percent agreement between the PT and RAI-R RMTS was 91.5%; 23.7% of PTs and 28.8% of RMTSs had positive ICS (positive PD-L1 tumor epithelial cells (TECs) and positive PD-L1/PD1 tumor-associated immune cells). ICS positivity of PTs was associated with pronounced oncocytic changes and high density of the p16INK4A-positive TECs in the invasive areas of PTs. In RMTSs, ICS positivity was associated with pronounced oncocytic changes and Ki-67 labeling index ≥ 4.5% of PTs, and the dominant solid-trabecular growth pattern, Ki-67 labeling index ≥ 7.6% and p16INK4A-positivity of RMTS. Discussion: The findings are of clinical relevance and may be useful for developing individual treatment approaches for patients with RAI-R recurrent PTCs possibly involving immunotherapy.

The high degree of similarity in histopathological and clinical characteristics between radiogenic and sporadic papillary thyroid microcarcinomas in young patients.

The potential overtreatment of patients with papillary thyroid microcarcinoma (MPTC) has been an important clinical problem in endocrine oncology over the past decade. At the same time, current clinical guidelines tend to consider prior radiation exposure as a contraindication to less extensive surgery, even for low-risk thyroid carcinomas, which primarily include microcarcinomas. This study aims to determine whether there are differences in the behavior of MPTC of two etiological forms (radiogenic and sporadic), including invasive properties, clinical data, and recurrence in patients aged up to 30 years. For this purpose, 136 radiogenic (from patients aged up to 18 years at the time of the Chornobyl accident) and 83 sporadic (from patients born after the Chornobyl accident) MPTCs were selected and compared using univariate and multivariate statistical methods in a whole group and in age and tumor size subgroups. No evidence of more aggressive clinical and histopathological behavior of radiogenic MPTCs as compared to sporadic tumors for basic structural, invasive characteristics, treatment options, and postoperative follow-up results was found. Moreover, radiogenic MPTCs were characterized by the lower frequencies of oncocytic changes (OR = 0.392, p = 0.004), nodal disease (OR = 0.509, p = 0.050), and more frequent complete remission (excellent response) after radioiodine therapy (OR = 9.174, p = 0.008). These results strongly suggest that internal irradiation does not affect tumor phenotype, does not associate with more pronounced invasive properties, and does not worsen prognosis in pediatric or young adult patients with MPTC, implying that radiation history may be not a pivotal factor for determining treatment strategy in such patients.

Clinicopathological Implications of the BRAF V600E Mutation in Papillary Thyroid Carcinoma of Ukrainian Patients Exposed to the Chernobyl Radiation in Childhood: A Study for 30 Years After the Accident.

With time after the Chernobyl accident, the number of papillary thyroid carcinomas (PTCs) driven by the BRAFV600E oncoprotein is growing in patients exposed to radiation at a young age. Clinicopathological associations of BRAFV600E in PTCs from patients with internal radiation history have not been sufficiently studied so far. This work analyzes the structural characteristics, proliferative activity, invasive features, clinical information, and dosimetric data in the BRAFV600E-positive and BRAFV600E-negative PTCs from the Ukrainian patients exposed to Chernobyl radiation and treated over 30 years after the accident. The study included 428 PTCs from patients aged 4-49 years at surgery who lived in the six northern regions of Ukraine most contaminated by 131I, were ≤18 years of age at the time of exposure, and were operated on from 1990 to 2017. Immunohistochemical staining for BRAFV600E was performed with the VE1 antibody. The probability of causation (POC) of a tumor due to radiation was determined using an interactive online NIH/NCI software. BRAFV600E was detected in 136/428 (31.8%) PTCs. In comparison with the BRAFV600E-negative PTCs, the BRAFV600E-positivity was associated with older patient age at the accident and at surgery, a longer period of latency, and lower POC. The BRAFV600E-positive PTCs were characterized by smaller tumor size, higher Ki67 labeling index, more frequent oncocytic changes, multifocality, and dominant papillary growth pattern. Tumor invasive features were less frequent in the BRAFV600E-positive PTCs and did not change with POC level. Despite a less aggressive tumor phenotype, BRAFV600E was a risk factor for recurrence, namely radioiodine-refractory (RAI-R) recurrent metastases. Multivariate models of RAI-R included BRAFV600E and/or histopathological parameters closely correlating with BRAFV600E such as tumor size, multifocality, dominant papillary growth pattern, or oncocytic changes. Thus, the BRAFV600E-positive PTCs from patients from a high-risk group for radiogenic thyroid cancer diagnosed in the 30 years after the Chernobyl accident did not display higher invasiveness regardless of POC level, but in view of the prognostic impact of this genetic alteration, knowledge of the BRAF status may be beneficial for middle-aged patients with radiogenic PTC considered for RAI therapy, and suggests more careful follow-up of patients with the BRAFV600E-positive tumors.

The relationship of the clinicopathological characteristics and treatment results of post-Chornobyl papillary thyroid microcarcinomas with the latency period and radiation exposure.

Introduction: A worldwide increase in the incidence of thyroid cancer during the last decades is largely due to papillary thyroid microcarcinomas (MPTCs), which are mostly low-risk tumors. In view of recent clinical recommendations to reduce the extent of surgery for low-risk thyroid cancer, and persisting uncertainty about the impact of radiation history, we set out to address whether clinicopathological characteristics and prognosis of post-Chornobyl MPTCs were changing with regard to: i) the latency period, ii) probability of causation (POC) of a tumor due to radiation, and iii) tumor size. Methods: Patients (n = 465) aged up to 50 years at diagnosis who lived in April, 1986 in six northern, most radiocontaminated regions of Ukraine were studied. Results: Latency period was statistically significantly associated with the reduction of POC level, tumor size and the frequency of fully encapsulated MPTCs. In contrast, the frequency of oncocytic changes and the BRAFV600E mutation increased. Invasive properties and clinical follow-up results did not depend on latency except for a lower frequency of complete remission after postsurgical radioiodine therapy. The POC level was associated with more frequent extrathyroidal extension, and lymphatic/vascular invasion, less frequent oncocytic changes and BRAFV600E , and did not associate with any clinical indicator. Tumor size was negatively associated with the latency period and BRAFV600E , and had a statistically significant effect on invasive properties of MPTCs: both the integrative invasiveness score and its components such as lymphatic/vascular invasion, extrathyroidal extension and lymph node metastases increased. The frequency of total thyroidectomy, neck lymph node dissection and radioiodine therapy also increased with the larger tumor size. The duration of the latency period, POC level or tumor size did not associate with the chance of disease recurrence. Discussion: In summary, we did not observe overall worsening of the clinicopathological features or treatment results of radiogenic MPTCs that could be associated with the latency period or POC level, suggesting that radiation history did not strongly affect those in the analyzed MPTC patients. However, the increase in the invasive properties with tumor size indicates the need for individual risk stratification for each MPTC patient, regardless of radiation history, for treatment decision-making.

The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age.

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.

Thyroid dose estimates for the genome-wide association study of thyroid cancer in persons exposed in Belarus to 131I after the Chernobyl accident.

The Chernobyl accident on 26 April 1986 led to a sharp increase in thyroid cancer (TC) incidence in the individuals exposed to radiation in childhood. The major risk factor for TC was exposure to Iodine-131 (131I). Here, we estimated the thyroid doses due to 131I intake for 2041 participants of the genome-wide association study of TC in Belarusian people exposed to radioactive fallout from the Chernobyl accident. The following parameter-values specially developed in this study were used to estimate individual thyroid doses: (i) scaling factors for adjustment of the model-based doses, (ii) age and gender diet to characterize 131I intake, and (iii) area-, age- and gender-specific S-values for the thyroid gland per 131I decay in the thyroid. The most reliable doses were calculated for 103 people with measured 131I thyroid activity (the arithmetic mean of 1.2 Gy, median 0.52 Gy), and 275 individuals with detailed residential history and dietary data (the arithmetic mean of 0.41 Gy, median 0.24 Gy). The arithmetic mean of thyroid doses among all study participants was 0.23 Gy (median 0.082 Gy); the highest individual dose was 9.0 Gy. Special attention was paid to the reliability and validity of the obtained estimates, in particular for the individuals without 131I thyroid activity measurements and individual data on residential history and diet, by comparing those with the doses from other post-Chernobyl epidemiological studies. Overall, the doses estimated in the current study were in reasonable agreement with previously reported thyroid doses. These doses will be used in the genome-wide association study of TC in people exposed in Belarus to 131I after the Chernobyl accident.

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus.

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

Preoperative detection of the TERT promoter mutations in papillary thyroid carcinomas.

OBJECTIVE: Telomerase reverse transcriptase promoter (TERT-p) mutations are strongly associated with tumour aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). Since the TERT-p mutations have been reported to be subclonal, it is unclear how accurately they can be detected by preoperative fine-needle aspiration (FNA). The objective of this study was to analyse the concordance rate of the TERT-p mutations between preoperative FNA and corresponding postoperative surgical specimens. DESIGN AND PATIENTS: Ninety-six cases of PTC aged 55 years or older were studied. The mutational status of TERT-p was detected by droplet digital polymerase chain reaction assay. RESULTS: The mutational status of the TERT-p in FNA samples was highly concordant with that in postoperative formalin-fixed and paraffin-embedded (FFPE) specimens. The TERT-p mutation was significantly associated with age, tumour size, extrathyroidal extension and the Ki-67 labelling index in multivariate analysis in both FNA and FFPE samples. CONCLUSIONS: The detection of the TERT-p mutations using FNA samples has a good ability to predict disease aggressiveness and, therefore, could be clinically useful in the determination of PTC management.

Molecular pathogenesis of pediatric thyroid carcinoma.

There has been little understanding of the molecular pathogenesis of pediatric thyroid cancers. Most of them are histologically classified as papillary thyroid carcinoma (PTC). Ionizing radiation is the most important environmental factor to induce PTC, especially in children. Particularly, radiation-related pediatric PTCs after the Chernobyl accident provided invaluable information. In addition, the recent accumulation of sporadic pediatric PTC cases, partly due to advances in diagnostic imaging, has also provided insight into their general pathogenesis. In PTC development, basically two types of genetic alterations, fusion oncogenes, mainly RET/PTC, and a point mutation, mainly BRAFV600E, are thought to play a key role as driver oncogenes. Their frequencies vary depending on patient age. The younger the age, the more prevalent the fusion oncogenes are. Higher incidence of fusion oncogenes was also observed in cases exposed to radiation. In short, fusion oncogenes are associated with both age and radiation and are not evidence of radiation exposure. The type of driver oncogene is shifted toward BRAFV600E during adolescence in sporadic PTCs. However, until about this age, fusion oncogenes seem to still confer dominant growth advantages, which may lead to the higher discovery rate of the fusion oncogenes. It has been postulated that RET/PTC in radiation-induced PTC is generated by ionizing radiation; however, there is an interesting hypothesis that thyroid follicular cell clones with pre-existing RET/PTC were already present, and radiation may play a role as a promoter/progressor but not initiator. Telomerase reverse transcriptase gene (TERT) promoter mutations, which are the strongest marker of tumor aggressiveness in adult PTC cases, have not been detected in pediatric cases; however, TERT expression without the mutations may play a role in tumor aggressiveness. In this paper, the recent information regarding molecular findings in sporadic and radiation-associated pediatric PTCs is summarized.

Cell competition between anaplastic thyroid cancer and normal thyroid follicular cells exerts reciprocal stress response defining tumor suppressive effects of normal epithelial tissue.

The microenvironment of an early-stage tumor, in which a small number of cancer cells is surrounded by a normal counterpart milieu, plays a crucial role in determining the fate of initiated cells. Here, we examined cell competition between anaplastic thyroid cancer cells and normal thyroid follicular cells using co-culture method. Cancer cells were grown until they formed small clusters, to which normal cells were added to create high-density co-culture condition. We found that co-culture with normal cells significantly suppressed the growth of cancer cell clusters through the activation of Akt-Skp2 pathway. In turn, cancer cells triggered apoptosis in the neighboring normal cells through local activation of ERK1/2. A bi-directional cell competition provides a suppressive mechanism of anaplastic thyroid cancer progression. Since the competitive effect was negated by terminal growth arrest caused by radiation exposure to normal cells, modulation of reciprocal stress response in vivo could be an intrinsic mechanism associated with tumor initiation, propagation, and metastasis.

A Search for Causes of Rising Incidence of Differentiated Thyroid Cancer in Children and Adolescents after Chernobyl and Fukushima: Comparison of the Clinical Features and Their Relevance for Treatment and Prognosis.

The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4-5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk.

Papillary Thyroid Carcinoma in Ukraine After Chernobyl and in Japan After Fukushima: Different Histopathological Scenarios.

Background: A significant increase in the incidence of papillary thyroid carcinoma (PTC) in subjects exposed to radiation at a young age is a well-documented health consequence of the Chernobyl accident. The ongoing Thyroid Ultrasound Examination (TUE) program in children and adolescents of Fukushima Prefecture in Japan also indicated a high prevalence of PTC although its attribution to radiation exposure is a subject of debate. The objective of this study was to perform histopathological analysis of tumor architecture and invasive properties in (i) radiogenic post-Chernobyl and sporadic PTCs from Ukraine, and (ii) PTCs in patients from Fukushima and other Prefectures of Japan of comparable age groups. Methods: The Ukrainian radiogenic PTCs included 245 PTCs from patients who resided in three highly 131I-contaminated regions and 165 sporadic PTCs diagnosed in residents of the same regions who were born after the accident and therefore not exposed to radioiodine. The Japanese series included 115 PTCs detected during the preliminary and the first full-scale surveys of the TUE in Fukushima and 223 PTCs from patients resident in other Prefectures. All of the subjects were included in the main statistical analysis. Three additional analyses were performed limiting the subjects to children, adolescents, and adults. Results: Ukrainian radiogenic PTC was characterized by the higher frequency of tumors with a dominant solid-trabecular growth pattern and higher invasiveness, more frequent extrathyroidal extension, lymphatic/vascular invasion, regional and distant metastases when compared with sporadic Ukrainian PTC. The integrative "invasiveness score," based on five cancer characteristics, was also higher in the radiogenic group. The differences were most pronounced in children. In contrast, no significant differences in tumor morphology or invasiveness were observed between the two Japanese groups or the three age subgroups. The only statistically significant findings were the higher proportion of male patients, smaller mean tumor size, and higher frequency of T1b tumors in the Fukushima group. Conclusions: The difference in morphological features that indicate biological behavior of PTC between the radiation-related and sporadic groups from Ukraine, together with the lack of such in the two groups from Japan, strongly suggest a nonradiogenic etiology of PTC from Fukushima and other Prefectures.

[Predictors of the efficacy of radioiodine therapy of Graves' disease in children and adolescents].

RATIONALE: Insufficient world-wide clinical experience in radioiodine therapy (RIT) for Graves' disease (GD) in children and adolescents, and limited knowledge of the predictors of RIT efficacy. AIMS: Analysis and identification of the most significant predictors of the efficacy of RIT in children and adolescents with Graves' disease. MATERIALS AND METHODS: A total of 55 patients (48 females and 7 males) aged from 8 to 18 years receiving primary RIT for GD were enrolled. RIT planning was based on the dosimetric method. Analyzed parameters included gender, age, ultrasound thyroid volume before and 6 months after treatment, the presence of endocrine ophthalmopathy, duration of antithyroid drug (ATD) therapy, relapse of thyrotoxicosis after ATD dose reduction, blood fT3, fT4 and TSH levels initially and at 1, 3, 6 months after treatment, TSH receptor Ab initially and at 3 and 6 months after treatment, thyroid 99mTc-pertechnetate uptake at 10-20 minutes (%), maximum thyroid 131I uptake (%), specific 131I uptake (MBq/g) and therapeutic 131I activity (MBq). Fisher exact test, non-parametric Mann-Whitney test, Wilcoxon signed-rank test, logistic regression modelling, ROC-analysis, proportional hazard model (the Cox regression), the Kaplan-Meier method and log-rank test were used for statistical analysis as appropriate. RESULTS: Six months after RIT, hypothyroidism was achieved in 45 (81.8%), euthyroid state - in 2 (3.6%), and in 8 (14.6%) patients thyrotoxicosis persisted. On univariate statistical analysis, the smaller thyroid volume, higher fT4 and lower TSH receptor Ab levels, lower 99mTc-pertechnetate uptake and higher specific 131I uptake were associated with hypothyroidism. On multivariate logistic regression analysis, the older patient's age (p=0.011), smaller thyroid volume (p=0.003) and higher fT4 (p=0.024) were independent predictors of RIT efficacy. Thyroid volume was also the only variable associated with achievement of hypothyroidism in time after RIT (p=0.011). CONCLUSION: The efficacy of dosimetry-based RIT in children and adolescents with GD 6 months after treatment was 81.2%. Older patients' age, smaller thyroid volume and higher fT4 level were independent predictors of therapy success. Smaller thyroid volume was also a predictor of the favorable time-related outcome. Statistical models obtained in this work may be used to prospectively estimate the chance of efficient RIT for GD in pediatric patients.

Theoretical Analysis of the Radiation-Induced Conductivity in Polymers Exposed to Pulsed and Continuous Electron Beams.

We have performed comparative numerical calculations using a multiple trapping (MT) formalism with an exponential and an aggregate two-exponential trap distributions for describing two mostly used experimental setups for studying the radiation-induced conductivity (RIC) and the time-of-flight (TOF) effects. Computations have been done for pulsed and long-time electron-beam irradiations in a small-signal regime. Predictions of these two approaches differ appreciably in both setups. The classical MT approach proved very popular in photoconductive polymers generally and in molecularly doped polymers in particular, while a newly proposed complex MT worked well in common polymers. It has been shown that the complex MT successfully accounts for the presence of inherent deep traps, which may or may not have an energy distribution.

The Contribution of Genetic Variants to the Risk of Papillary Thyroid Carcinoma in the Kazakh Population: Study of Common Single Nucleotide Polymorphisms and Their Clinicopathological Correlations.

Objective: Risk for developing papillary thyroid carcinoma (PTC), the most common endocrine malignancy, is thought to be mediated by lifestyle, environmental exposures and genetic factors. Recent progress in the genome-wide association studies of thyroid cancer leads to the identification of several genetic variants conferring risk to this malignancy across different ethnicities. We set out to elucidate the impact of selected single nucleotide polymorphisms (SNPs) on PTC risk and to evaluate clinicopathological correlations of these genetic variants in the Kazakh population for the first time. Methods: Eight SNPs were genotyped in 485 patients with PTC and 1,008 healthy control Kazakh subjects. The association analysis and multivariable modeling of PTC risk by the genetic factors, supplemented with rigorous statistical validation, were performed. Result: Five of the eight SNPs: rs965513 (FOXE1/PTCSC2, P = 1.3E-16), rs1867277 (FOXE1 5'UTR, P = 7.5E-06), rs2439302 (NRG1 intron 1, P = 4.0E-05), rs944289 (PTCSC3/NKX2-1, P = 4.5E-06) and rs10136427 (BATF upstream, P = 9.8E-03) were significantly associated with PTC. rs966423 (DIRC3, P = 0.07) showed a suggestive association. rs7267944 (DHX35) was associated with PTC risk in males (P = 0.02), rs1867277 (FOXE1) conferred the higher risk in subjects older than 55 years (P = 7.0E-05), and rs6983267 (POU5F1B/CCAT2) was associated with pT3-T4 tumors (P = 0.01). The contribution of genetic component (unidirectional independent effects of rs965513, rs944289, rs2439302 and rs10136427 adjusted for age and sex) to PTC risk in the analyzed series was estimated to be 30-40%. Conclusion: Genetic factors analyzed in the present work display significant association signals with PTC either on the whole group analysis or in particular clinicopathological groups and account for about one-third of the risk for PTC in the Kazakh population.

Time-Resolved Radiation-Induced Conductivity of Polyimide and Its Description Using the Multiple Trapping Formalism.

Polymer dielectrics subjected to intense radiation fluxes exhibit a radiation-induced conductivity (RIC). Polyimide is a good dielectric with excellent mechanical and thermal properties featuring high radiation resistance currently widely used in the spacecraft industry. Its RIC has been extensively studied in several laboratories. The purpose of the present study is to make a direct measurement of the RIC for both pulsed and continuous irradiation using a current sensing technique, which is contrary to the indirect method employing a surface-potential decay technique that is now preferred by spacecraft charging engineers. Our experiments are done in a small-signal regime excluding any recombination and dose effects. In combination with existing computer codes, we managed to develop further the conventional multiple trapping formalism and the RIC theory based on it. The main idea is to supplement an exponential trap distribution responsible for a dominant dispersive carrier transport in polymers with a small concentration of inherent deep traps which may or may not have an energy distribution. In line with this reasoning, we propose a tentative set of RIC model parameters for polyimide that accounts for the observed experimental data. The findings and their implications are discussed in a broad context of previous studies.

Radiation-Induced Thyroid Cancers: Overview of Molecular Signatures.

Enormous amounts of childhood thyroid cancers, mostly childhood papillary thyroid carcinomas (PTCs), after the Chernobyl nuclear power plant accident have revealed a mutual relationship between the radiation exposure and thyroid cancer development. While the internal exposure to radioactive 131I is involved in the childhood thyroid cancers after the Chernobyl accident, people exposed to the external radiation, such as atomic-bomb (A-bomb) survivors, and the patients who received radiation therapy, have also been epidemiologically demonstrated to develop thyroid cancers. In order to elucidate the mechanisms of radiation-induced carcinogenesis, studies have aimed at defining the molecular changes associated with the thyroid cancer development. Here, we overview the literatures towards the identification of oncogenic alterations, particularly gene rearrangements, and discuss the existence of radiation signatures associated with radiation-induced thyroid cancers.

TERT mRNA Expression as a Novel Prognostic Marker in Papillary Thyroid Carcinomas.

Background: Telomerase reverse transcriptase (TERT) promoter mutations have been found in a subset of papillary thyroid carcinomas (PTCs) and are associated with tumor aggressiveness and worse prognosis. However, little is known about the status of TERT mRNA expression and its relationship between TERT promoter mutations and clinicopathological features. Methods: We analyzed 159 PTC samples for TERT promoter mutations using direct DNA sequencing. TERT expression was measured using quantitative reverse transcription polymerase chain reaction. To examine low allelic frequency of TERT promoter mutations with high sensitivity, we used droplet digital polymerase chain reaction (ddPCR). The relationship between the status of the TERT promoter mutation/expression and clinicopathological features including recurrence risk was statistically analyzed. Results:TERT promoter mutations were found in 20 cases (12.6%). However, TERT expression was observed not only in the mutation-positive tumors but also in 56 of 139 (40.3%) mutation-negative tumors. Among them, we detected low allelic frequency of TERT promoter mutations in three samples (5.4%) using ddPCR. We confirmed a significant association between TERT promoter mutations and aggressive clinicopathological features in this series. The risk of recurrence of TERT mutation-negative/expression-positive tumors was significantly higher than that of the mutation-negative/expression-negative tumors, suggesting that TERT expression even in absence of a mutation confers a negative influence on PTCs. Moreover, when we reclassified the mutation-negative cases into two groups based on the TERT expression levels: expression-negative/expression levels <80th percentile and expression levels >80th percentile because minimal expression may have a negligible clinical impact, a higher hazard ratio for recurrence was observed. Interestingly, TERT expression levels in the mutation-negative PTCs were inversely correlated with patient age and the presence of BRAF mutations. Conclusions: We confirm a strong correlation between the presence of TERT promoter mutations and aggressive clinicopathological features in this PTC series. In addition, there were PTCs showing high TERT mRNA expression even in the absence of TERT promoter mutations. These cases also showed a significantly higher recurrence rate. Since the TERT promoter mutations are observed only in elderly patients, TERT mRNA expression can be a useful prognostic marker especially in younger PTC patients.