Construction and validation of a nomogram for predicting lateral lymph node metastasis in pediatric and adolescent with differentiated thyroid carcinoma.

BACKGROUND: Limited research has been conducted to specifically investigate the identification of risk factors and the development of prediction models for lateral lymph node metastasis (LNM) in pediatric and adolescent differentiated thyroid carcinoma (DTC) populations, despite its significant association with unfavorable prognosis. METHODS: This study entails a retrospective analysis of the clinical characteristics exhibited by pediatric and adolescent patients who have been diagnosed with DTC. The data utilized for this analysis was sourced from the Surveillance, Epidemiology, and End Results (SEER) database, spanning the time frame from 2000 to 2020. Furthermore, the study incorporates patients who were treated at the Departments of Breast and Thyroid Surgery in the Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine, as well as The General Hospital of Western Theater Command, during the period from 2010 to 2020. RESULTS: A cohort of 2631 patients from the SEER database, along with an additional 339 patients from our departments who met the specified inclusion criteria, were included in this study. Subsequently, four clinical variables, namely age, tumor size, multifocality, and extrathyroidal invasion, were identified as being significantly associated with lateral LNM in pediatric and adolescent DTC patients. These variables were then utilized to construct a nomogram, which demonstrated effective discrimination with a concordance index (C-index) of 0.731. Furthermore, the performance of this model was validated through both internal and external assessments, yielding C-index values of 0.721 and 0.712, respectively. Afterward, a decision curve analysis was conducted to assess the viability of this nomogram in predicting lymph node metastasis. CONCLUSION: The current investigation has effectively constructed a nomogram model utilizing visualized multipopulationsal data. Our findings demonstrate a significant association between various clinical characteristics and lateral LNM in pediatric and adolescent DTC patients. These outcomes hold substantial significance for healthcare practitioners, as they can employ this model to inform individualized clinical judgments for the pediatric and adolescent cohorts.

Retrospective case-control study examining the relationship between recurrence-free survival and changes in pre- and post-radioiodine therapy serum thyroglobulin levels in patients with differentiated thyroid cancer.

PURPOSE: Thyroglobulin assay is important to assess the residual or recurrence of differentiated thyroid cancer (DTC). Patients with positive serum thyroglobulin levels after radioactive iodine (RAI) adjuvant therapy could achieve long-term recurrence-free survival (RFS). The patient's prognosis could not be confidently estimated based solely on the evaluation of thyroglobulin levels. We investigated the recurrence rate and RFS of patients who received adjuvant RAI therapy after surgery for DTC to clarify the relationship between changes in pre- and post-therapy serum thyroglobulin levels and RFS. MATERIALS AND METHODS: Patients who underwent adjuvant RAI therapy between May 2007 and March 2021 were included in this study, whereas those with positive anti-thyroglobulin antibodies, distant metastases, or gross residual tumors were excluded. The change in pre- and post-treatment serum thyroglobulin levels under thyroid-stimulating hormone stimulation was calculated and classified as follows: group A, thyroglobulin levels decreased by ˃10%; group B, thyroglobulin levels within a range of 10% or less; and group C, thyroglobulin levels increased by ˃10%. RFS outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, and multivariate analysis was performed using the Cox proportional hazard model. RESULTS: A total of 74 patients were included. Relapse was seen in 13 of 46 patients in group A, 9 of 15 in group B, and 10 of 13 in group C. Median RFS was 129.00 (95% confidence interval CI 77.79-180.21), 113.00 (95% CI 86.83-139.17), and 33 months (95% CI 6.026-59.974) in groups A, B, and C, respectively. Patients in group C exhibited significantly shorter RFS than those in groups A and B (P = 0.001). CONCLUSIONS: Changes in thyroglobulin levels pre- and post-therapy were associated with RFS. Patients with decreased post-therapy thyroglobulin levels had a favorable prognosis, even if their thyroglobulin levels were positive after RAI therapy.

Body composition changes in patients with differentiated thyroid cancer after iodine-131 treatment and short-term levothyroxine replacement and suppression therapy.

PURPOSE: The purposes of this study were to assess the changes in body composition in patients who underwent thyroidectomy due to differentiated thyroid cancer (DTC) after radioactive iodine therapy (RAI) and short-term levothyroxine (LT4) supplementation and to explore the correlations between body composition distribution and corresponding blood indices. METHODS: Fifty-seven thyroidectomized DTC patients were included. Serum was tested for several biochemical indices of thyroid function, lipids, and bone metabolism, and body composition parameters were measured via dual-energy X-ray absorptiometry before and 4-6 weeks after RAI and LT4 supplementation. RESULTS: The body composition of DTC patients changed after RAI. Fat mass in all parts of the body decreased (range of relative change (RRC) -12.97--2.80%). Bone mineral content (BMC) increased throughout the body (relative change (RC) 12.12%), head (RC 36.23%), pelvis (RC 9.00%), and legs (RC 3.15%). Similarly, bone mineral density (BMD) increased in different regions (RRC 3.60-26.43%), except for the arms. Notably, lean mass in the arms (RC 4.30%) and legs (RC 3.67%) increased, while that in the head decreased (RC -2.75%), while total lean mass did not change at 4-6 weeks after LT4 supplementation. Furthermore, changes in fat distribution in the android region were related to the changes in total cholesterol (r = -0.390) and low-density lipoprotein cholesterol (r = -0.354), and changes in the BMC and BMD of the lumbar spine were positively associated with the changes in calcitonin (r = 0.302 and 0.325, respectively). CONCLUSIONS: After RAI and short-term LT4 supplementation in DTC patients, body composition rapidly and positively changed and was characterized by decreased fat mass and increased BMC and BMD.

Update on iodine-refractory differentiated thyroid carcinoma.

Radioiodine therapy represents a fundamental pillar in the routine adjuvant therapy of patients with high-risk differentiated thyroid carcinoma. However, a non-negligible percentage of these patients will develop iodine refractoriness, showing a worse prognosis, as well a lower survival, which demonstrates a clear need to explore different therapeutic approaches. Iodine refractory patient treatment continues to be a challenge, currently having different novel therapeutic options that should be known by the different specialties related to differentiated thyroid carcinoma (DTC). The aim of this work is to review iodine refractory thyroid carcinoma treatment, focusing especially on the definition of iodine refractoriness, highlighting its importance due to its high mortality, and introducing the different therapeutic options available for these patients.

Retrospective analysis of low-risk differentiated thyroid tumours: is lobectomy the adequate approach? / Kis rizikójú differenciált pajzsmirigydaganatok retrospektív analízise: lobectomia a megfelelo választás?

Introduction: According to the recommendation of the American Thyroid Association 2015 guideline, the treatment of 1-4 cm (T1b-2) low-risk differentiated thyroid cancer (DTC) is lobectomy without radioiodine therapy. Objective: Retrospective analysis of multifocality in surgical and histological data of T1-2 patients living on moderate iodine intake. Methods: Analysis of the pathological characterisation of 81 low-risk (T1-2) DTC patients who underwent total thy-roidectomy. Patients were treated at Flor Ferenc Hospital, Kistarcsa, Hungary, between 2013 and 2019. Results: 64 patients had T1, while 17 patients had T2 status. 65/81 (80.2%) patients had papillary, and 16/81 (19.8%) had follicular subtype. Lymph node metastasis was detected up to 18.4% in papillary and 18% in follicular patients. Multifocal tumours were detected in 25% (16/64) of T1 patients, of these 10.9% (7/64) was unilateral and 14.1% (9/64) was bilateral. Multifocal tumours were detected in 11.7% (2/17) of T2 patients; both were bilateral. Distribution of T1-2 bilateral multifocal patients (11/81; 13.5%) was n = 3 T1a-, n = 6 T1b and n = 2 T2 stadium, from these 10 patients received radioiodine treatment. The sizes of contralateral tumours were <5 mm in 9 patients, and >5 mm in 2 patients. Conclusions: Due to the frequent (13.5%) bilateral multifocality in T1-2 DTC patients, we suggest total thyroidec-tomy instead of lobectomy. After lobectomy, the follow-up of the contralateral tumours is almost impossible by ul-trasonography due to the small tumour size (on average 2.8 mm) and frequently detected benign nodules; therefore the multifocality might remain undetected, which can distort the plan for adjuvant treatment.

Prognostic Value of Hybrid PET/MR Imaging in Patients with Differentiated Thyroid Cancer.

Background: Hybrid positron emission tomography (PET)/magnetic resonance (MR) is an emerging imaging modality with great potential to provide complementary data acquired at the same time, under the same physiological conditions. The aim of this study was to evaluate the prognostic value of hybrid 18F-fluorodeoxyglucose (FDG) PET/MR in patients with differentiated thyroid cancer (DTC) who underwent total thyroidectomy and radioactive iodine therapy for suspicion of disease relapse. Methods: Between November 2015 and February 2017, 55 patients underwent hybrid 18F-FDG PET/MR. Assessment of positive MR was made considering all sequences in terms of malignancy based on the morphological T2-weighted features and the presence of restricted diffusivity on diffusion-weighted imaging images and both needed to be positive on the same lesion. Both foci with abnormal 18F-FDG uptake, which corresponded to tissue abnormalities on the MR, and tracer accumulation, which did not correspond to normal morphological structures, were considered positive. Results: During follow-up (mean 42 ± 27 months), 29 patients (53%) had disease recurrence. In the Cox univariate regression analysis age, serum Tg level ≥ 2 ng/mL, positive short tau inversion recovery (STIR), and positive PET were significant predictors of DTC recurrence. Kaplan−Meier survival analyses showed that patients with Tg ≥ 2 ng/mL had poorer outcomes compared to those with serum Tg level < 2 ng/mL (p < 0.05). Similarly, patients with positive STIR and positive PET had a worst outcome compared to those with negative STIR (p < 0.05) and negative PET (p < 0.005). Survival analysis performed in the subgroup of 36 subjects with Tg level ≥ 2 ng/mL revealed that patients with positive PET had a worst outcome compared to those with negative PET (p < 0.05). Conclusions: Age, serum Tg level ≥ 2 ng/mL, positive STIR, and positive 18F-FDG PET were significant predictors of DTC recurrence. However, the serum Tg level was the only independent predictor of DTC. Hybrid PET/MR imaging may have the potential to improve the information content of one modality with the other and would offer new opportunities in patients with DTC. Thus, further studies in a larger patient population are needed to understand the additional value of 18F-FDG PET/MR in patients with DTC.

Differentiated thyroid carcinoma in the elderly: influence of age on disease-free and overall survival.

PURPOSE: We investigated whether age at diagnosis of differentiated thyroid carcinoma (DTC) may be a risk factor for structural disease and mortality after primary treatment in aging patients. METHODS: A multicenter, retrospective analysis including patients older than 60 years at DCT diagnosis was designed. All subjects were treated by surgery with or without radioiodine adjuvant therapy and had a minimum follow-up of one year. We compared elderly patients (group 1, 60-74 years) with very old patients (group 2, ≥75 years). RESULTS: The study involved 1668 patients (74.3% women, median age 67 years, 87.6% papillary thyroid cancer, 73.3% treated with radioiodine), including 1397 in group 1 and 271 in group 2. Patients in group 2 had larger tumor size (1.8 [0.8-3.0] vs 1.5 [0.7-2.8] cm; P = 0.005), higher proportions of tumors with vascular invasion (23.8 vs 16.4%; P = 0.006), and lower proportion of lymphocytic thyroiditis (18.6 vs 24.9%; P = 0.013) than subjects in group 1. Kaplan-Meier survival analysis showed that patients in group 2 had significantly lower structural disease-free survival (DFS) and overall survival (OS) than patients in group 1 (P = 0.035 and <0.001, respectively). In multivariate Cox regression analysis, age was a risk factor significantly associated with OS. However, age was significantly associated with DFS in unadjusted analysis and in analysis adjusted by gender and risk classification variables, but not when pathological and therapy-related variables were introduced in the model. On the other hand, patients who received radioiodine had worse DFS (P < 0.001) compared to those who did not. CONCLUSION: Although age is a conditioning factor for OS, very old patients do not have a greater risk of developing structural disease throughout the follow-up than elderly patients with DTC.

Delayed Initial Radioiodine Adjuvant Therapy Does Affect Biochemical Response in Intermediate- to High-Risk Differentiated Thyroid Cancer.

Background: There are no definite recommendations on the optimal time of initiating radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC) patients in current relevant guidelines. This study aimed to investigate the relationship between the timing of initiating radioiodine adjuvant therapy (RAT) and the clinical outcomes based on dynamic follow-ups and assessments in intermediate- to high-risk DTC patients. Methods: A total of 206 patients with intermediate- to high-risk DTC receiving RAT of 150 mCi were retrospectively reviewed. According to the time interval (TI: between thyroidectomy and initial RAT), the patients were divided into 2 groups: Group 1: TI < 3 months (n=148), and Group 2: TI ≥ 3 months (n=58). The RAT therapy response was evaluated as excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR), structural incomplete response (SIR). The univariate and multivariate analyses were conducted to screen out factors associated with incomplete response (IR= BIR+SIR). Finally, the prognostic nomogram was used to explain IR rates as a valuable tool in clinical practice. Results: Response to initial RAT was significantly different between 2 groups during dynamic follow-ups (all P<0.05). Group 2 had significantly lower ER rates (37.9 vs 63.5, 52.0 vs 73.9, 64.4 vs 80.3, all P<0.05, respectively) and higher IR rates (39.7 vs 14.9, 36.0 vs 9.7, 12.2 vs 3.9, all P<0.05, respectively) than group 1 during dynamic follow-ups. By univariate and multivariate analyses, prolonged TI (HR: 6.67, 95%CI: 2.241-19.857, P=0.001), soft tissue invasion (HR: 7.35, 95%CI: 1.624-33.296, P=0.010), higher sTg (HR: 7.21, 95%CI: 1.991-26.075, P=0.003) were manifested to be independent risk factors for IR. The nomogram showed that soft tissue invasion, sTg, and TI were the top 3 contributors to the IR. Conclusions: Early RAT is associated with greater biochemical response but has no impact on SIR. Delayed initial RAT (≥3 months after thyroidectomy) related to IR in intermediate- to high-risk DTC.

Only peak thyroglobulin concentration on day 1 and 3 of rhTSH-aided RAI adjuvant treatment has prognostic implications in differentiated thyroid cancer.

OBJECTIVE: In patients with differentiated thyroid carcinoma (DTC), serum thyroglobulin levels measured at the time of remnant ablation after thyroid hormone withdrawal were shown to have prognostic value for disease-free status. We sought to evaluate serial thyroglobulin measurements at the time of recombinant human thyroid-stimulating hormone (rhTSH)-aided iodine 131 (131I) adjuvant treatment as prognostic markers of DTC. METHODS: Six hundred-fifty patients with DTC given total/near-total thyroidectomy and adjuvant radioiodine post-rhTSH stimulation were evaluated. Thyroglobulin was measured on day 1 (Tg1; at the time of the first rhTSH injection), day 3 (Tg3; 1 day after the second, final rhTSH injection), and day 6 (Tg6; 3 days post-radioiodine administration). Treatment failure was defined as histopathologically confirmed locoregional recurrence, or radiologically-evident distant metastases (signs of disease on computer tomography (CT) or magnetic resonance imaging (MRI), or abnormal foci of radioiodine or [18F] fluorodeoxyglucose ([18F]FDG) uptake. RESULTS: In univariate analysis, Tg1 (p < 0.001) and Tg3 (p < 0.001), but not Tg6, were significantly associated with structural recurrence. In multivariate analysis of the overall cohort, only Tg3 was independently associated with structural recurrence. In multivariate analysis of the subgroup (n = 561) with anti-Tg antibodies titers below the institutional cut-off, 115 IU/mL, Tg1 was an independent prognostic marker. Tg1 and Tg3 cutoffs to best predict structural recurrence were established at 0.7 ng/mL and 1.4 ng/mL, respectively. CONCLUSIONS: Tg1 and Tg3, measurements made after rhTSH stimulation but before radioiodine treatment, independently predict a low risk of treatment failure in patients with DTC. Levels measured post-radioiodine application (e.g., Tg6) are highly variable, lack prognostic value, and hence can be omitted.

Ultrasound-guided implantation of radioactive 125I seed in radioiodine refractory differentiated thyroid carcinoma.

BACKGROUND: Treatment for radioiodine refractory differentiated thyroid carcinoma (RR-DTC) is challenging. The purpose of this study was to assess the efficacy and safety of ultrasound-guided implantation of radioactive 125I-seed in radioiodine refractory differentiated thyroid carcinoma. METHODS: Thirty-six cervical metastatic lymph nodes (CMLNs) diagnosed with RR-DTC from 18 patients were enrolled in this retrospective study. US and contrast-enhanced ultrasound (CEUS) examinations were performed before implantation. Follow-up comprised US, CEUS, thyroglobulin (Tg) level and routine hematology at 1-3, 6, 9 and 12 months and every 6 months thereafter. The volumes of the nodules were compared before implantation and at each follow-up point. The volume reduction rate (VRR) of nodules was also recorded. RESULTS: The median volume of the nodules was 523 mm3 (148, 2010mm3) initially, which decreased significantly to 53mm3 (0, 286mm3) (P < 0.01) at the follow-up point of 24 months with a median VRR as 95% (86,100%). During the follow-up period (the range was 24-50 months), 25 (69%) nodules had VRR greater than 90%, of which 12 (33%) nodules had VVR ≈ 100% with unclear structures and only 125I seed images were visible in the US. At the last follow-up visit, the serum Tg level decreased from 57.0 (8.6, 114.8) ng/ml to 4.9 (0.7, 50.3) ng/ml, (P < 0.01). CONCLUSION: US-guided 125I seed implantation is safety and efficacy in treating RR- DTC. It could be an effective supplement for the comprehensive treatment of thyroid cancer.

Parathyroid Changes After RAI in Patients With Differentiated Thyroid Carcinoma.

Objective: The purpose of this study was to investigate parathyroid hormone (PTH), serum calcium, phosphorus, and 25-hydroxyvitamin D (25-OH-VD) changes before and after radioactive iodine (RAI) in differentiated thyroid carcinoma (DTC) patients at different time points. Methods: A total of 259 DTC patients who received RAI were prospectively enrolled. We evaluated PTH, serum calcium, phosphorus, and 25-OH-VD levels at baseline pre-RAI, five days, six weeks, and six months post-RAI, respectively. We analyzed the risk factors of hypocalcemia at five days post-RAI. Results: The mean PTH, serum calcium and phosphorus values decreased five days post-RAI compared with pre-RAI (PTH 4.18 ± 1.23 pmol/L vs. 3.95 ± 1.41 pmol/L; calcium 2.27 ± 0.09 mmol/L vs. 2.20 ± 0.11 mmol/L; phosphorus 1.25 ± 0.17 vs. 0.98 ± 0.20 mmol/L, P < 0.05), and the differences were statistically significant. The mean 25-OH-VD levels did not significantly decrease at five days post-RAI. 21.2% (55/259) of patients had hypocalcemia at five days post-RAI, and all of them were given oral calcium supplements. At six weeks post-RAI, all of the above parameters were higher than those at five days post-RAI. Multivariate regression analysis showed that baseline pre-RAI serum calcium < 2.27 mmol/L, PTH < 4.18 pmol/L and negative 99mTcO4- thyroid imaging were risk factors for hypocalcemia at five days post-RAI. Conclusion: For DTC patients with normal PTH and serum calcium levels at pre-RAI, their PTH, serum calcium, and phosphorus levels decreased at five days post-RAI. About one-fifth of patients could have hypocalcemia at five days post-RAI. Lower baseline pre-RAI serum calcium and PTH levels and negative 99mTcO4- thyroid imaging were risk factors for hypocalcemia five days post-RAI.

The Optimal Activity of Radioactive Iodine for Remnant Ablation in Low/Intermediate Risk Differentiated Thyroid Carcinoma: A Continuous Controversy and Meta-Analysis.

Radioactive iodine (RAI) is widely used for remnant ablation in low/intermediate differentiated thyroid carcinoma (DTC). However, the optimal effective dose that overweighs the benefits over unwanted side effects is a matter of controversy. This meta-analysis aimed to assess low versus high doses of RAI activity for DTC remnant ablation. Two authors independently searched PubMed and Cochrane Library using the keywords low dose radioactive iodine, high dose radioactive iodine, low-risk/intermediate risk, differentiated thyroid carcinoma, and remnant ablation. Two hundred and twenty references were identified when limiting the engine to controlled trials in English and during the period from January 2010 to December 2020. Nine trials (five from Europe and four from Asia) including 3137 patients fulfilled the inclusion and exclusion criteria. The data were then entered in an extraction sheet detailing the trial information including the author's name, year of publication, country, and type of surgery, preparation for RAI, the patients and control number in the low and high-dose groups, follow-up period, and the results. Out of 220 articles retrieved, nine controlled trials were included (follow-up period range, six months to 12 years, 3137 patients, and low risk of bias). The analysis favored the high dose for remnants ablation, odd ratio, 0.73, 95% CI, 0.50-1.07; P-value for the overall effect was 0.10. However, the results were limited due to the significant heterogeneity observed (56%, P-value 0.03). High-dose RAI was better for DTC remnants ablation. Further studies focusing on intermediate-risk DTC and adjusting for preoperative and postoperative factors are recommended.

Sorafenib and Lenvatinib Treatment for Metastasis/Recurrence of Radioactive Iodine-refractory Differentiated Thyroid Carcinoma.

BACKGROUND/AIM: Radioactive iodine-refractory differentiated thyroid carcinoma (RR-DTC) has been treated with multi-kinase inhibitors (MKIs), e.g., sorafenib (SOR) and lenvatinib (LEN). We analyzed the outcomes of RR-DTC patients who underwent SOR or LEN treatment at Kuma Hospital. PATIENTS AND METHODS: We enrolled 21 and 18 patients treated with SOR and LEN, respectively. RESULTS: The incidence of partial response in the LEN group was significantly higher than that in the SOR group. Serum thyroglobulin significantly decreased from the beginning of treatment to 1 month later in the LEN group (not in the SOR group). The neutrophil-lymphocyte ratio (NLR) was significantly decreased at 1 month later in both groups. An NLR ≥3 at the start of MKI treatment had a prognostic impact. CONCLUSION: For RR-DTC, LEN could be more effective than SOR, at least in the short term. The first-line drug should be selected based on other factors (e.g., adverse events, patient background).

Patterns of radioiodine use for differentiated thyroid carcinoma in Brazil: insights and a call for action from a 20-year database.

OBJECTIVE: This study aimed to explore the patterns of radioactive iodine (RAI) use for differentiated thyroid cancer (DTC) in Brazil over the past 20 years. METHODS: A retrospective analysis of the DTC-related RAI prescriptions, from 2000 to 2018, retrieved from the Department of Informatics of the Unified Health System (Datasus) and National Supplementary Health Agency (ANS) database was performed. RAI activities prescriptions were re-classified as low (30-50 mCi), intermediate (100 mCi), or high activities (>100 mCi). RESULTS: The number of DTC-related RAI prescriptions increased from 0.45 to 2.28/100,000 inhabitants from 2000 to 2015, declining onwards, closing 2018 at 1.87/100,000. In 2018, population-adjusted RAI prescriptions by state ranged from 0.07 to 4.74/100,000 inhabitants. Regarding RAI activities, in the 2000 to 2008 period, the proportion of high-activities among all RAI prescriptions increased from 51.2% to 74.1%. From 2009 onwards, there was a progressive reduction in high-activity prescriptions in the country, closing 2018 at 50.1%. In 2018, the practice of requesting high-activities varied from 16% to 82% between Brazilian states. Interestingly, variability of RAI use do not seem to be related to RAI referral center volume nor state socio-economic indicators. CONCLUSION: In recent years, there has been a trend towards the lower prescription of RAI, and a reduction of high-activity RAI prescriptions for DTC in Brazil. Also, significative inter-state and inter-institutional variability on RAI use was documented. These results suggest that actions to advance DTC healthcare quality surveillance should be prioritized.

Patterns of radioiodine use for differentiated thyroid carcinoma in Brazil: insights and a call for action from a 20-year database

ABSTRACT Objective: This study aimed to explore the patterns of radioactive iodine (RAI) use for differentiated thyroid cancer (DTC) in Brazil over the past 20 years. Materials and methods: A retrospective analysis of the DTC-related RAI prescriptions, from 2000 to 2018, retrieved from the Department of Informatics of the Unified Health System (Datasus) and National Supplementary Health Agency (ANS) database was performed. RAI activities prescriptions were re-classified as low (30-50 mCi), intermediate (100 mCi), or high activities (>100 mCi). Results: The number of DTC-related RAI prescriptions increased from 0.45 to 2.28/100,000 inhabitants from 2000 to 2015, declining onwards, closing 2018 at 1.87/100,000. In 2018, population-adjusted RAI prescriptions by state ranged from 0.07 to 4.74/100,000 inhabitants. Regarding RAI activities, in the 2000 to 2008 period, the proportion of high-activities among all RAI prescriptions increased from 51.2% to 74.1%. From 2009 onwards, there was a progressive reduction in high-activity prescriptions in the country, closing 2018 at 50.1%. In 2018, the practice of requesting high-activities varied from 16% to 82% between Brazilian states. Interestingly, variability of RAI use do not seem to be related to RAI referral center volume nor state socio-economic indicators. Conclusion: In recent years, there has been a trend towards the lower prescription of RAI, and a reduction of high-activity RAI prescriptions for DTC in Brazil. Also, significative inter-state and inter-institutional variability on RAI use was documented. These results suggest that actions to advance DTC healthcare quality surveillance should be prioritized.

Relapse-free survival after adjuvant radioactive iodine therapy in patients with differentiated thyroid carcinoma with a microscopically positive tumor margin.

OBJECTIVE: In patients with differentiated thyroid carcinoma (DTC) with a microscopically positive tumor margin, the optimal first dose of I-131 during adjuvant radioactive iodine (RAI) therapy to improve relapse-free survival (RFS) is unclear. Due to the limited number of hospital beds, 1110 MBq of I-131 is administered to such patients in Japan. This study primarily aimed to retrospectively determine the difference in RFS between high-dose (3700 MBq) and low-dose (1110 MBq) adjuvant RAI therapies in DTC patients with a microscopically positive tumor margin. The secondary aim was to investigate the background factors affecting RFS. METHODS: Forty-eight consecutive patients (15 men and 33 women) who underwent total thyroidectomy between April 2007 and December 2017 for DTC without gross residual tumors and distant metastasis, and who were diagnosed with a positive margin histopathologically, followed by RAI therapy, were enrolled. We retrospectively investigated initial I-131 dose, classifying it into high-dose and low-dose groups. The primary endpoint was RFS. Relapse was considered in the following cases: patients with visible recurrent tumor and/or metastasis on neck ultrasound and/or computed tomography, and patients without visible tumor, but with clearly increasing thyroglobulin levels on follow-up every 3-6 months. RFS outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, and multivariate analysis was undertaken using the Cox proportional hazard model. RESULTS: There were nine cases of recurrence (52.9%) in the low-dose group and seven in the high-dose group (22.5%) during follow-up. The estimated median RFS was 69.4 months in the low-dose group and 120.7 months in the high-dose group. High-dose administration was associated with improved RFS, as demonstrated by Kaplan-Meier survival curves (log-rank test [P = 0.009]). Patient factors associated with worse RFS included low-dose administration (hazard ratio [HR] = 91.9; 95% confidence interval [CI] = 7.66-1102.79); P < 0.001), T4 stage (HR = 1.88; 95% CI = 0.44-8.10; P = 0.015), and presence of central lymph node metastases (HR = 190; 95% CI = 3.80-9496; P = 0.009). The most common type of recurrence was lymph node metastasis. CONCLUSION: Patients with microscopically positive tumor margins could benefit from RAI with high activities.

Plasma branched chain amino acids are lower in short-term profound hypothyroidism and increase in response to thyroid hormone supplementation.

Branched chain amino acids (BCAA) are implicated in the pathogenesis of cardiometabolic diseases conceivably by affecting insulin resistance and mitochondrial dysfunction. Circulating BCAA levels may predict (subclinical) atherosclerosis, diabetes and hypertension development but the factors involved in BCAA regulation are incompletely understood. Given the key role of thyroid hormones on many metabolic processes including protein metabolism, we aimed to determine effects of thyroid dysfunction on circulating BCAA. Effects of short-term profound hypothyroidism on plasma BCAA were determined in 17 patients who had undergone total thyroidectomy for differentiated thyroid carcinoma. Patients were studied during hypothyroidism, i.e. after thyroidectomy, and after thyroid hormone supplementation. Plasma BCAA (sum of valine, leucine and isoleucine) and alanine were measured by nuclear magnetic resonance spectroscopy. During hypothyroidism (median thyroid-stimulating hormone 81 (IQR 67-120.5) mU/L), plasma BCAA were lower (255 (IQR 222-289) µmol/L) compared to a euthyroid reference population (n = 5579; 377 µmol/L (2.5th to 97.5th percentile 258-548), p < 0.001). After 20 weeks of thyroid hormone supplementation (thyroid-stimulating hormone 0.03 (IQR 0.01-0.14 mU/L) plasma BCAA had increased (328 (IQR 272-392) µmol/L, p = .001), but plasma alanine concentrations were unaltered (p = .50). Changes in body weight in response to thyroid hormone supplementation were correlated with changes in plasma BCAA (r = 0.721 p = .001, but not with changes in cholesterol or glucose (p > .80). In conclusion, plasma BCAA concentrations are lower during short-term profound hypothyroidism in humans, and increase in response to thyroid hormone supplementation. Changes in BCAA and in body weight after reversal of the hypothyroid state appear to be interrelated.

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.

Recombinant human thyrotropin versus thyroid hormone withdrawal in an Asian population.

CONTEXT: To prepare for radioactive iodine therapy in post total thyroidectomy patients with well-differentiated thyroid cancer (WDTC), either thyroid hormone withdrawal (THW) or administration of recombinant human thyrotropin (rhTSH) can be performed. OBJECTIVE: Our objective is to compare quality of life (QoL) parameters using the SF-36v2 questionnaire (Short Form health survey) and a self-evaluated item, and the hypothyroid status using modified Billewicz scores in an Asian population undergoing either THW or rhTSH for remnant ablation or adjuvant treatment following total thyroidectomy for WDTC. We will also assess the proportion of patients achieving TSH level of >30 mU/L after 4 weeks of thyroid hormone withdrawal. RESULTS: Patients in the rhTSH group were better in the QoL domains of physical functioning, role functioning/physical and bodily pain, while patients in THW group were better in mental health. This was however, not statistically significant. Modified Billewicz scores were higher in patients in THW group as compared with rhTSH group and statistically significant. A total of 96.3% of patients achieved TSH level >30 mU/L after 4 weeks of THW. CONCLUSION: Clinical symptoms and signs of hypothyroidism as assessed with modified Billewicz scores were statistically significantly higher in the THW group. However, there was no statistically significant difference in QoL in the rhTSH group.

Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade.

BACKGROUND: Since the last major review of literature on the benefit of I-131 therapy, the continued debate on postoperative radioiodine treatment (RIT) in differentiated thyroid carcinoma (DTC) has led to a number of further studies being published on this topic. AIM: The aim of the present paper is to report the results of an updated structured review of the literature pertaining to the prognostic benefits of postoperative RIT in DTC in terms of recurrence-free and disease-specific survival. METHODS: A systematic search of the literature was performed using the Medline and Cochrane Library database. The search period started in August 2007 and ended on December 6, 2017. Search terms used included "differentiated thyroid cancer" and "radioiodine therapy" amended by specific terms for recurrence/disease-free survival or overall and/or cancer-specific survival. Included in the search were systematic reviews, randomized clinical trials, or cohort studies consisting of both patients who underwent postoperative RIT and patients treated by surgery alone. RESULTS: Eleven retrospective cohort studies met the defined inclusion criteria and were included in the present review. Results of the studies were mixed, with some showing a benefit of RIT even in microcarcinoma whereas others showed no benefit at all. CONCLUSION: Literature published in the last decade offers data that support adjuvant postoperative RIT in DTC patients with a tumor diameter exceeding 1 cm. Therefore, at least until randomized prospective studies prove otherwise, the prescription of adjuvant I-131 treatment to all DTC patients with a primary tumor diameter exceeding 1 cm remains a reasonable option.