Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident.
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ABSTRACT:
SUBMITTER: Zablotska LB
PROVIDER: S-EPMC3039791 | biostudies-other | 2011 Jan
REPOSITORIES: biostudies-other
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Project description:The 1986 accident at the Chernobyl nuclear power plant remains the most serious nuclear accident in history, and excess thyroid cancers, particularly among those exposed to releases of iodine-131 remain the best-documented sequelae. Failure to take dose-measurement error into account can lead to bias in assessments of dose-response slope. Although risks in the Ukrainian-US thyroid screening study have been previously evaluated, errors in dose assessments have not been addressed hitherto. Dose-response patterns were examined in a thyroid screening prevalence cohort of 13,127 persons aged <18 at the time of the accident who were resident in the most radioactively contaminated regions of Ukraine. We extended earlier analyses in this cohort by adjusting for dose error in the recently developed TD-10 dosimetry. Three methods of statistical correction, via two types of regression calibration, and Monte Carlo maximum-likelihood, were applied to the doses that can be derived from the ratio of thyroid activity to thyroid mass. The two components that make up this ratio have different types of error, Berkson error for thyroid mass and classical error for thyroid activity. The first regression-calibration method yielded estimates of excess odds ratio of 5.78 Gy(-1) (95% CI 1.92, 27.04), about 7% higher than estimates unadjusted for dose error. The second regression-calibration method gave an excess odds ratio of 4.78 Gy(-1) (95% CI 1.64, 19.69), about 11% lower than unadjusted analysis. The Monte Carlo maximum-likelihood method produced an excess odds ratio of 4.93 Gy(-1) (95% CI 1.67, 19.90), about 8% lower than unadjusted analysis. There are borderline-significant (p = 0.101-0.112) indications of downward curvature in the dose response, allowing for which nearly doubled the low-dose linear coefficient. In conclusion, dose-error adjustment has comparatively modest effects on regression parameters, a consequence of the relatively small errors, of a mixture of Berkson and classical form, associated with thyroid dose assessment.
| S-EPMC3906013 | biostudies-literature
Project description:BackgroundThyroid dysfunction after exposure to low or moderate doses of radioactive iodine-131 (131I) at a young age is a public health concern. However, quantitative data are sparse concerning 131I-related risk of these common diseases.ObjectiveOur goal was to assess the prevalence of thyroid dysfunction in association with 131I exposure during childhood (≤ 18 years) due to fallout from the Chernobyl accident.MethodsWe conducted a cross-sectional analysis of hypothyroidism, hyperthyroidism, autoimmune thyroiditis (AIT), serum concentrations of thyroid-stimulating hormone (TSH), and autoantibodies to thyroperoxidase (ATPO) in relation to measurement-based 131I dose estimates in a Belarusian cohort of 10,827 individuals screened for various thyroid diseases.ResultsMean age at exposure (± SD) was 8.2 ± 5.0 years. Mean (median) estimated 131I thyroid dose was 0.54 (0.23) Gy (range, 0.001-26.6 Gy). We found significant positive associations of 131I dose with hypothyroidism (mainly subclinical and antibody-negative) and serum TSH concentration. The excess odds ratio per 1 Gy for hypothyroidism was 0.34 (95% CI: 0.15, 0.62) and varied significantly by age at exposure and at examination, presence of goiter, and urban/rural residency. We found no evidence of positive associations with antibody-positive hypothyroidism, hyperthyroidism, AIT, or elevated ATPO.ConclusionsThe association between 131I dose and hypothyroidism in the Belarusian cohort is consistent with that previously reported for a Ukrainian cohort and strengthens evidence of the effect of environmental 131I exposure during childhood on hypothyroidism, but not other thyroid outcomes.
| S-EPMC3701991 | biostudies-literature
Project description:The U.S. National Cancer Institute, in collaboration with the Belarusian Ministry of Health, is conducting a study of thyroid cancer and other thyroid diseases in a cohort of about 12,000 persons who were exposed to fallout from the Chernobyl accident in April 1986. The study subjects were 18 years old or younger at the time of exposure and resided in Belarus in the most contaminated areas of the Gomel and Mogilev Oblasts, as well as in the city of Minsk. All cohort members had at least one direct thyroid measurement made in April-June 1986. Individual data on residential history, consumption of milk, milk products and leafy vegetables as well as administration of stable iodine were collected for all cohort members by means of personal interviews conducted between 1996 and 2007. Based on the estimated (131)I activities in the thyroids, which were derived from the direct thyroid measurements, and on the responses to the questionnaires, individual thyroid doses from intakes of (131)I were reconstructed for all cohort members. In addition, radiation doses to the thyroid were estimated for the following minor exposure pathways: (a) intake of short-lived (132)I, (133)I and (132)Te by inhalation and ingestion; (b) external irradiation from radionuclides deposited on the ground; and (c) ingestion intake of (134)Cs and (137)Cs. Intake of (131)I was the major pathway for thyroid exposure; its mean contribution to the thyroid dose was 92%. The thyroid doses from (131)I intakes varied from 0.5 mGy to almost 33 Gy; the mean was estimated to be 0.58 Gy, while the median was 0.23 Gy. The reconstructed doses are being used to evaluate the risk of thyroid cancer and other thyroid diseases in the cohort.
| S-EPMC3682838 | biostudies-literature
Project description:A large excess risk of thyroid cancer was observed among Belarusian/Russian/Baltic Chornobyl cleanup workers. A more recent study of Ukraine cleanup workers found more modest excess risks of thyroid cancer. Dose errors in this data are substantial, associated with model uncertainties and questionnaire response. Regression calibration is often used for dose-error adjustment, but may not adequately account for the full error distribution. We aimed to examine the impact of exposure-assessment uncertainties on thyroid cancer among Ukrainian cleanup workers using Monte Carlo maximum likelihood, and compare with results derived using regression calibration. Analyses assessed the sensitivity of results to various components of internal and external dose. Regression calibration yielded an excess odds ratio per Gy (EOR/Gy) of 0.437 (95% CI - 0.042, 1.577, p = 0.100), compared with the EOR/Gy using Monte Carlo maximum likelihood of 0.517 (95% CI - 0.039, 2.035, p = 0.093). Trend risk estimates for follicular morphology tumors exhibited much more extreme effects of full-likelihood adjustment, the EOR/Gy using regression calibration of 3.224 (95% CI - 0.082, 30.615, p = 0.068) becoming ~ 50% larger, 4.708 (95% CI - 0.075, 85.143, p = 0.066) when using Monte Carlo maximum likelihood. Results were sensitive to omission of external components of dose. In summary, use of Monte Carlo maximum likelihood adjustment for dose error led to increases in trend risks, particularly for follicular morphology thyroid cancers, where risks increased by ~ 50%, and were borderline significant. The unexpected finding for follicular tumors needs to be replicated in other exposed groups.
| S-EPMC10641599 | biostudies-literature
Project description:BackgroundMetastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.MethodsWe conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.ResultsOf 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.ConclusionsSelumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
| S-EPMC3615415 | biostudies-literature
Project description:Differentiated thyroid cancer (DTC) is the most common subtype of thyroid cancer and has an excellent overall prognosis. However, metastatic DTC in certain cases may have a poor prognosis as it becomes radioiodine-refractory. Molecular imaging is essential for disease evaluation and further management. The most commonly used tracers are [18F]FDG and isotopes of radioiodine. Several other radiopharmaceuticals may be used as well, with different diagnostic performances. This review article aims to summarize radiopharmaceuticals used in patients with radioiodine-refractory DTC (RAI-R DTC), focusing on their different molecular pathways. Additionally, it will demonstrate possible applications of the theranostics approach to this subgroup of metastatic DTC.
| S-EPMC10486510 | biostudies-literature
Project description:BackgroundThyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease.MethodsWhole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R in AA patients whose primary tumor samples were available (28/55).ResultsTG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, and HRASQ61R.ConclusionsThe identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insights into the mechanisms underlying RAI-R disease.
| S-EPMC6457887 | biostudies-literature
Project description:Background: Pediatric differentiated thyroid cancer (P-DTC) frequently presents with advanced disease. The study aim was to evaluate the outcome of P-DTC and a modified 2015 American Thyroid Association risk classification (ATA-R). Methods: A retrospective study of consecutive P-DTC patients was performed. The ATA-R for P-DTC was used with a cut-off of ≤ 5 N1a for low-risk. The outcome could be excellent response (ER) (thyroglobulin < 1 ng/mL and no evidence of disease (EoD) at imaging), biochemical incomplete response (BIR) (thyroglobulin ≥ 1 ng/mL and no EoD at imaging) or structural incomplete response (SIR) (EoD at imaging). Results: We studied 260 P-DTC (70% females; median age at diagnosis 14 years; 93% total thyroidectomy and 82% lymph node dissection). The ATA-R was low in 30% cases, intermediate in 15% and high in 55%, including 31.5% with distant metastases. Radioiodine treatment was administered in 218 (83.8%), and further radioiodine and surgery was performed in 113 (52%) and 76 (29%) patients, respectively. After a median follow-up of 8.2 years, the outcome was ER in 193 (74.3%), BIR in 17 (6.5%) and SIR in 50 (19.2%). Independent predictors of SIR or BIR at first and last visits were ATA-R intermediate or high. Conclusion: P-DTC has an excellent prognosis. Modified ATA-R is a useful prognostic tool in P-DTC to guide management.
| S-EPMC8345030 | biostudies-literature
Project description:The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient's features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.
| S-EPMC8790300 | biostudies-literature
Project description:Thyroid cancer is the most frequent endocrine tumor. However, in locally advanced or metastatic disease we have only two types of treatment at our disposal: radioactive iodine (RAI) when the disease is RAI-sensitive and multikinase inhibitors (MKIs), lenvatinib and sorafenib, when the disease becomes RAI-refractory (RR). This review revisits the published data on the potential combination of MKIs/lenvatinib with RAI in RR-differentiated thyroid cancer and evaluates some special situations where this combination may be of particular interest. The combination of MKIs/lenvatinib with RAI could, at least hypothetically, improve the efficacy seen in both treatments alone via a synergistic effect and with a lower rate of toxicity rates. Early preclinical data support this notion, while its generalized use awaits the results of ongoing clinical trials.
| S-EPMC9537052 | biostudies-literature