Radioactive Iodine Therapy of Graves' Disease in Patients Pretreated With Methimazole Without Radioiodine Uptake for Dose Estimation.

OBJECTIVE: To assess response predictors to radioactive iodine (RAI) therapy without using thyroid uptake for dose estimate in patients pretreated with methimazole. METHODS: Retrospective analysis was performed of patients with Graves' disease treated with RAI doses determined without using uptake studies. RESULTS: In 242 patients (median age, 41.9 years; 66.1% female), initial mean free thyroxine (FT4) level was 4.7 ng/dL with an estimated thyroid size of 49.15 g. Prior to RAI therapy, average methimazole dose was 22.7 mg/day. Mean RAI dose was 737.0 ±199.4 MBq (19.9 ± 5.4 mCi). Two hundred eight patients (85.9%) responded to RAI therapy; 185 (88.9%) became hypothyroid and 23 (11.1%) became euthyroid. The majority (90.4%) responded within 6 months of therapy with a quicker response (13.9 ± 8.3 vs 17.5 ± 13.5 weeks) for those treated with doses per gram of ≥14.8 MBq (0.4 mCi). Thirty-four nonresponders had a higher initial FT4 level and larger thyroid size with a lower RAI dose per gram of thyroid tissue. In multivariate analysis, the independent response predictor to therapy was dose per gram of thyroid tissue of ≥14.8 MBq (0.4 mCi) (hazard ratio, 3.18; 95% CI, 1.1-9.7). Doses per gram of 14.8 to 18.1 MBq (0.4-0.5 mCi) achieved maximal response rate without added advantage of higher doses. Thyroid size prior to RAI therapy, FT4 levels at diagnosis, and age were inversely related to response. CONCLUSION: RAI therapy for Graves' disease without uptake studies for dose estimates is an effective treatment method. In patients pretreated with methimazole, an RAI dose per gram of thyroid tissue of ≥14.8 MBq (0.4 mCi) showed high response rate. Prospective studies are needed to confirm the viability of this simplified and cost-effective approach.

The EANM guideline on radioiodine therapy of benign thyroid disease.

This document provides the new EANM guideline on radioiodine therapy of benign thyroid disease. Its aim is to guide nuclear medicine physicians, endocrinologists, and practitioners in the selection of patients for radioiodine therapy. Its recommendations on patients' preparation, empiric and dosimetric therapeutic approaches, applied radioiodine activity, radiation protection requirements, and patients follow-up after administration of radioiodine therapy are extensively discussed.

Hypothyroidism and hyponatremia: data from a series of patients with iatrogenic acute hypothyroidism undergoing radioactive iodine therapy after total thyroidectomy for thyroid cancer.

PURPOSE: The aim of the present study was to evaluate the role of hypothyroidism as a cause of hyponatremia in a clinical model of iatrogenic acute hypothyroidism due to thyroid hormone withdrawal prior to ablative radioactive iodine (RAI) therapy after total thyroidectomy. METHODS: The study group consisted of 101 differentiated thyroid cancer (DTC) patients (77 women and 24 men). Plasma concentration of thyroid-stimulating hormone ([TSH]) and sodium ([Na+]) was evaluated before total thyroidectomy (pre[TSH] and pre[Na+]) and on the day of RAI therapy (post[TSH] and post[Na+]). RESULTS: The frequency of hypothyroidism-associated hyponatremia was 4 % (4/101). Pre[Na+] was significantly higher than post[Na+] (140.7 ± 1.6 vs 138.7 ± 2.3 mEq/L, p = 0.012). Moreover, a linear correlation was identified between pre[Na+] and post[Na+]. CONCLUSIONS: Iatrogenic acute hypothyroidism-related hyponatremia is uncommon. However, because of the significant reduction of [Na+] in the transition from euthyroidism to iatrogenic hypothyroidism, the value of pre[Na+] should be viewed as a parameter to be considered. Since it acts as an independent risk factor for the development of hyponatremia, patients with a pre[Na+] close to the lower limit of normal range may deserve a closer monitoring of [Na+].

Outcomes of Differentiated Thyroid Cancer in Children and Adolescents at King Abdulaziz Medical City, Jeddah.

Objective Differentiated thyroid cancer (DTC) is rare in the pediatric population, with most data from the Western world. We aimed to describe the clinical presentation, treatment intervention, histopathological characteristics, complications, follow-up, and response to treatment in 17 patients with DTC at or below the age of 20 years. Interventions This was a retrospective cohort study at King Abdulaziz Medical City, Jeddah, Saudi Arabia. We included patients aged younger than 20 years with DTC. Total or near-total thyroidectomy was performed in 82% of the patients, central and/or lateral neck dissection in 35% of cases, and radioactive iodine (RAI) ablation in 76% of cases. Results The study included 17 patients (14 females), with a median age of 16 years at the time of diagnosis. Thyroid nodules were the main complaint in 88% of the patients. Thyroid ultrasonography was the main method for the initial evaluation. Papillary cancer was the most common type of tumor, and lymph node spread was found in 82% of the patients. Moreover, 40% of the patients exhibited excellent responses to therapy, with 35% showing indeterminate results. Only 23.5% of the patients developed hypocalcemia postoperatively. Conclusions Classical papillary thyroid carcinoma was the predominant histopathological type, and most patients showed excellent responses to therapy, followed by indeterminate in most of the cases. The most common presentation was a neck nodule, signifying the role of thorough physical neck examinations. Finally, recurrence occurred in a minority of patients. However, none of these patients died.

High RPMB predicts poor disease-free survival of male N1 papillary thyroid cancer after adjuvant radioiodine therapy.

The current recommendation for the use of adjuvant radioactive iodine (RAI) therapy in papillary thyroid cancer (PTC) after radical surgery is based on clinicopathological factors; however, this recommendation remains controversial. Our present study established a new biomarker, RPMB (promotor methylation burden of DNA repair genes (DRGs)), to identify a patient subgroup suitable for adjuvant RAI therapy. We defined RPMB as the ratio of methylated DRGs to the total number of DRGs. Methylation profiles of 498 PTC tumors and their clinical data were retrieved from the Cancer Genome Atlas (TCGA) database. DRGs of PTC subjects were found to be much more hypomethylated than controls across the whole profile (all p < 0.001). PTC patients with higher RPMBs tended to be ≥45 years old and female, and these PTCs were commonly unifocal, with N0 disease, wild-type BRAF, and mutated RAS. The subgroup analysis indicated that high RPMBs were significantly associated with poor disease-free survival (DFS) in male patients with PTC (HR = 4.855, 95% CI: 1.527-15.433, p = 0.007). Moreover, Kaplan-Meier analysis showed that high RPMBs could significantly predict poor DFS in male patients after R0 resection for N1 disease (HR: 5.431, 95% CI: 1.045-28.219, p = 0.024), and the p-value was very close to significance in these patients after adjuvant RAI therapy (HR: 6.269, 95% CI: 0.693-56.714, p = 0.062). Multivariate analysis indicated that both male sex (HR = 14.565, 95%CI: 2.153-98.507, p = 0.006) and high RPMBs (HR = 11.206, 95%CI: 1.622-77.405, p = 0.014) were independent unfavorable factors for DFS after adjuvant RAI therapy. Therefore, RPMB might be a potential predictor for identifying suitable male patients with PTC who can benefit from adjuvant RAI therapy.

MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells.

The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.

[Anxiety and depression in patients treated for differentiated thyroid microcarcinoma]. / L'anxiété et la dépression chez les patients suivis pour microcarcinome différencié de la thyroïde.

INTRODUCTION: Thyroid microcarcinoma is a cancer associated with good prognosis but it may affect patients' quality of life. The purpose of this study is to assess depression and anxiety in patients treated for differentiated thyroid microcarcinoma and to compare them to patients with other cancer stages. METHODS: We conducted a cross-sectional observational study between October 2013 and February 2015. The study included adult patients treated for differentiated thyroid cancer. Depression and anxiety were assessed using two quality of life scales, whose translation was validated in Arabic: Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale. Patients were divided into two groups: thyroid microcarcinoma group and non-microcarcinoma group. Data analysis was performed using SPSS software 16. RESULTS: The study involved 37 patients treated for differentiated thyroid microcarcinoma and a comparison group of 87 patients treated for other stages of differentiated thyroid cancer. Patients? quality of life in the thyroid microcarcinoma group was better than that of patients with other stages of differentiated thyroid cancer. Thyroid microcarcinoma was significantly associated with lack of anxiety (p=0.042), Hamilton Depression Rating Scale revealed a positive trend (p value was not significant). CONCLUSION: Patients' quality of life in thyroid microcarcinoma group was better than that of patients to with other stages of differentiated thyroid cancer. This can be explained by a non-aggressive treatment (absence of radioactive iodine treatment and lower TSH level).

Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening.

Patients with well-differentiated thyroid cancer, especially papillary thyroid cancer (PTC), are treated with surgical resection of the thyroid gland. This is followed by post-operative radioactive iodine (I131), resulting in total thyroid ablation. Unfortunately, about 15-33% of PTC patients are unable to take up I131, limiting further treatment options. The aim of our study was to develop a cancer organoid model with the potential for pre-treatment diagnosis of these I131-resistant patients. PTC tissue from thirteen patients was used to establish a long-term organoid model. These organoids showed a self-renewal potential for at least five passages, suggesting the presence of cancer stem cells. We demonstrated that thyroid specific markers, a PTC marker, and transporters/receptors necessary for iodine uptake and thyroid hormone production were expressed on a gene and protein level. Additionally, we cultured organoids from I131-resistant PTC material from three patients. When comparing PTC organoids to radioactive iodine (RAI)-refractory disease (RAIRD) organoids, a substantial discordance on both a protein and gene expression level was observed, indicating a treatment prediction potential. We showed that patient-derived PTC organoids recapitulate PTC tissue and a RAIRD phenotype. Patient-specific PTC organoids may enable the early identification of I131-resistant patients, in order to reduce RAI overtreatment and its many side effects for thyroid cancer patients.

Radioiodine-Induced Salivary Gland Damage Detected by Ultrasonography in Patients Treated for Papillary Thyroid Cancer: Radioactive Iodine Activity and Risk.

Background: An important side effect of radioactive iodine (RAI) therapy in patients treated for papillary thyroid cancer (PTC) is chronic sialadenitis. Neck ultrasonography (US) easily recognizes radioiodine-induced salivary gland abnormalities. The objectives of this study were to determine the prevalence of US-detected sialadenitis caused by RAI and to identify the risk factors associated with this damage. Methods: This nonconcurrent cohort study includes all PTC-operated patients who were treated with RAI between 2007 and 2017 and were systematically evaluated with preoperative and follow-up neck US that included targeted exploration of the major salivary glands. Patients with pre-existing salivary gland diseases were excluded. The anatomical damage (diminished glandular volume, wavy contours, hypoechogenicity, and heterogeneity) was qualitatively assessed and compared with the preoperative study. RAI activity, sex, age, and preparation method were evaluated as risk factors using univariate and multivariate analyses with logistic regression. Results: Enrolled in this study were 570 patients who received a median RAI activity of 3700 MBq (100 mCi). On US, we found 143 patients (25.1%) with damage in at least one of their salivary glands: all had parotid damage (77 bilaterally) and 14 (9.8%) also had submandibular gland damage (7 of them bilaterally). The multivariate analysis indicated that the risk of sialadenitis was significantly (p < 0.01) correlated with both RAI activity and sex (14.1% of males vs. 28.5% of females). However, the main risk factor was RAI activity; no injury was detected in 156 patients who received 1110 MBq (30 mCi) and 1850 MBq (50 mCi) of RAI. In the groups of patients receiving 3700 MBq (100 mCi), 5550 MBq (150 mCi) and ≥7400 MBq (≥200 mCi), atrophy was found in 21%, 46.9%, and 77.7% of patients, respectively. Age and preparation method were not related to an increased risk of atrophy in this study. Conclusions: Chronic sialadenitis is common and affects approximately one fourth of patients who receive 3700 MBq (100 mCi) or higher RAI activity. The main risk factor for this injury is the total RAI activity administered. By using the lowest effective activity possible, irreversible anatomical damage in salivary glands can be minimized. US is an excellent tool to diagnose post-RAI atrophy.

Clinical significance of the BRAFV600E mutation in PTC and its effect on radioiodine therapy.

The goal of this study was to explore the relationship of the BRAFV600E mutation with clinicopathologic factors and evaluate the effect of radioactive iodine (RAI) therapy in a large group of intermediate- and high-risk papillary thyroid cancer (PTC) patients with the BRAFV600E mutation and without distant metastases. We collected data for PTC patients who underwent total or near-total thyroidectomy and RAI treatment in our hospital from January 2014-December 2017. There were 1220 PTC patients who met the criteria, and the BRAFV600E mutation was observed in 979 of them (80.2%). Multivariate analysis identified that the BRAFV600E mutation remained independently associated with age at diagnosis, and bilaterality (OR = 1.023, 95% CI = 1.012-1.039, P < 0.001; OR = 1.685, 95% CI = 1.213-2.341, P = 0.002, respectively). In addition, the patients with bilateral PTCs had a higher prevalence of extrathyroid invasion, capsular invasion and fusion of metastatic lymph nodes than the unilateral PTC patients. The response to RAI therapy was evaluated in both the entire series and the patients with a high recurrence risk; no significant difference was discerned between the BRAFV600E mutation and the wild-type groups (P = 0.237 and P = 0.498, respectively). To summarize, our results confirmed that PTC patients with the BRAFV600E mutation exhibit more aggressive characteristics. In addition, the patients with bilateral PTC have a higher incidence of extrathyroid invasion. Moreover, BRAFV600E mutation PTC patients did not show a poorer clinical response after postsurgical RAI therapy, suggesting that RAI therapy may improve the general clinical outcome of these patients.

Cardiovascular Morbidity and Mortality After Treatment of Hyperthyroidism with Either Radioactive Iodine or Thyroidectomy.

BACKGROUND: Hyperthyroid patients remain at an increased risk of cardiovascular diseases (CVDs) after restoring euthyroidism. The impact of the different treatment modalities of hyperthyroidism on future CVD risk remains unclear. The aims of this study were to assess cardiovascular morbidity and mortality in hyperthyroidism before and after treatment, and to compare the effects of two different treatment modalities: radioactive iodine (RAI) and thyroid surgery. METHODS: A comparative cohort study was conducted among 6148 hyperthyroid patients treated with either RAI or thyroidectomy and 18,432 age- and sex-matched controls. First, hospitalizations due to CVDs prior to the treatment were analyzed. Second, the hazard ratios (HR) for any new hospitalization and mortality due to CVDs after treatment were estimated among all the hyperthyroid patients compared to the age- and sex-matched controls and also in the RAI-treated patients compared to the thyroidectomy-treated patients. The results were adjusted for prevalent CVDs at the time of treatment. RESULTS: Before treatment for hyperthyroidism, hospitalizations due to all CVDs were more common in the hyperthyroid patients compared to the controls (odds ratio = 1.61 [confidence interval (CI) 1.49-1.73]). During the post-treatment follow-up, hospitalizations due to CVDs remained more frequent among the patients (HR = 1.15 [CI 1.09-1.21]), but there was no difference in CVD mortality (HR = 0.93 [CI 0.84-1.03]). Compared to the patients treated with thyroidectomy, the RAI-treated patients had a higher risk of hospitalization due to all CVDs (HR = 1.17), atrial fibrillation (HR = 1.28), as well as a higher CVD mortality rate (HR = 2.56). Yet, treatment with RAI resulting in hypothyroidism was not associated with increased CVD morbidity compared to thyroidectomy. CONCLUSIONS: Hyperthyroidism increases the risk of CVD-related hospitalization, and the risk is sustained for up to two decades after treatment with RAI or surgery. Hyperthyroid patients treated with RAI remain at a higher CVD risk compared to patients treated with thyroidectomy. Hypothyroidism during follow-up, however, predicts better cardiovascular outcomes.