The relationship between the quantitative evaluation of thyroid bed uptake and the disappearance of accumulation in adjuvant radioactive iodine therapy for differentiated thyroid cancer.

OBJECTIVE: Iodine-131 (I-131) radioactive iodine therapy (RAI) after total thyroidectomy is the standard treatment for patients with differentiated thyroid cancer (DTC). We investigated the relationship between the quantitative parameters of the iodine uptake and the disappearance of the accumulation in the thyroid bed in adjuvant therapy using a 1.11 GBq or 3.70 GBq dose of I-131. METHODS: We retrospectively analyzed the cases of 40 patients with DTC who were treated with RAI at our institution between April 2017 and August 2019. The patients were treated with the I-131 dose of 1.11 GBq (n = 25) or 3.70 GBq (n = 15) after total thyroidectomy. The I-131 whole-body scan and hybrid single-photon emission computed tomography/X-ray computed tomography (SPECT/CT) were performed 3 days after RAI. Using image analysis software, we measured the standardized uptake value (SUV) and absolute radioactivity concentration (kBq/ml) on the target lesions with the highest uptake in the thyroid bed. RESULTS: The median period from RAI to the evaluation of the absence of uptake of the thyroid bed was 6.75 months. After RAI, uptake of the thyroid bed disappeared in 26 of the 40 patients. The disappearance rate was significantly higher in the 3.70 GBq group than in the 1.11 GBq group (86.7% vs. 52.0%, respectively; p = 0.029). However, there were no significant differences in the values of kBq/ml or SUV between the 1.11 GBq group and 3.70 GBq group. On the other hand, the group in which the uptake disappeared after RAI showed significantly higher kBq/ml max and kBq/ml mean values than the group in which the uptake did not disappear after RAI (p = 0.028, p = 0.032, respectively). The SUVmax and SUVmean also tended to be higher in the disappeared-uptake group than the not-disappeared-uptake group, but the differences were not significant (p = 0.166, p = 0.176, respectively). CONCLUSIONS: The quantitative evaluation might be useful as one of the predictive indicators of the disappearance of the accumulation of radioactive iodine in the thyroid bed.

Association between clinical and tumor features with postoperative thyroglobulin in pediatric papillary thyroid cancer.

BACKGROUND: Why certain patients after total thyroidectomy for thyroid cancer who do not have distant metastasis have increased serum stimulated thyroglobulin (s-Tg) is unknown. The aim of our study was to systematically investigate the associations of preablation s-Tg with clinical and tumor characteristics in children and young adults less than 20 years old after total thyroidectomy for papillary thyroid cancer. METHODS: We performed a retrospective analysis of 93 children and young adults younger than 20 years old who had undergone total thyroidectomy and were without known distant metastases who underwent remnant ablation. Before any remnant preablation, we assessed the association of s-Tg after thyroid hormone withdrawal with the clinical and histopathologic characteristics according to the American Thyroid Association pediatric initial risk classification system. RESULTS: The median age was 18 years, and the majority of patients were female (80%). The preablation s-Tg ranged from 0.02 to 902.00 ng/mL, with a median of 9.2 ng/mL. Forty-five (48%) patients had an increased preablation s-Tg >10 ng/mL. In multivariate analyses of clinical and tumor characteristics, high-risk stratification and high neck uptake (>2%) were the independent predictive factors for the presence of an increased preablation s-Tg. CONCLUSION: Children and young adults younger than 20 years old with high-risk stratification and high neck uptake are likely to present a high level of preablation s-Tg after total thyroidectomy for papillary thyroid cancer. Continued long-term surveillance is necessary in this cohort of patients to confirm the role of preablation s-Tg as a biomarker for monitoring postoperative residual disease.

Uncertainty quantification of bioassay functions for the internal dosimetry of radioiodine.

Bioassay functions, which are provided by the International Commission on Radiological Protection, are used to estimate the intake activity of radionuclides; however, they include considerable uncertainties in terms of the internal dosimetry for a particular individual. During a practical internal dose assessment, the uncertainty in the bioassay function is generally not introduced because of the difficulty in quantification. Therefore, to clarify the existence of uncertainty in the bioassay function and provide dosimetrists with an insight into this uncertainty, this study attempted to quantify the uncertainty in the thyroid retention function used for radioiodine exposure. The uncertainty was quantified using a probabilistic estimation of the thyroid retention function through the propagation of the distribution of biokinetic parameters by the Monte Carlo simulation technique. The uncertainties in the thyroid retention function, expressed in terms of the scattering factor, were in the ranges of 1.55-1.60 and 1.40-1.50 for within 24 h and after 24 h, respectively. In addition, the thyroid retention function within 24 h was compared with actual measurement data to confirm the uncertainty due to the use of first-order kinetics in the biokinetic model calculation. Significantly higher thyroid uptakes (by a factor of 1.9) were observed in the actual measurements. This study indicates that consideration of the uncertainty in the thyroid retention function can avoid a significant over- and under-estimation of the internal dose, particularly when a high dose is predicted.

Systemic Effects of Photobiomodulation on the Morphology of the Thyroid and Sublingual Glands: A Study in Rabbits.

Objective: To investigate whether photobiomodulation (PBM) applied in a clinical situation with the purpose of improving the healing process of implants placed in the rabbit mandible would cause any morphological change in the thyroid and sublingual glands as a systemic effect of laser irradiation. Methods: Thirty-two New Zealand rabbits were randomly divided into four groups of eight animals each, one control group (CI, nonirradiated animals) and three experimental groups (EI, EII, and EIII) that received PBM postoperatively with an aluminum/gallium/arsenide laser diode (Theralase®) at a wavelength of 830 nm (infrared) and 50 mW output power applied to two irradiation fields per session, for a total of seven sessions. All rabbits underwent surgical extraction of the mandibular left incisor, followed by immediate placement of an osseointegrated implant in the fresh socket. The experimental groups EI, EII, and EIII received PBM at an energy density of 5, 2.5, and 10 J/cm2, respectively, per irradiation field. Results: There was no histomorphometric change in any of the groups. Conclusions: PBM, based on the irradiation protocol used in this study, does not cause morphological changes in the thyroid and sublingual glands when used to stimulate peri-implant bone healing in the rabbit mandible.

Randomised comparison of 1.1 GBq and 3.7 GBq radioiodine to ablate the thyroid in the treatment of low-risk thyroid cancer: a 13-year follow-up.

Purpose: The optimal activity of radioiodine (I-131) administered for ablation therapy in papillary and follicular thyroid cancer after thyroidectomy remains unknown in a long-term (> 10 year) follow-up. Some, shorter follow-up studies suggest that activities 1.1 GBq and 3.7 GBq are equally effective. We evaluated the long-term outcomes after radioiodine treatment to extend current knowledge about the optimal ablative dose of I-131.Methods: One hundred and sixty consecutive adult patients (129 females, 31 males; mean age 46 ± 14 y, range 18-89 y) diagnosed with histologically confirmed differentiated thyroid cancer, were randomised in a prospective, phase III, open-label, single-centre study, to receive either 1.1 GBq or 3.7 GBq of I-131 after thyroidectomy. At randomisation, patients were stratified according to the histologically verified cervical lymph node status and were prepared for ablation using thyroid hormone withdrawal. No uptake in the whole-body scan with I-131 and serum thyroglobulin concentration less than 1 ng/mL at 4-8 months after treatment was considered successful ablation.Results: Median follow-up time was 13.0 years (mean 11.0 ± 4.8 y; range 0.3-17.1 y). Altogether 81 patients received 1.1 GBq with successful ablation in 45 (56%) patients. In the original study, thirty-six patients (44%) needed one or more extra administrations to replete the ablation. Of these, 4 (8.9%) and 5 (14%) patients relapsed during the follow-up, respectively. Of the 79 patients treated with 3.7 GBq 45 (57%) had successful ablation after one administration of radioiodine and 34 (43%) needed several treatments. Of these, 2 (4.4%) and 9 (26.5%) patients relapsed, respectively. The groups did not differ in the proportion of patients relapsing (p = .591).Conclusion: During follow-up of median 13 years, 3.7 GBq is not superior to 1.1 GBq in the radioiodine treatment after thyroidectomy in papillary and follicular thyroid cancer.

Longer-term recurrence rate after low versus high dose radioiodine ablation for differentiated thyroid Cancer in low and intermediate risk patients: a meta-analysis.

BACKGROUND: Regarding the longer-term recurrence rate the optimal activity for the remnant thyroid ablation in patients with differentiated thyroid cancer (DTC) is discussed controversially. For the short-term ablation success rate up to 12 months there are already several meta-analyses. In this study we performed the first meta-analysis regarding the longer-term recurrence rate after radioactive 131-I administration. METHODS: We conducted an electronic search using PubMed/MEDLINE, EMBASE and the Cochrane Library. All randomized controlled trials (RCTs) assessed the recurrence rate after radioactive iodine ablation in patients with DTC, with a follow-up of at least two years were selected. Statistics were performed by using Review Manager version 5.3 and Stata software. RESULTS: Four RCTs were included in the study, involving 1501 patients. There was no indication for heterogeneity (I2 = 0%) and publication bias. The recurrence rate among patients who had a low dose 131-iodine ablation was not higher than for a high dose activity (odds ratio (OR) 0.93 [95% confidence interval (CI) 0.53-1.63]; P = 0.79). The mean follow-up time was between 4.25 and 10 years. The subgroup analysis regarding the TSH stimulated thyroglobulin values (< 10 ng/mL versus < 2 ng/mL versus ≤1 ng/mL) showed no influence on recurrence rate. CONCLUSIONS: For the first time we showed that the longer-term, at least 2-year follow-up, recurrence rate among patients who had 131-iodine ablation with 1.1 GBq was not higher than with 3.7 GBq.

Effect of Different 131I Dose Strategies for Treatment of Hyperthyroidism on Graves' Ophthalmopathy.

PURPOSE: The study aims to define the effect of different dose strategies on ophthalmic complications in patients with Graves' disease (GD). METHODS: All the patients with GD and no or inactive ophthalmopathy (clinical activity score; CAS < 3) underwent Snellen chart examination, measurement of proptosis, thyroid volume, and radioactive iodine uptake, and randomized into 1 of 3 groups. In group 1, all the patients received fixed low dose (FLD) of 259 MBq of I, whereas in group 2, all the patients received fixed high dose (FHD) of 555 MBq, and in group 3, calculated dose (CD) was administered to deliver 5.55 MBq/g (thyroid weight) of I. All examinations were repeated 6 months after treatment. The measurement of thyroid function tests and clinical examination were repeated after 12 months. RESULTS: We studied 92 patients (58 female and 34 male) with mean age of 38.2 ± 12.0 years. Overall, 29, 32, and 31 patients were studied in FLD, FHD, and CD groups, respectively. The patients in CD received a mean activity of 240.5 MBq. The 3 groups were not significantly different regarding age, sex ratio, radioactive iodine uptake, smoking, visual acuity, and proptosis. The response rate 12 months after radioactive iodine therapy was 66.7%, 94.4%, and 92.9% in FLD, FHD, and CD groups, respectively (P = 0.05). Overall, CAS was increased significantly after treatment. Delta proptosis and delta CAS were increased significantly in FHD group compared with other groups (P < 0.05). The highest increment in proptosis was seen in FHD group. CONCLUSIONS: The administration of 5.55 MBq/g of I has fewer ophthalmic complications compared with high fixed dose model and is more effective than low fixed dose strategy.

Contemporary considerations in adjuvant radioiodine treatment of adults with differentiated thyroid cancer.

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy with a growing incidence worldwide. The initial conventional management is surgery, followed by consideration of 131 I treatment that includes three options. These are termed remnant ablation (targeting benign thyroid remnant), adjuvant (targeting presumed microscopic DTC) and known disease (targeting macroscopic DTC) treatments. Some experts mostly rely on clinicopathologic assessment for recurrence risk to select patients for the 131 I treatment. Others, in addition, apply radioiodine imaging to guide their treatment planning, termed theranostics (aka theragnostics or radiotheragnostics). In patients with low-risk DTC, remnant ablation rather than adjuvant treatment is generally recommended and, in this setting, the ATA recommends a low 131 I activity. 131 I adjuvant treatment is universally recommended in patients with high-risk DTC (a primary tumor of any size with gross extrathyroidal extension) and is generally recommended in intermediate-risk DTC (primary tumor >4 cm in diameter, locoregional metastases, microscopic extrathyroidal extension, aggressive histology or vascular invasion). The optimal amount of 131 I activity for adjuvant treatment is controversial, but experts reached a consensus that the 131 I activity should be greater than that for remnant ablation. The main obstacles to establishing timely evidence through randomized clinical trials for 131 I therapy include years-to-decades delay in recurrence and low disease-specific mortality. This mini-review is intended to update oncologists on the most recent clinical, pathologic, laboratory and imaging variables, as well as on the current 131 I therapy-related definitions and management paradigms, which should optimally equip them for individualized patient guidance and treatment.

Association between Uranium Exposure and Thyroid Health: A National Health and Nutrition Examination Survey Analysis and Ecological Study.

: Besides specific, incidental radiation exposure, which has been associated with increased thyroid cancer risk, the effects of exposure to background radiation from uranium, a naturally occurring, radioactive, and ubiquitous element, on the thyroid gland has not been widely studied. We therefore investigated the association between uranium exposure and thyroid health in the US. Using the National Health and Nutrition Examination Survey (NHANES), we assessed the association between urinary uranium levels and thyroid-related antibodies, including thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase (anti-TPO), in the general population. Secondly, we performed an ecological study of age-adjusted thyroid cancer incidence rates per state and sources of uranium exposure. We included 3125 eligible participants from the NHANES and found a significant association between increased TgAb and increased urinary uranium levels when analyzed as quartiles (p = 0.0105), while no association was found with anti-TPO. In addition, although no significant correlation was found in the ecological study, certain states had high age-adjusted thyroid cancer incidence rates and a high number of uranium activity locations and high uranium concentrations in water. The present study suggests that uranium exposure may affect thyroid health, which warrants increased sampling of soil and water in high-risk states.

MnTnBuOE-2-PyP treatment protects from radioactive iodine (I-131) treatment-related side effects in thyroid cancer.

Treatment of differentiated thyroid cancer often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. However, there is morbidity associated with I-131 therapy, which can result in both acute and chronic complications. Currently, there are no approved radioprotectors that can be used in conjunction with I-131 to reduce complications in thyroid cancer therapy. It is well known that the damaging effects of ionizing radiation are mediated, in part, by the formation of reactive oxygen species (ROS). A potent scavenger of ROS, Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnTnBuOE-2-PyP), has radioprotective and anti-tumor effects in various cancer models including head and neck, prostate, and brain tumors exposed to external beam radiation therapy. Female C57BL/6 mice were administered I-131 orally at doses of 0.0085-0.01 mCi/g (3.145 × 105 to 3.7 × 105 Bq) of body weight with or without MnTnBuOE-2-PyP. We measured acute external inflammation, blood cell counts, and collected thyroid tissue and salivary glands for histological examination. We found oral administration of I-131 caused an acute decrease in platelets and white blood cells, caused facial swelling, and loss of thyroid and salivary tissues. However, when MnTnBuOE-2-PyP was given during and after I-131 administration, blood cell counts remained in the normal range, less facial inflammation was observed, and the salivary glands were protected from radiation-induced killing. These data indicate that MnTnBuOE-2-PyP may be a potent radioprotector of salivary glands in thyroid cancer patients receiving I-131 therapy.

The effect of radioiodine treatment on the diseased thyroid gland.

Purpose: Radioiodine (I131) therapy is the treatment mainstay for several benign and malignant thyroid disorders, however I131 is known to cause DNA damage and liberation of thyroidal self-antigens inducing secondary immunoreactivity. The exact mechanisms underpinning cellular death and subsequent induction of autoimmune thyroid disease following I131 treatment have not yet been fully elucidated. This manuscript aims to review the literature concerning the effects of I131 on the thyroid gland.Conclusion: The effects of I131 on malignant thyroid cells appears to depend on absorbed dose with the literature demonstrating a clear initial delay in the triggering of apoptosis in response to I131-mediated cellular damage. Some studies also observed necrotic cellular death following high-dose I131 treatment. Liberation of thyroidal self-antigen following I131 treatment helps to explain phenomena such as the subsequent induction of autoimmune thyroid disease. The clinical utility of cytokines and autoantibodies for prognostication of hypothyroidism and treatment failure following I131 remains uncertain and further appropriately-powered studies are required to clarify their role. The potential role of other cell death mechanisms activated after treatment with I131 should also be explored in order to fully delineate the thyroidal response.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.

Clinical outcomes of patients with T4 or N1b well-differentiated thyroid cancer after different strategies of adjuvant radioiodine therapy.

We aimed to determine whether recombinant human thyrotropin (rhTSH) plus 3.7 GBq could replace thyroid hormone withdrawal (THW) plus 5.55 GBq for adjuvant radioactive iodine (RAI) therapy in differentiated thyroid cancer (DTC) patients with T4 or N1b disease. This study was a retrospective study comparing ablation success rate, response to initial therapy, and recurrence-free survival (RFS) of patients with rhTSH plus 3.7 GBq versus those with THW plus 5.55 GBq in 253 DTC patients with T4 or N1b disease. There were no differences in the TSH-stimulated thyroglobulin level, rate of incomplete response after initial treatment, or the RFS between the two treatment strategies. However, thyroid bed uptake on follow-up diagnostic RAI whole-body scanning (WBS) was more frequently observed in the group treated with rhTSH plus 3.7 GBq than in the group with THW plus 5.55 GBq. Adjuvant RAI therapy with rhTSH plus 3.7 GBq had comparable results in the absence of persistent tumor, compared with that with THW plus 5.55 GBq. Although thyroid bed uptake was more frequently observed, rhTSH plus 3.7 GBq may be used instead of THW plus 5.55 GBq for adjuvant RAI therapy in patients with T4 or N1b disease.

Low dose radiation regulates BRAF-induced thyroid cellular dysfunction and transformation.

BACKGROUND: The existence of differentiated thyroid cells is critical to respond radioactive iodide treatment strategy in thyroid cancer, and loss of the differentiated phenotype is a trademark of iodide-refractive thyroid disease. While high-dose therapy has been beneficial to several cancer patients, many studies have indicated this clinical benefit was limited to patients having BRAF mutation. BRAF-targeted paired box gene-8 (PAX8), a thyroid-specific transcription factor, generally dysregulated in BRAF-mutated thyroid cancer. METHODS: In this study, thyroid iodine-metabolizing gene levels were detected in BRAF-transformed thyroid cells after low and high dose of ionizing radiation. Also, an mRNA-targeted approach was used to figure out the underlying mechanism of low (0.01Gyx10 or 0.1Gy) and high (2Gy) radiation function on thyroid cancer cells after BRAFV600E mutation. RESULTS: Low dose radiation (LDR)-induced PAX8 upregulation restores not only BRAF-suppressive sodium/iodide symporter (NIS) expression, one of the major protein necessary for iodine uptake in healthy thyroid, on plasma membrane but also regulate other thyroid metabolizing genes levels. Importantly, LDR-induced PAX8 results in decreased cellular transformation in BRAF-mutated thyroid cells. CONCLUSION: The present findings provide evidence that LDR-induced PAX8 acts as an important regulator for suppression of thyroid carcinogenesis through novel STAT3/miR-330-5p pathway in thyroid cancers.

Thyroid Uptake and Effective Half-Life of Radioiodine in Thyroid Cancer Patients at Radioiodine Therapy and Follow-Up Whole-Body Scintigraphy Either in Hypothyroidism or Under rhTSH.

Adjuvant radioiodine therapy (RITh) for differentiated thyroid carcinoma is performed either with thyroid hormone withdrawal or with administration of recombinant human thyroid-stimulating hormone (rhTSH). Heterogeneous results have been obtained on the impact of the method of patient preparation on thyroid uptake and whole-body effective half-life. A higher radiation exposure using thyroid hormone withdrawal for several weeks compared with rhTSH was reported in prior studies. It was the aim to examine whether these findings are reproducible in a modern protocol with a short interval between surgery and RITh. Methods: A retrospective study was performed on patients admitted for adjuvant RITh for differentiated thyroid carcinoma at the University Hospital of Cologne over a 5-y period from 2010. Dose rate measurements were analyzed for 366 patients, and subgroup analyses were performed for papillary thyroid cancer (n = 341) and follicular thyroid cancer (n = 25) patients, sex, length of hypothyroidism, and normal versus decreased glomerular filtration rate (GFR). Results: The median interval between surgery and RITh was 18 d for thyroid hormone withdrawal and 25 d for rhTSH (P < 0.01). The mean thyroid uptake was 4.2% ± 1.8% for the 300 hypothyroid patients versus 3.8% ± 1.6% (P = 0.12) for the 66 rhTSH patients. Whole-body half-life in the hypothyroid group was significantly longer at 19.3 ± 7.7 h versus 16.4 ± 4.6 h in the rhTSH group (P < 0.01). Results were predominantly influenced by data from the largest subgroup, that is, female papillary thyroid cancer patients. Within this group, whole-body half-life was significantly shorter in the rhTSH treatment arm. Duration of hypothyroidism and a decrease in GFR less than 60 mL/min/1.73 m2 significantly influenced results, with an increased whole-body half-life occurring in the hypothyroid group. When patients returned for whole-body scintigraphy, thyroid, half-life, and whole-body half-life were significantly shorter in the rhTSH groups, resulting in a low thyroid and remaining-body dose. Conclusion: With a shortening of the time between surgery and adjuvant RITh, thyroid uptake is not significantly changed but whole-body half-life becomes longer in the hypothyroid group. Radiation exposure for most patients is not significantly different. However, patients with a hypothyroid phase of more than 4 wk, and in particular those with a decreased GFR, experience higher radiation exposure.

Recombinant Thyrotropin vs Levothyroxine Withdrawal in 131I Therapy of N1 Thyroid Cancer: A Large Matched Cohort Study (ThyrNod).

CONTEXT: Recombinant human thyrotropin (rhTSH) has been shown to be an effective stimulation method for radioactive iodine (RAI) therapy in differentiated thyroid cancer, including in those with nodal metastases (N1 DTC). OBJECTIVES: To demonstrate the noninferiority of rhTSH vs thyroid hormone withdrawal (THW) in preparation to RAI regarding disease status at the first evaluation in the real-life setting in patients with N1 DTC. DESIGN: This was a French multicenter retrospective study. Groups were matched according to age (<45/≥45 years), number of N1 nodes (≤5/>5 lymph nodes), and stage (pT1-T2/pT3). RESULTS: The cohort consisted of 404 patients pT1-T3/N1/M0 DTC treated with rhTSH (n = 205) or THW (n = 199). Pathological characteristics and initially administrated RAI activities (3.27 ± 1.00 GBq) were similar between the two groups. At first evaluation (6 to 18 months post-RAI), disease-free status was defined by thyroglobulin levels below threshold and a normal ultrasound. Disease-free rate was not inferior in the rhTSH group (75.1%) compared with the THW group (71.9%). The observed difference between the success rates was 3.3% (-6.6 to 13.0); rhTSH was therefore considered noninferior to THW because the upper limit of this interval was <15%. At the last evaluation (29.7 ± 20.7 months for rhTSH; 36.7 ± 23.8 months for THW), 83.5% (rhTSH) and 81.5% (THW) of patients achieved a complete response. This result was not influenced by any of the known prognostic factors. CONCLUSIONS: A preparation for initial RAI treatment with rhTSH was noninferior to that with THW in our series of pT1-T3/N1/M0-DTC on disease-free status outcomes at the first evaluation and after 3 years.

Radiation-related thyroid autoimmunity and dysfunction.

The thyroid gland is vulnerable not only to external radiation but also to internal radiation, because the thyroid cells can incorporate radioactive iodine when synthesizing thyroid hormones. Since radiation-induction of thyroid neoplasia, including thyroid cancer, is well recognized, the data on radiation-related thyroid autoimmunity and dysfunction are summarized and reviewed. High-dose irradiation, irrespective of being external or internal, is strongly associated with a risk of hypothyroidism (with the prevalence ranging from 2.4% to 31%) and of Graves' hyperthyroidism (with the prevalence being up to 5%). It is easy to understand that high-dose irradiation induces hypothyroidism with some frequency, because high-dose irradiation destroys the thyroid gland. On the other hand, the basis for development of hyperthyroidism is mechanistically unclear, and it is merely speculative that autoantigens may be released from damaged thyroid glands and recognized by the immune system, leading to the development of anti-thyrotropin receptor antibodies and Graves' hyperthyroidism in subjects who are immunologically predisposed to this ailment. In contrast, the data on moderate to low-dose irradiation on thyroid autoimmunity and dysfunction are inconsistent. Although it is difficult to draw a definitive conclusion, some data may suggest a transient effect of moderate- to low-dose irradiation on hypothyroidism and autoimmune thyroiditis, implying that the effect, if it exists, is reversible. Finally, no report has shown a statistically significant increase in the prevalence of moderate- to low-dose irradiation-induced Graves' hyperthyroidism.

18F-FDG-Avid Thyroid Incidentalomas: The Importance of Contextual Interpretation.

18F-FDG-avid thyroid incidentaloma (TI) is seen in approximately 2.5% of patients imaged for staging or response assessment of malignancy and represents thyroid cancer in approximately 35% of cases. Consequently, the 2015 American Thyroid Association guidelines strongly recommend investigation of all 18F-FDG-avid nodules 1 cm or larger with ultrasound and fine-needle aspiration cytology (FNA). This study aimed to assess the overall and thyroid cancer-specific survival in a large cohort of patients with 18F-FDG-avid TI with long-term follow-up to assess the validity of this approach. Methods: Retrospective review of 45,680 PET/CT scans performed at a comprehensive cancer center from January 2007 to January 2015 identified 2,588 18F-FDG PET/CT reports referring to the thyroid. After exclusion of nonavid thyroid nodules, diffuse 18F-FDG uptake, known thyroid cancer, abnormalities adjacent to the thyroid, and repeat studies, 500 patients (1.1%) with TI were identified, of whom 362 had confirmed death or more than 12 mo of clinical follow-up. Variables including age, sex, primary malignancy, overall survival, thyroid cancer-specific survival, FNA, and histopathology were collected until January 2016. Multivariate logistic regression and survival analysis were performed. Results: The 362 analyzed patients (65% female) had a median age of 65 y (range, 19-96 y) and follow-up of 24 mo (range, 1-103 mo). Lymphoid, lung, and colorectal malignancy were the most common staging indications. Median overall survival was 20 mo (interquartile range, 9.5-39 mo). Most of the 180 observed deaths were due to the primary malignancy under investigation (92.2%) or to causes not related to cancer (7.2%); one patient (0.6%) died from incidentally detected medullary thyroid cancer. 18F-FDG avidity in the index malignancy, an advanced stage for that malignancy, and a clinician decision not to investigate 18F-FDG-avid TI were all predictors of mortality, with hazard ratios of 8.5, 3.0, and 3.3, respectively, and 95% confidence intervals of 4.6-15.8, 2.3-3.9, and 2.0-5.0, respectively (P < 0.001). Of 131 patients suitable for cytologic or histopathologic evaluation, 47 (36%) had incidental thyroid cancer (24 papillary, 11 malignant FNA, 5 oncocytic/Hürthle cell, 2 medullary, 1 follicular, and 4 metastases from underlying malignancy). Conclusion: Overall survival with 18F-FDG-avid TI was poor because of the prognosis associated with underlying malignancy, which must be considered before investigation of 18F-FDG-avid TI and certainly before aggressive treatment. Active surveillance should be considered in this group of patients.

Pilot study of parathyroid glands in adult and pediatric subjects exposed to ionizing radiation after the ChNPP accident, methodology of parathyroid diagnostic ultrasound. / PILOTNE DOSLIDZhENNIa STANU PRYShchYTOPODIBNYKh ZALOZ OSIB, OPROMINENYKh VNASLIDOK AVARIÏ NA ChAES DOROSLOGO TA DYTIaChOGO VIKU, METODOLOGIIa ÏKh UL'TRAZVUKOVOGO DOSLIDZhENNIa.

OBJECTIVE: Estimation of the parathyroid hyperplasia prevalence after the ChNPP accident in adults exposed to ion izing radiation and their descendants using the diagnostic ultrasound and its methodology elaboration. MATERIALS AND METHODS: The pilot prospective study of the prevalence of parathyroid hyperplasia among the Chornobyl Nuclear Power Plant (ChNPP) accident adult survivors (n=686) and their descendants (54 children) was performed using diagnostic ultrasound examination of thyroid and parathyroids. Among the study subjects there were 339 ChNPP accident clean up workers (ACUW), 32 persons were evacuated from the 30 km exclusion zone and 224 ones were included to the control group. Diagnostic ultrasound of thyroid and parathyroids was performed according to the standard method. Additionally, in children with parathyroid hyperplasia an additional assay of 25 hydroxyvitamin D levels in serum was performed. In calculating the statistical significance, its level p < 0.05 was considered statistically significant. RESULTS: Parathyroids are a few small but critically important endocrine glands that synthesize parathyroid hormone, regulating mainly phosphoric calcium metabolism. Insufficient (hypoparathyroidism) or excessive (hyperparathy roidism) function of parathyroids is harmful to the patients affecting the state of nervous and cardiovascular sys tem. Parathyroidss can accumulate isotopes of cesium, strontium and radioactive iodine. The available data testify to an increased incidence of clinically significant hyperplasia of parthyroids (more than 9 mm in adults and more than 5 mm in children) among persons exposed toionizng radiation as a result of the accident at the ChNPP (28.64%) and their descendants (23.8-70.6%). First of all are concerned those adults who live in contaminated areas in comparison with the control group (24.15% in not irradiated). Evacuees from the 30 km exclusion zone being the category of people who were exposed to the absorbed iodine isotopes in the first days of the Chernobyl accident are the another risk group. These data demonstrate sensitivity of parathyroidss to the impact of incorpo rated isotopes (iodine, cesium and strontium), which in the long term exposure create conditions for structural and functional changes in regulation of phosphorous calcium metabolism being the basis for a significant prevalence of osteopenia and osteoporosis in irradiated individuals and their descendants. A number of further studies are required to clarify the findings and to disclose the hormonal mechanisms of radiation effects on parathyroids. CONCLUSIONS: Parathyroid glands are radiosensitive and susceptible to effects of strontium, cesium and iodine iso topes, which cause parathyroid irradiation and subsequent structural and functional changes, being a prerequisite for development of osteopenia and osteoporosis in the ChNPP accident survivors and their descendants. High inci dence of parathyroid hypertrophy is found in the inhabitants of the radiation contaminated territories (long term irradiation by cesium isotopes), as well as in evacuated from the 30 km exclusion zone (irradiation by iodine iso topes in the early days of the accident).

N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation.

We evaluated the effect of the antioxidant N-acetyl-L-cysteine (NAC) on the levels of reactive oxygen species (ROS), DNA double strand breaks (DSB) and micronuclei (MN) induced by internal and external irradiation using a rat thyroid cell line PCCL3. In internal irradiation experiments, ROS and DSB levels increased immediately after 131I addition and then gradually declined, resulting in very high levels of MN at 24 and 48 h. NAC administration both pre- and also post-131I addition suppressed ROS, DSB and MN. In external irradiation experiments with a low dose (0.5 Gy), ROS and DSB increased shortly and could be prevented by NAC administration pre-, but not post-irradiation. In contrast, external irradiation with a high dose (5 Gy) increased ROS and DSB in a bimodal way: ROS and DSB levels increased immediately after irradiation, quickly returned to the basal levels and gradually rose again after >24 h. The second phase was in parallel with an increase in 4-hydroxy-2-nonenal. The number of MN induced by the second wave of ROS/DSB elevations was much higher than that by the first peak. In this situation, NAC administered pre- and post-irradiation comparably suppressed MN induced by a delayed ROS elevation. In conclusion, a prolonged ROS increase during internal irradiation and a delayed ROS increase after external irradiation with a high dose caused serious DNA damage, which were efficiently prevented by NAC. Thus, NAC administration even both after internal or external irradiation prevents ROS increase and eventual DNA damage.