eleRecombinant human thyrotropin to help confirm lack of evidence of radiation-induced differentiated thyroid cancer in young women seeking pregnancy

BACKGROUND: Women with a history of differentiated thyroidcarcinoma who are contemplating pregnancy may wish reassuranceregarding apparent remission. However, the thyroidhormone withdrawal needed to obtain serum thyroglobulintesting (Tg) results in weeks-long biochemical and clinical hypothyroidism,which could increase miscarriage and fetal deathrates if pregnancy occurred during withdrawal of thyroxine orsoon thereafter. Recombinant human thyrotropin (rhTSH) elevates thyrotropin exogenously, allowing uninterrupted thyroidhormone therapy and avoids hypothyroidism.MATERIAL AND METHODS: Thirty female radiation-inducedpapillary thyroid carcinoma survivors who had undergonetotal- or near-total thyroidectomy and who were now seekingpregnancy (mean age 23.9 ± 1.8 years), and who were consideredcancer-free by local standards, underwent rhTSH-aided Tgtesting to help confirm remission. At the time of rhTSH testing,mean follow-up after primary surgical treatment was 11.1 ±3.9 years, and all patients had negative neck ultrasonography,undetectable unstimulated serum Tg (< 0.2 ng/mL) and nointerfering anti-Tg antibodies. However, based on T3, N1 or M1status, 28/30 (93.3%) patients had high recurrence risk.RESULTS: rhTSH produced no serum Tg increase in 27/30women (90.0%). Serum Tg increases to 0.4-0.9 ng/ml wereobserved in 3 women, but careful neck ultrasonography foundno lymphadenopathy. Reassured about their remission, 14/30women (46%) have become pregnant and delivered healthychildren in the 3 years since rhTSH-aided testing.CONCLUSIONS: rhTSH-aided Tg testing is useful in confirmingabsence of tumor in female patients with a history of radiation-inducedthyroid cancer who are seeking pregnancy, but who alsohave a high risk of thyroid cancer recurrenceBACKGROUND: Women with a history of differentiated thyroidcarcinoma who are contemplating pregnancy may wish reassuranceregarding apparent remission. However, the thyroidhormone withdrawal needed to obtain serum thyroglobulintesting (Tg) results in weeks-long biochemical and clinical hypothyroidism,which could increase miscarriage and fetal deathrates if pregnancy occurred during withdrawal of thyroxine orsoon thereafter. Recombinant human thyrotropin (rhTSH) elevates thyrotropin exogenously, allowing uninterrupted thyroidhormone therapy and avoids hypothyroidism.MATERIAL AND METHODS: Thirty female radiation-inducedpapillary thyroid carcinoma survivors who had undergonetotal- or near-total thyroidectomy and who were now seekingpregnancy (mean age 23.9 ± 1.8 years), and who were consideredcancer-free by local standards, underwent rhTSH-aided Tgtesting to help confirm remission. At the time of rhTSH testing,mean follow-up after primary surgical treatment was 11.1 ±3.9 years, and all patients had negative neck ultrasonography,undetectable unstimulated serum Tg (< 0.2 ng/mL) and nointerfering anti-Tg antibodies. However, based on T3, N1 or M1status, 28/30 (93.3%) patients had high recurrence risk.RESULTS: rhTSH produced no serum Tg increase in 27/30women (90.0%). Serum Tg increases to 0.4-0.9 ng/ml wereobserved in 3 women, but careful neck ultrasonography foundno lymphadenopathy. Reassured about their remission, 14/30women (46%) have become pregnant and delivered healthychildren in the 3 years since rhTSH-aided testing.CONCLUSIONS: rhTSH-aided Tg testing is useful in confirmingabsence of tumor in female patients with a history of radiation-inducedthyroid cancer who are seeking pregnancy, but who alsohave a high risk of thyroid cancer recurrence

Polymorphisms of DNA damage response genes in radiation-related and sporadic papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) etiologically occurs as a radiation-induced or sporadic malignancy. Genetic factors contributing to the susceptibility to either form remain unknown. In this retrospective case-control study, we evaluated possible associations between single-nucleotide polymorphisms (SNPs) in the candidate DNA damage response genes (ATM, XRCC1, TP53, XRCC3, MTF1) and risk of radiation-induced and sporadic PTC. A total of 255 PTC cases (123 Chernobyl radiation-induced and 132 sporadic, all in Caucasians) and 596 healthy controls (198 residents of Chernobyl areas and 398 subjects without history of radiation exposure, all Caucasians) were genotyped. The risk of PTC and SNPs interactions with radiation exposure were assessed by logistic regressions. The ATM G5557A and XRCC1 Arg399Gln polymorphisms, regardless of radiation exposure, associated with a decreased risk of PTC according to the multiplicative and dominant models of inheritance (odds ratio (OR) = 0.69, 95% confidence interval (CI) 0.45-0.86 and OR = 0.70, 95% CI 0.59-0.93 respectively). The ATM IVS22-77 T > C and TP53 Arg72Pro SNPs interacted with radiation (P = 0.04 and P = 0.01 respectively). ATM IVS22-77 associated with the increased risk of sporadic PTC (OR = 1.84, 95% CI 1.10-3.24) whereas TP53 Arg72Pro correlated with the higher risk of radiogenic PTC (OR = 1.80, 95% CI 1.06-2.36). In the analyses of ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC genotype strongly associated with radiation-induced PTC (OR = 2.10, 95% CI 1.17-3.78). The GG/CC/GG/GG genotype displayed a significantly increased risk for sporadic PTC (OR = 3.32, 95% CI 1.57-6.99). The results indicate that polymorphisms of DNA damage response genes may be potential risk modifiers of ionizing radiation-induced or sporadic PTCs

The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.

Papillary thyroid cancer (PTC) among individuals exposed to radioactive iodine in their childhood or adolescence is a major internationally recognized health consequence of the Chernobyl accident. To identify genetic determinants affecting individual susceptibility to radiation-related PTC, we conducted a genome-wide association study employing Belarusian patients with PTC aged 0-18 years at the time of accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Meta-analysis by the Mantel-Haenszel method combining the two studies identified four SNPs at chromosome 9q22.33 showing significant associations with the disease (Mantel-Haenszel P: mhp = 1.7 x 10(-9) to 4.9 x 10(-9)). The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with a new set of samples (overall mhp = 4.8 x 10(-12), OR = 1.65, 95% CI: 1.43-1.91). Rs965513 is located 57-kb upstream to FOXE1, a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was recently reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 (mhp = 0.17) at 14p13.3 which showed the second strongest association with sporadic PTC in Europeans. These results show that the complex pathway underlying the pathogenesis may be partly shared by the two etiological forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC

Major Factors Affecting Incidence of Childhood Thyroid Cancer in Belarus after the Chernobyl Accident: Do Nitrates in Drinking Water Play a Role?

One of the major health consequences of the Chernobyl Nuclear Power Plant accident in 1986 was a dramatic increase in incidence of thyroid cancer among those who were aged less than 18 years at the time of the accident. This increase has been directly linked in several analytic epidemiological studies to iodine-131 (131I) thyroid doses received from the accident. However, there remains limited understanding of factors that modify the 131Irelated risk. Focusing on post-Chernobyl pediatric thyroid cancer in Belarus, we reviewed evidence of the effects of radiation, thyroid screening, and iodine deficiency on regional differences in incidence rates of thyroid cancer. We also reviewed current evidence on content of nitrate in groundwater and thyroid cancer risk drawing attention to high levels of nitrates in open well water in several contaminated regions of Belarus, i.e. Gomel and Brest, related to the usage of nitrogen fertilizers. In this hypothesis generating study, based on ecological data and biological plausibility, we suggest that nitrate pollution may modify the radiationrelated risk of thyroid cancer contributing to regional differences in rates of pediatric thyroid cancer in Belarus. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer

Hypothyroidism after radiation exposure: brief narrative review

The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10–20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 “internal radiation therapy” of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3–5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered

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