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1.
Gene network and biological pathways associated with susceptibility to differentiated thyroid carcinoma.
Kulkarni, O, Sugier, PE, Guibon, J, Boland-Augé, A, Lonjou, C, Bacq-Daian, D, Olaso, R, Rubino, C, Souchard, V, Rachedi, F, et al
Scientific reports. 2021;(1):8932
Abstract
Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
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2.
Long-Term Results of a Phase II Trial of Apatinib for Progressive Radioiodine Refractory Differentiated Thyroid Cancer.
Lin, YS, Zhang, X, Wang, C, Liu, YQ, Guan, WM, Liang, J
The Journal of clinical endocrinology and metabolism. 2021;(8):e3027-e3036
Abstract
CONTEXT Radioiodine refractory differentiated thyroid cancer (RAIR-DTC) has been a global challenge due to its poor prognosis and limited treatment options. OBJECTIVE We report here the long-term results of the phase II clinical trial of apatinib, an anti-angiogenic tyrosine kinase inhibitor, for RAIR-DTC. METHODS This was an open-label, exploratory phase II clinical trial among progressive RAIR-DTC patients. Apatinib treatment was given once daily until disease progression, unmanageable toxicity, withdrawal, or death. The primary end points were objective response rate (ORR) and disease control rate (DCR). Progression-free survival (PFS), overall survival (OS), duration of response, long-term safety, and the association between patients with different tumor genotype (BRAFV600E and TERT promotor mutation) and their PFS rates were also assessed. RESULTS The ORR was 80%, and the DCR was 95%. The overall median PFS was 18.4 months (95% CI, 9.2-36.8 months) and the median OS was 51.6 months (95% CI, 29.2-not reached [NR]). Patients with BRAFV600E mutation (10 of 18 evaluated) had a longer median PFS compared with patients with BRAF wild-type (NR vs 9.2 months; P = 0.002). The most common adverse events included palmar-plantar erythrodysesthesia syndrome (19/20), proteinuria (18/20), and hypertension (16/20). CONCLUSION In this long-term evaluation, apatinib displayed sustainable efficacy and tolerable safety profile, warranting it as a promising treatment option for progressive RAIR-DTC.
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The Efficacy and Safety of Anlotinib in Neoadjuvant Treatment of Locally Advanced Thyroid Cancer: A Single-Arm Phase II Clinical Trial.
Huang, NS, Wei, WJ, Xiang, J, Chen, JY, Guan, Q, Lu, ZW, Ma, B, Sun, GH, Wang, YL, Ji, QH, et al
Thyroid : official journal of the American Thyroid Association. 2021;(12):1808-1813
Abstract
Background: Surgery is the primary treatment for locally advanced thyroid cancer. For some cases, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. Anlotinib is a multitarget tyrosine kinase inhibitor, which demonstrated antitumor activity in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer. We aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting. Methods: This single-arm phase II study investigated the efficacy and safety of anlotinib (12 mg orally daily, 2 weeks on/1 week off) for 2-6 cycles in patients with locally advanced thyroid cancer in the neoadjuvant setting. The key eligibility criteria included age 14-80 years old; locally advanced thyroid cancer that would benefit from surgery, and at least one measurable lesion. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were enrolled and received an average of 3.5 cycles of anlotinib treatment. The ORR of anlotinib was 76.9% (95% confidence interval: 46.2-95.0%). The R0/R1 resection rate in the intent-to-treat population was 61.5% and in the per-protocol population was 72.7%. The median time to response was 61.5 days, and the disease control rate at 18 weeks was 92.3%. No patients had blood transfusion or tracheotomy. Most adverse events (AEs) were grade 1 or 2 and tended to discontinue when neoadjuvant treatment ceased. Common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (53.8%), and hand-foot syndrome (38.5%). Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer. Clinical Trial Registration Number: NCT04309136.
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Shared and unique metabolic features of the malignant and benign thyroid lesions determined with use of 1H HR MAS NMR spectroscopy.
Skorupa, A, Ciszek, M, Chmielik, E, Boguszewicz, Ł, Oczko-Wojciechowska, M, Kowalska, M, Rusinek, D, Tyszkiewicz, T, Kluczewska-Gałka, A, Czarniecka, A, et al
Scientific reports. 2021;(1):1344
Abstract
The purpose of this work was to investigate the distinct and common metabolic features of the malignant and benign thyroid lesions in reference to the non-transformed tissue from the contralateral gland (chronic thyroiditis and colloid goiter). 1H HR MAS NMR spectra of 38 malignant lesions, 32 benign lesions and 112 samples from the non-tumoral tissue (32 from chronic thyroiditis and 80 samples from colloid goiter) were subjected both to multivariate and univariate analysis. The increased succinate, glutamine, glutathione, serine/cysteine, ascorbate, lactate, taurine, threonine, glycine, phosphocholine/glycerophosphocholine and decreased lipids were found in both lesion types in comparison to either colloid goiter or chronic thyroiditis. The elevated glutamate and choline, and reduced citrate and glucose were additionally evident in these lesions in reference to goiter, while the increased myo-inositol-in comparison to thyroiditis. The malignant lesions were characterized by the higher alanine and lysine levels than colloid goiter and thyroiditis, while scyllo-inositol was uniquely increased in the benign lesions (not in cancer) in comparison to both non-tumoral tissue types. Moreover, the benign lesions presented with the unique increase of choline in reference to thyroiditis (not observed in the cancerous tissue). The metabolic heterogeneity of the non-tumoral tissue should be considered in the analysis of metabolic reprogramming in the thyroid lesions.
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Real-time quantitation of thyroidal radioiodine uptake in thyroid disease with monitoring by a collar detection device.
Santhanam, P, Solnes, L, Nath, T, Roussin, JP, Gray, D, Frey, E, Sgouros, G, Ladenson, PW
Scientific reports. 2021;(1):18479
Abstract
Radioactive iodine (RAI) is safe and effective in most patients with hyperthyroidism but not all individuals are cured by the first dose, and most develop post-RAI hypothyroidism. Postoperative RAI therapy for remnant ablation is successful in 80-90% of thyroid cancer patients and sometimes induces remission of nonresectable cervical and/or distant metastatic disease but the effective tumor dose is usually not precisely known and must be moderated to avoid short- and long-term adverse effects on other tissues. The Collar Therapy Indicator (COTI) is a radiation detection device embedded in a cloth collar secured around the patient's neck and connected to a recording and data transmission box. In previously published experience, the data can be collected at multiple time points, reflecting local cervical RAI exposure and correlating well with conventional methods. We evaluated the real-time uptake of RAI in patients with hyperthyroid Graves' disease and thyroid cancer. We performed a pilot feasibility prospective study. Data were analyzed using R© (version 4.0.3, The R Foundation for Statistical Computing, 2020), and Python (version 3.6, Matplotlib version 3.0.3). The COTI was able to provide a quantitative temporal pattern of uptake within the thyroid in persons with Graves' disease and lateralized the remnant tissue in persons with thyroid cancer. The study has demonstrated that the portable collar radiation detection device outside of a healthcare facility is accurate and feasible for use after administration of RAI for diagnostic studies and therapy to provide a complete collection of fractional target radioactivity data compared to that traditionally acquired with clinic-based measurements at one or two time-points.Clinical Trials Registration NCT03517579, DOR 5/7/2018.
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Surufatinib in Chinese Patients with Locally Advanced or Metastatic Differentiated Thyroid Cancer and Medullary Thyroid Cancer: A Multicenter, Open-Label, Phase II Trial.
Chen, J, Ji, Q, Bai, C, Zheng, X, Zhang, Y, Shi, F, Li, X, Tang, P, Xu, Z, Huang, R, et al
Thyroid : official journal of the American Thyroid Association. 2020;(9):1245-1253
Abstract
Background: Thyroid cancer is the most common endocrine tumor with an increasing incidence. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Surufatinib targets multiple kinases (vascular endothelial growth factor receptors, fibroblast growth factor receptor-1, and colony-stimulating factor-1 receptor) involved in tumor angiogenesis and tumor immune evasion. Surufatinib has demonstrated promising antitumor activity in various advanced solid tumors. This study aimed to determine the objective response rate (ORR) of surufatinib in patients with locally advanced or distant metastatic differentiated thyroid cancer (DTC) or medullary thyroid cancer (MTC). Methods: This Phase II open-label study by Simon's two-stage design was conducted at 10 sites across China. Patients with radioiodine (RAI)-refractory DTC with locally advanced disease or distant metastasis (DTC1 group); patients who received limited initial surgery and then developed locally advanced unresectable recurrences and were not considered candidates for RAI therapy due to residual normal thyroid tissue (DTC2 group); or patients with MTC with locally advanced disease or distant metastasis (MTC group) were enrolled. A total of 59 patients were enrolled (26 in DTC1, 6 in DTC2, and 27 in MTC) and received 300 mg surufatinib daily in 28-day cycles. The primary endpoint was ORR as determined by the investigators. Results: Overall ORR was 23.2% [95% confidence interval, CI 12.98-36.42]: 21.7% in the DTC1 cohort, 33.3% in the DTC2 cohort, and 22.2% in the MTC cohort. Forty-nine patients achieved disease control (87.5% [CI 75.93-94.82]): 87.0% in the DTC1 cohort, 83.3% in the DTC2 cohort, and 88.9% in the MTC cohort. Median time to response was 59.0 days, and 59.0, 85.5, and 59.0 days in the DTC1, DTC2, and MTC cohorts. Overall median progression-free survival was 11.1 months [CI 5.98-16.69]; 11.1 months in DTC1 and MTC cohorts, while the DTC2 cohort had not reached the median at the data cutoff. The most common treatment-emergent adverse events grade ≥3 were hypertension (20.3%), proteinuria (11.9%), and then elevated blood pressure, hypertriglyceridemia, and pulmonary inflammation (5.1% each). Conclusions: Surufatinib demonstrated promising efficacy with a tolerable and manageable safety profile for patients with locally advanced or metastatic MTC, RAI-refractory DTC, or locally advanced unresectable recurrences unable to receive RAI.
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SELIMETRY-a multicentre I-131 dosimetry trial: a clinical perspective.
Wadsley, J, Gregory, R, Flux, G, Newbold, K, Du, Y, Moss, L, Hall, A, Flanagan, L, Brown, SR
The British journal of radiology. 2017;(1073):20160637
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Abstract
Treatment options for patients with thyroid cancer that is no longer sensitive to iodine therapy are limited. Those treatments which currently exist are associated with significant toxicity. The SELIMETRY trial (EudraCT No 2015-002269-47) aims to investigate the role of the MEK inhibitor Selumetinib in resensitizing advanced iodine refractory differentiated thyroid cancer to radioiodine therapy. Patients deemed to have sufficient iodine uptake in previously iodine refractory lesions after 4 weeks of Selumetinib therapy will be given an empirical activity of 5.5 GBq I-131, and response to therapy will be assessed. The trial presents an opportunity to investigate the dosimetric aspects of radioiodine therapy for advanced thyroid cancer. Patients will undergo serial I-123 single-photon emission CT (SPECT)/CT scans following Selumetinib therapy to determine whether there has been a change in the degree of iodine uptake to justify further I-131 therapy, and to allow dosimetric calculations to predict absorbed dose to target lesions following therapy. Patients receiving I-131 therapy will undergo a further series of post-therapy SPECT/CT scans to allow dosimetric calculations. We describe the challenges in setting up a multicentre trial in a relatively underinvestigated field, describing the work that has been carried out to calibrate and validate measurements to ensure that standardized image data are collected at each site. We hope that this trial will lead to individualization and optimization of therapy for patients with advanced thyroid cancer and that the ground work carried out in setting up a network of centres capable of standardized molecular radiotherapy dosimetry will lead to further clinical trials in this field.
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Higher urinary bisphenol A concentration and excessive iodine intake are associated with nodular goiter and papillary thyroid carcinoma.
Zhou, Z, Zhang, J, Jiang, F, Xie, Y, Zhang, X, Jiang, L
Bioscience reports. 2017;(4)
Abstract
In the present study, we investigated whether bisphenol A (BPA) levels and excessive iodine intake were associated with papillary thyroid carcinoma (PTC) and nodular goiter (NG). We determined total BPA concentrations (TBC) in paired serum and urine samples, and urinary iodine concentrations (UIC) in urine samples collected from PTC patients, NG patients, and healthy individuals, then compared BPA concentrations and UIC within and between each patient group. The results showed that there were no gender-specific differences in serum TBC and UIC in each group, and no differences across all patient groups. Urinary BPA concentrations (UBC) were higher in the NG and PTC groups compared with the control group. UBC showed gender-specific differences in the NG and PTC group. Furthermore, UIC were higher in the NG and PTC groups compared with the control group. Higher UBC and excessive iodine intake were risk factors for NG and PTC according to multivariate logistic regression analysis. There was a significant correlation between UBC and UIC in each group. These data suggested that higher UBC and excessive iodine intake are associated with NG and PTC. The metabolic and functional pathways between BPA and iodine are potentially linked to the pathogenesis and progression of NG and PTC.
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Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis--A Cohort Study in a Group of Thyroid Carcinoma Patients.
Broeders, EP, Vijgen, GH, Havekes, B, Bouvy, ND, Mottaghy, FM, Kars, M, Schaper, NC, Schrauwen, P, Brans, B, van Marken Lichtenbelt, WD
PloS one. 2016;(1):e0145049
Abstract
BACKGROUND/OBJECTIVES Thyroid hormone receptors are present on brown adipose tissue (BAT), indicating a role for thyroid hormone in the regulation of BAT activation. The objective of this study was to examine the effect of thyroid hormone withdrawal followed by thyroid hormone in TSH-suppressive dosages, on energy expenditure and brown adipose tissue activity. SUBJECTS/METHODS This study was a longitudinal study in an academic center, with a follow-up period of 6 months. Ten patients with well-differentiated thyroid carcinoma eligible for surgical treatment and subsequent radioactive iodine ablation therapy were studied in a hypothyroid state after thyroidectomy and in a subclinical hyperthyroid state (TSH-suppression according to treatment protocol). Paired two-tailed t-tests and linear regression analyses were used. RESULTS Basal metabolic rate (BMR) was significantly higher after treatment with synthetic thyroid hormone (levothyroxine) than in the hypothyroid state (BMR 3.8 ± 0.5 kJ/min versus 4.4 ± 0.6 kJ/min, P = 0.012), and non-shivering thermogenesis (NST) significantly increased from 15 ± 10% to 25 ± 6% (P = 0.009). Mean BAT activity was significantly higher in the subclinical hyperthyroid state than in the hypothyroid state (BAT standard uptake value (SUVMean) 4.0 ± 2.9 versus 2.4 ± 1.8, P = 0.039). CONCLUSIONS Our study shows that higher levels of thyroid hormone are associated with a higher level of cold-activated BAT. TRIAL REGISTRATION ClinicalTrials.gov NCT02499471.
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[Shielding effect of distance in (131)I-131 therapy for differentiated thyroid cancer].
Chi, X, Liu, F, Li, G, Wang, Q, Deng, Z
Nan fang yi ke da xue xue bao = Journal of Southern Medical University. 2014;(2):286-8
Abstract
OBJECTIVE To investigate the shielding effect of distance in radioactive iodine treatment in patients with differentiated thyroid cancer (DTC). METHODS Eighty-seven DTC patients underwent postoperative radioactive iodine treatment at the therapeutic doses ranging from 2.96 GBq to 7.4 GBq. The patients were divided into two groups to receive high-dose therapy (≥3.7 GBq, 48 patients) and low-dose therapy (<3.7 GBq, 39 patients). The radiation doses at 0.05 m, 1 m, and 3 m were recorded at different days; the doses at 1 m and 3 m on the third day, the dose of standard radioactivity source of 1.11GBq (131)I, and the natural background radioactivity were also recorded. RESULTS The radiation dose at a 1-meter distance was significantly higher in the high-dose group than in the low-dose group (P<0.05). The radiation doses in different dose groups at the other distances or at different time points showed no significant differences (P>0.05). On the third day after therapy, the radiation dose at 1 m was significantly lower than the reference radioactivity source of 1.11 GBq (131)I (P=0.000), but still higher than the natural background radioactivity at 3 m (P=0.000). CONCLUSION In DTC patients who receive radioactive iodine therapy, the radioactive radiation dose decreases rapidly after 3 days. The radioactive radiation dose on the third day is significantly lower than the reference radioactive radiation dose, so that the patients can be discharged with safety for contact at a distance beyond one meter.