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We aimed to evaluate the clinical efficacy and safety of lenvatinib in patients with advanced anaplastic thyroid cancer (ATC) in real-world practice. This multicenter, retrospective cohort study included 14 patients with advanced ATC who received lenvatinib. We evaluated the response rate according to RECIST. Ten patients had de novo ATC, and lenvatinib was used as a neoadjuvant treatment in eight patients. During a median follow-up of 6.7 months, patients received lenvatinib at a median dose of 13 mg daily. Overall, four patients (29%) showed partial response, nine (64%) had stable disease, and one (7%) had progressive disease. Tumor burden was reduced in 13 patients (93%), and the median best percent change from the baseline was −15.8%. The median progression-free survival and overall survival were 5.7 months (95% confidence interval [CI], 2.2–8.3) and 6.7 months (95% CI, 3.0–8.4), respectively. All patients experienced adverse events (AEs). Most AEs were manageable but two AEs—tracheal perforation, and pneumothorax and pneumomediastinum—were life-threatening. One patient underwent flap surgery for reconstruction of their tracheal perforation, and another died of pneumothorax and pneumomediastinum, which seemed to be related to lenvatinib. In this multicenter real-world study, lenvatinib demonstrated limited clinical activity in advanced ATC. It effectively reduced the tumor burden but showed doubtful survival benefit. Although most AEs were manageable, one fatal AE was related to rapid tumor shrinkage. Further studies are needed to clarify the efficacy and optimal dose of lenvatinib in patients with advanced ATC.

Serum thyroid-stimulating hormone level was influenced by several factors, including age, gender, thyroid auto-antibodies, race, and intake of dietary iodine. We evaluated age-specific reference interval of serum thyroid-stimulating hormone levels in Korea, an iodine excess area. This nationwide population-based cross-sectional study included representative civilian, non-institutional population (n = 6564) who underwent thyroid function tests from Korea National Health and Nutrition Examination Survey VI (2013–2015). The reference interval of serum thyroid-stimulating hormone levels was defined between the 2.5th and 97.5th percentiles in the reference population. The geometric mean of serum thyroid-stimulating hormone levels in the reference population was 2.17 mIU/L with a reference interval of 0.62–6.84 mIU/L. In the reference population, the geometric mean of serum TSH levels in each age group of 10–18, 19–29, 30–39, 40–49, 50–59, 60–69, and equal or older than 70 years was 2.47, 2.20, 2.07, 2.04, 2.23, 2.12, and 2.27 mIU/L, with a reference interval of 0.74–7.35, 0.67–6.42, 0.63–6.04, 0.62–6.20, 0.56–7.37, 0.57–6.90, and 0.42–6.58 mIU/L, respectively. In the reference population, the urinary iodine concentrations were consistently high in all age groups (median 298.5 μg/L). Subjects aged 10–18 years had the highest urinary iodine concentrations. There was no shift toward higher levels with age in the distribution of serum thyroid-stimulating hormone levels. The reference interval of serum thyroid-stimulating hormone levels was consistently high in all age group, especially from adolescence 10–18 years in a Korean population who had excessive intake of dietary iodine.

The aim of this study was to evaluate the long-term clinical outcomes of papillary thyroid carcinoma (PTC) patients exhibiting biochemical incomplete response (BIR) to initial therapy. We evaluated 102 patients with PTC showing a BIR during the first 12–24 months after total thyroidectomy and radioactive iodine therapy. Patients were divided into three groups according to changes in stimulated thyroglobulin (Tg) and anti-Tg antibody (TgAb) levels: the increasing TgAb group (n = 19, 18.6%), the decreasing Tg group (n = 58, 56.9%), and the increasing Tg group (n = 25, 24.5%). With a median follow-up of 12 years, 43 (42%) patients had structural persistent disease as follows: 36 (84%) at regional sites and 7 (16%) at distant sites. The rate of structural persistent disease was significantly different between groups, with 21%, 41%, and 60% in the increasing TgAb, decreasing Tg, and increasing Tg groups, respectively (P = 0.012). Among patients without structural persistent disease, only 19 (18.6%) showed no evidence of disease and 40 (39.2%) were of a biochemical persistent status at the time of final follow-up. Increasing Tg after initial therapy was a significant risk factor for structural persistent disease in patients with BIR (HR, 4.16; 95% confidence interval (CI): 1.38–12.54, P = 0.011). PTC patients with BIR showed a high rate of structural persistent disease and Tg change after initial therapy is the most important prognostic factor for determining clinical outcomes of these patients.

The use of antithyroid drug (ATD) therapy in patients with Graves' disease (GD) hyperthyroidism has been increasing, but ATD therapy is associated with a higher relapse rate. We aimed to evaluate clinical factors for predicting relapse of GD after ATD therapy.Patients (n = 149) with newly diagnosed GD who achieved remission of hyperthyroidism after ATD therapy (≥6 months) were followed up for18 months after ATD withdrawal. We evaluated the predictive factors of relapse during a median of 6.9 years of follow-up.Disease relapse occurred in 52 patients (34.9%). By multivariate analyses, a duration of the minimum maintenance dose therapy (MMDT) of 6 months was a significant factor in disease relapse (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.47-4.52; p 0.001), and a T3/free T4 (fT4) ratio 120 at ATD withdrawal was significantly more frequent in patients with relapse (HR 2.43; 95% CI, 1.36-4.34; p = 0.002). In the prediction-of-relapse model, the likelihood of relapse was greater in the high-risk group, which had a short MMDT duration and a T3/fT4 ratio ≥120 (HR, 5.81; 95% CI, 2.52-13.39; p 0.001) and the intermediate-risk group, which had a short MMDT duration or a T3/fT4 ratio 120 (HR, 2.77; 95% CI, 1.26-6.13; p 0.001), than in the low-risk group, which had a long MMDT duration and a T3/fT4 ratio 120.An MMDT longer than 6 months and a high T3/fT4 ratio at ATD withdrawal were independent predictors of relapse in patients who achieved initial remission after ATD for GD. These factors could be used to determine the optimal time to withdraw ATD during the treatment of GD hyperthyroidism.

Papillary thyroid microcarcinoma (PTMC) has excellent outcomes, but extensive lymph node (LN) metastasis can be associated with fatal outcomes. We evaluated the mutational profiles of primary tumors and their metastatic LNs of PTMCs with extensive lateral cervical LN metastases. Formalin-fixed, paraffin-embedded archival samples from 16 sets of normal thyroid tissue, the primary PTMC, and the largest metastatic LN were used for targeted sequencing. A total of seven somatic variants were confirmed in the PTMCs compared to the normal tissue. The BRAFV600E mutation was the most common and seen in 12 primary tumors (75%) and 11 metastatic LNs (69%). A nonsense mutation in AR and an in-frame deletion in ACVR2A were detected in one primary tumor and its metastatic LN (6%). Missense mutations in KMT2A, RAF1, and ROS1 were detected in one primary tumor (3%). A frameshift deletion mutation in JAK2 was detected in a metastatic LN (3%). In PTMCs without the BRAF mutation, an ALK and RET rearrangement (one PTMC and its metastatic LN, 6%) was detected. In one patient, the BRAF mutation was detected in the primary tumor, but only a RET rearrangement was detected in its metastatic LN. No mutations were detected in two patients. The mutational frequency of PTMCs was really low, even in those with extensive LN metastasis. The mutational status of the primary tumor and its metastatic LNs were not significantly different, and this suggests a minor role for genetic alterations in the process of LN metastasis in PTMC.

A repeat fine needle aspiration (FNA) is recommended for thyroid nodules diagnosed as atypia of undetermined significance (AUS) in a previous cytology. We evaluated the utility of NRAS codon 61 (NRAS61) mutation analysis and core needle biopsy (CNB) for the diagnosis of thyroid nodules previously diagnosed as AUS. This study enrolled 236 patients who underwent both NRAS61 mutation analysis and CNB of thyroid nodules previously diagnosed as AUS at cytology. The NRAS61 mutation was detected in 36 nodules and was more frequently detected in the AUS and follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN) categories, as determined by histological analysis of CNB, than in the benign group (p = 0.005). Sixty-one patients underwent surgery, and 29 nodules were finally diagnosed as malignant after surgery. Among 61 patients who underwent surgery, nodules with the NRAS61 mutation (42-65 %) had a significantly higher malignancy rate than nodules with wild-type NRAS61 (7-37 %, p = 0.038). The association between malignancy and the NRAS61 mutation was significant after adjusting for age, sex, nodule size, and histological diagnosis of CNB (p = 0.01). NRAS61 mutation analysis together with CNB could be helpful for arriving at a clinical decision in patients with thyroid nodules showing AUS in a previous cytology.

We evaluated the effects of vitamin D levels and iodine intake on thyroid autoimmunity and dysfunction in the Korean population. In this nationwide population-based study, data were obtained from the Korea National Health and Nutrition Examination Survey VI-1 and 2 (2013 and 2014), which was the first nationwide survey that measured both serum 25-hydroxy vitamin D [25(OH)D] levels and urinary iodine concentrations (UICs) in Korea. A total of 4181 participants who underwent laboratory tests for thyroid function, serum 25(OH)D levels, and UICs were included. Anti-thyroid peroxidase antibody (TPOAb) positivity was more prevalent in the vitamin D deficient group (9.1%) than the vitamin D insufficient and sufficient groups (5.3% each; P = 0.016). The rate of TPOAb positivity was significantly higher in the iodine deficient group (P = 0.032). Thyroid dysfunction was significantly more prevalent in the iodine excessive group than in the other groups in total (P = 0.016) and TPOAb negative participants (P = 0.007). In the vitamin D deficient group, excessive iodine intake was significantly associated with high prevalence of thyroid dysfunction in total and TPOAb negative participants (P = 0.021 and P = 0.033, respectively). In the vitamin D insufficient and sufficient groups, association between thyroid dysfunction and iodine intake disappeared in total and TPOAb negative participants. This nationwide survey revealed a significant association between vitamin D deficiency and high prevalence of thyroid autoimmunity and dysfunction in participants with excessive iodine intake. Our findings might be helpful for elucidating the potential benefit of vitamin D supplements in TPOAb negative patients with excessive iodine intake.

Detecting persistent/recurrent disease of medullary thyroid carcinoma (MTC) is important. The tumor-node-metastasis (TNM) staging system is useful for predicting disease-specific mortality, but is a static system and does not include postoperative serum calcitonin levels. We have focused on the clinical usefulness of dynamic risk stratification (DRS) using the best response to the initial therapy in MTC patients. A total of 120 MTC patients were classified into three DRS groups based on their responses to initial therapy. Clinical outcomes were assessed according to TNM staging and DRS. In the DRS, 70, 23 and 7 % of the MTC patients were classified into excellent, biochemical incomplete, or structural incomplete response groups, respectively. On TNM staging, 37, 16, 13 and 35 % of patients were stages I-IV, respectively. There were significant differences in survivals according to TNM staging (p = 0.03) and DRS (p = 0.005). During the median follow-up of 6.2 years, 75 patients (63 %) demonstrated no evidence of disease (NED). About 60 and 17 % of patients in stages III and IV were NED, respectively. DRS predicted NED better than TNM staging according to the proportion of variance explained (PVE) (49.1 vs. 28.7 %, respectively). At the final follow-up, 88, 4 and 0 % of patients in excellent, biochemical incomplete, and structural incomplete response groups attained NED, respectively. DRS based on the best response to the initial therapy can provide useful prognostic information in addition to initial TNM staging for predicting of mortality, as well as the likelihood of NED in MTC patients.