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Background Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. Methods This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. Results Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. Conclusion TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.

[Purpose] Gait-training robots have been developed for stroke patients with gait disturbance. It is important to survey the views of physiatrists and physical therapists on the characteristics of these devices during their development. [Subjects and Methods] A total of 100 physiatrists and 100 physical therapists from 38 hospitals participated in our questionnaire survey. [Results] The most common answers about the merits of gait-training robots concern improving the treatment effects (28.5%), followed by standardizing treatment (19%), motivating patients about treatment (17%), and improving patients’ self-esteem (14%). The subacute period (1–3 months post-stroke onset) was most often chosen as the ideal period (47.3%) for the use of these devices, and a functional ambulation classification of 0–2 was the most selected response for the optimal patient status (27%). The preferred model was the treadmill type (47.5%) over the overground walking type (40%). The most favored commercial price was $50,000–$100,000 (38.3%). The most selected optimal duration for robot-assisted gait therapy was 30–45 min (47%), followed by 15–30 min (29%), 45–60 min (18%), ≥ 60 min (5%), and < 15 min (1%). [Conclusion] Our study findings could guide the future designs of more effective gait-training robots for stroke patients.

Background The early detection of papillary thyroid cancer has contributed to the increase in the incidence and improved clinical outcomes. However, recent changes of medullary thyroid carcinoma (MTC) over time remain unclear. We evaluated changes of the clinicopathological characteristics and clinical outcomes in patients with MTC in recent years. Methods A total of 109 MTC patients were classified based on the year of initial surgery: 1996–2000 (n = 14), 2001–2006 (n = 39), and 2007–2011 (n = 56). Results The primary tumor size significantly decreased and the proportion of microMTCs (size ≤1 cm) increased over time (P = 0.002 and P

Supplemental Digital Content is available in the text, Background: Previous systemic reviews have examined the efficacy of individual therapeutic agents, but which type of treatment is superior to another has not been pooled or analyzed. The objective of the current study was to compare the clinical effectiveness of epidural steroid injection (ESI) versus conservative treatment for patients with lumbosacral radicular pain. Methods: A systematic search was conducted with MEDLINE, EMBASE, and CENTRAL databases with a double-extraction technique for relevant studies published between 2000 and January 10, 2019. The randomized controlled trials which directly compared the efficacy of ESI with conservative treatment in patients with lumbosacral radicular pain were included. Outcomes included visual analog scale, numeric rating scale, Oswetry disability index, or successful events. Two reviewers extracted data and evaluated the methodological quality of papers using the Cochrane Collaboration Handbook. A meta-analysis was performed using Revman 5.2 software. The heterogeneity of the meta-analysis was also assessed. Results: Of 1071 titles initially identified, 6 randomized controlled trials (249 patients with ESI and 241 patients with conservative treatment) were identified and included in this meta-analysis. The outcome of the pooled analysis showed that ESI was beneficial for pain relief at short-term and intermediate-term follow-up when compared with conservative treatment, but this effect was not maintained at long-term follow-up. Successful event rates were significantly higher in patients who received ESI than in patients who received conservative treatment. There were no statistically significant differences in functional improvement after ESI and conservative treatment at short-term and intermediate-term follow-up. The limitations of this meta-analysis resulted from the variation in types of interventions and small sample size. Conclusions: According to the results of this meta-analysis, the use of ESI is more effective for alleviating lumbosacral radicular pain than conservative treatments in terms of short-term and intermediate-term. Patients also reported more successful outcomes after receiving ESI when compared to conservative treatment. However, this effect was not maintained at long-term follow-up. This meta-analysis will help guide clinicians in making decisions for the treatment of patients with lumbosacral radicular pain, including the use of ESI, particularly in the management of pain at short-term.

Both sarcopenia and obesity are associated with decreased physical function of the elderly. Sarcopenic obesity (SO), which is the coexistence of sarcopenia and obesity, is expected to have a synergistic effect on physical function deterioration, but previous studies have shown varied results. This study aimed to investigate the impact of SO on the physical function of the elderly.Community-dwelling elderly subjects (1091 males; 1212 females; 70-84 years) were recruited in South Korea (eight cities). Body composition was measured via dual-energy X-ray absorptiometry and physical function was measured by grip strength, timed up and go test, and short physical performance battery (SPPB).In males, grip strength and the total SPPB score in the SO group were significantly lower than those in the normal or pure obesity groups (p 0.05). However, physical functions were not significantly different between the SO and the pure sarcopenia groups (p 0.05). The trend for grip strength in females was similar to that in males, but the total SPPB score of the SO group was significantly lower than that of the other three groups (p 0.05). Logistic regression analysis after covariate adjustment revealed that SO group males exhibited the highest risk of being in the lower SBBP score category (OR, 2.12; 95 % CI = 1.04-4.31); this trend was more prominent in females (OR, 3.75; 95 % CI = 2.01-7.00).SO has a synergistic effect on physical function deterioration in the elderly compared with sarcopenia or obesity alone. Additionally, such an effect is more remarkable in females.

Piezoceramic systems [(Bi0.5Na0.5)0.935Ba0.065)]1-yLayTi1-zTazO3 (BNBT-LT) with (y, z) = (0, 0), (0.01, 0.01), (0.02, 0.01), (0.03, 0.01) and (0.04, 0.01) have been synthesized using solid state reaction method. The effect of La3+ and Ta5+ on the structural, ferroelectric, dielectric, bipolar and unipolar strain properties of the parent matrix BNBT was studied. X-ray diffraction (XRD) spectra of samples with (y, z) ≤ (0.01, 0.01) were of ABO3 character and indexed according to the coexistence of rhombohedral and tetragonal symmetry; whereas the systems with (y, z) = (0.02, 0.01), (0.03, 0.01) demonstrated coalescence of reflections (200) & (002) into a single peak (200), indicating a (rhombohedral & tetragonal) ↔ (pseudocubic) structural phase transition. The polarization & strain vs. field loops of the LT rich systems displayed diffused phase transition. The system (x, y) = (0.02, 0.01) attained highest value of strain (0.38%) and dynamic strain ( d 33 ∗ = 542 p.m./V) under the field 70 kV/cm.

The increased incidence of thyroid cancer is a worldwide phenomenon; however, the issue of overdiagnosis has been most prominent in South Korea. The age-standardized mortality rate of thyroid cancer in Korea steeply increased from 1985 to 2004 (from 0.17 per 100,000 to 0.85 per 100,000), and then decreased until 2015 to 0.42 per 100,000, suggesting that early detection reduced mortality. However, early detection of thyroid cancer may be cost-ineffective, considering its very high prevalence and indolent course. Therefore, risk stratification and tailored management are vitally important, but many prognostic markers can only be evaluated postoperatively. Discovery of preoperative marker(s), especially for small cancers, is the most important unmet clinical need for thyroid cancer. Herein, we discuss some such factors that we recently discovered. Another unmet clinical need is better treatment of radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) and undifferentiated cancers. Although sorafenib and lenvatinib are available, better drugs are needed. We found that phosphoglycerate dehydrogenase, a critical enzyme for serine biosynthesis, could be a novel therapeutic target, and that the lymphocyte-to-monocyte ratio is a prognostic marker of survival in patients with anaplastic thyroid carcinoma or RAIR DTC. Deeper insights are needed into tumor-host interactions in thyroid cancer to improve treatment.

Background and objectives Sarcopenia and metabolic syndrome (MetS) increase incidence with age. This study evaluated the prevalence of MetS in middle-age to elderly men according to knee and grip strength and muscle mass. Methods Data from 256 males aged 40–69 years were analyzed. The impedance method was used to assess appendicular skeletal muscle mass (ASM). Muscle strength was measured grip strength with a dynamometer and 60°/s knee strength with isokinetic machine. Strength and muscle mass were divided into quartiles, and logistic regression analyses were performed. Results Absolute strength was not significantly prevalent in MetS, but MetS prevalence was significantly higher in participants with lower relative strength and muscle mass values (p

Current guidelines allow lobectomy as treatment for 1-4 cm papillary thyroid carcinomas (PTCs), as previous studies reported no clear survival advantages for total thyroidectomy (TT). However, data on recurrence based on surgical extent are limited.This study enrolled 2345 patients with 1-4 cm PTC. Those with lateral cervical lymph node metastasis or initial distant metastasis were excluded. Disease-free survival (DFS) was compared after 1:1 propensity score matching by age, sex, tumor size, extrathyroidal extension, multifocality, and cervical lymph node metastasis.Lobectomy was performed in 383 (16.3%) and TT in 1962 (83.7%) patients. In the matched-pair analysis (381 patients in each group), no significant difference in DFS was observed during the median follow-up of 9.8 years (hazard ratio [HR] = 1.35 [confidence interval (CI) 0.40-1.36], p = 0.33). When stratified by tumor size, DFS did not differ between the group with 1-2 cm tumors and that with 2-4 cm tumors (HR = 1.57 [CI 0.75-3.25], p = 0.228; HR = 0.93 [CI 0.30-2.89], p = 0.902, respectively). Multivariate analysis showed that the surgical extent did not play an independent role in structural persistent/recurrent disease development (HR = 1.43 [CI 0.72-2.83], p = 0.306).Patients with 1-4 cm PTCs who underwent lobectomy exhibited DFS rates similar to those who underwent TT after controlling for major prognostic factors. This supports the feasibility of lobectomy as initial surgical approach for these patients and emphasizes that tumor size should not be an absolute indication for TT.

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.

Lipid profiles of men and women change differently during the aging process. Guidelines recommend that dyslipidemia patients should consider screening for hypothyroidism without consideration of age or sex.Data from the sixth Korean National Health and Nutrition Examination Survey were used. A total of 4275 participants without thyroid disease and without a past history of dyslipidemia or dyslipidemia medication were evaluated. The association between thyroid dysfunction and lipid profiles (total cholesterol [TC], low-density lipoprotein cholesterol [LDLC], and triglycerides [TG]) was analyzed by age and sex.The prevalence of thyroid dysfunction was significantly different according to TC and LDLC levels (p = 0.003 and p = 0.021, respectively). In women, the weighted prevalence of thyroid dysfunction was significantly different according to levels of TC, LDLC, and TG (p = 0.007, p = 0.016, and p = 0.044, respectively). However, in men, no association was found in any of the lipid profiles. Female participants were divided into two groups using a cutoff age of 55 years. In younger women, the weighted prevalence of thyroid dysfunction was different according to the levels of TC, LDLC, and TG (p = 0.013, p = 0.007, and p = 0.007, respectively). However, in older women, no association was found for any of the lipid profiles.The prevalence of thyroid dysfunction was significantly different according to lipid profiles, and this association differed by age and sex.

The aims of this study were to stratify the risk of malignancy in thyroid incidentalomas detected onFrom a historical cohort of 96,942 consecutive patients who underwentThe overall malignancy risk of thyroid incidentalomas detected onUltrasound examinations can be used to stratify the malignancy risk of thyroid incidentalomas detected on

Tumor-associated macrophages (TAMs) play a role in thyroid cancer tumor progression and metastasis. This study aimed to investigate the association of TAM density and cluster of differentiation 68 (CD68) expression with thyroid tumors as a prognostic marker and the relationship of these factors with BRAFThis study included 275 thyroid specimen tissues, including benign and malignant lesions. We compared the clinicopathological features according to thyroid tumor types and evaluated the presence of CD68 expression and BRAFCD68 positive expression increased with aggressiveness of thyroid tumor histologic grades (P 0.001). In patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), CD68 positivity was associated with aggressive adverse clinical outcomes such as extrathyroidal extension, cervical lymph node metastases, and distant metastases (P 0.05).CD68 positivity was more frequent in advanced and aggressive thyroid cancer types such as PDTC/ATC.

Total thyroidectomy and cervical lymph node (LN) dissection is generally recommended in patients with medullary thyroid carcinoma (MTC). However, there is no clear evidence for whom to perform prophylactic lateral neck dissection in MTC patients without evident lateral cervical lymph node (LCLN) metastasis in preoperative images. This study evaluated the preoperative features for predicting the LCLN metastasis of MTC.The study included 26 MTC patients with LCLN metastasis at initial surgery (N1b group) and 47 MTC patients without any LN metastasis or recurrence of disease (N0-NED group). The association between LCLN metastasis and preoperative clinical and sonographic characteristics (size, location, solid component, shape, margin, echogenicity, calcification, and subcapsular location of the tumor) were evaluated.There were no significant differences in age and sex between the N1b and N0-NED groups. Preoperative serum levels of calcitonin65 pg/mL were associated with LCLN metastasis (p 0.001). In preoperative neck ultrasonography (US), patients in the N1b group were more commonly found with a larger tumor (1.5 cm) of irregular shape with a spiculated margin and a subcapsular location than those in the N0-NED group (p = 0.029, p 0.001, p 0.001, and p 0.001, respectively). Increases in the number of these LCLN metastasis-related features were significantly associated with higher risk for LCLN metastasis (p 0.001). The presence of two or more predictors was an appropriate cutoff point for predicting LCLN metastasis of MTC with 73.1% sensitivity and 91.5% specificity.MTC tumors with high preoperative calcitonin levels (65 pg/mL), larger size (1.5 cm), irregular shape, spiculated margins, and subcapsular locations in the neck US are at higher risk for LCLN metastasis. MTC patents with fewer than two predictors might be suitable for treatment without prophylactic LCLN dissection.

To evaluate the efficacy of ultrasound (US)-guided radiofrequency ablation (RFA) according to the types of thyroid carcinoma, particularly in patients with a high-surgical risk.Eight patients with nine tumours of pathologically proven papillary and anaplastic carcinoma were treated by US-guided RFA. Patients with primary thyroid carcinoma were divided into three groups; group (1) Anaplastic carcinoma, group (2) papillary macrocarcinoma, and group (3) papillary microcarcinoma. We evaluated changes in clinical symptoms, tumour volume and local tumour recurrence/metastasis after RFA. Patients were followed up at 1, 6 and 12 months and annually thereafter.Among nine tumours, one anaplastic carcinoma was treated three times and the other anaplastic carcinoma and one papillary macrocarcinoma were treated twice. Group 3 were treated once. The initial mean tumour volume was 107.9 ± 78.6 (with neck bulging), 126.9 (with neck bulging) and 0.16 ± 0.08 mL (without cosmetic or symptomatic problems) in groups 1-3, respectively. Group 1 showed no improvement in clinical symptoms or neck bulging after RFA, whereas group 2 demonstrated a decreased tumour volume measuring 0.7 mL with improved neck bulging. In group 3, mean volume decreased measuring 0.07 ± 0.12 mL. No local tumour recurrence or metastatic lesion was detected during the mean follow-up of 19.3 months in papillary carcinomas. No major complications were encountered.In patients with primary thyroid carcinoma, RFA achieved excellent local tumour control for papillary macro- and microcarcinoma; however, its clinical effect on anaplastic carcinoma was questionable.

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.

Objectives Malignant pheochromocytoma (PCC)/paraganglioma (PG) are rare neuroendocrine malignancies, and their clinical courses and prognoses are not well understood. This study aimed to evaluate prognostic factors associated with the survival of malignant PCC/PG. Methods This retrospective study reviewed 299 patients with PCC and 46 with PG treated between 1997 and 2013 at our single tertiary hospital. Malignant PCC/PG was defined as the presence of distant metastasis or recurrence at sites where neuroendocrine tissue is normally not present. Results Twenty-seven patients (9%) were confirmed with malignant PCC and six patients (13%) with malignant PG. Twenty-seven patients (82%) had distant metastases, nine patients (27%) presented with a metastasis at the initial diagnosis, whilst 24 patients (73%) were diagnosed with malignant PCC/PG during follow-up (median, 4.3 year). The median survival was 7.2 years, and the 5 year survival rate was 75.4%. Older age (>45 years), larger tumor size (>6 cm), synchronous metastasis, and absence of surgical excision were associated with poor survival by univariate analysis. By multivariate analysis, older age (HR = 4.3, P = 0.02) and synchronous metastasis (HR = 4.3, P = 0.01) were significantly associated with a poor prognosis. Conclusions Patients with malignant PCC/PG have diverse clinical courses. Poor survival was independently associated with older age and synchronous metastasis. J. Surg. Oncol. 2015;112:815–821. © 2015 Wiley Periodicals, Inc.

The BRAF(V600E) mutation is a promising prognostic biomarker for patients with papillary thyroid carcinoma (PTC), but its prevalence differs widely among different geographic regions. A recent study reported that loss of the Cleavage and Polyadenylation Specificity Factor Subunit 2 (CPSF2) gene was associated with increased cellular invasion, cancer stem cells, and aggressiveness of PTC. This study aimed at evaluating CPSF2 protein expression as a prognostic marker for PTC in a region with a high prevalence of the BRAF(V600E) mutation, Korea.This study included 159 patients with classical PTC who underwent a total thyroidectomy and received ablative doses of (131)I. The expression of CPSF2 protein was evaluated by immunohistochemistry and graded semi-quantitatively. The presence of the BRAF(V600E) mutation was evaluated by direct sequencing.Negative protein expression of CPSF2 was observed in 34 (21.3%) of the 159 PTCs. In multivariate analysis, negative CPSF2 expression was significantly associated with cervical lymph node metastasis (odds ratio [OR]=2.56, p=0.28), and distant metastasis (OR=3.48, p=0.02). After adjusting for age, sex, tumor size, extrathyroidal invasion, lymphovascular invasion, and the BRAF(V600E) mutation, the CPSF2-negative group had a significantly lower recurrence-free survival compared to the CPSF2-positive group (hazard ratio=2.14, p=0.03).Negative protein expression of CPSF2 is independently associated with a poor clinical outcome in PTC. CPSF2 could be a useful prognostic marker for PTC in regions with a high prevalence of the BRAF(V600E) mutation.

Background: Obesity is associated with aggressive pathological features and poor clinical outcomes in breast and prostate cancers. In papillary thyroid carcinoma (PTC), these relationships remain still controversial. This study aimed to evaluate the associations between body mass index (BMI) and the clinical outcomes of patients with PTC. Methods: This retrospective study included 1,189 patients who underwent total thyroidectomy for PTCs equal to or larger than 1 cm in size. Clinical outcomes were evaluated and compared based on the BMI quartiles. Results: There were no significant associations between BMI quartiles and primary tumor size, extrathyroidal invasion, cervical lymph node metastasis, or distant metastasis. However, an increase in mean age was associated with an increased BMI (P for trend

Mesenchymal stem cell therapy is a novel regenerative approach for treating tendinopathy. Here, we evaluated the safety and efficacy of allogeneic adipose-derived mesenchymal stem cells (allo-ASC) in treating lateral epicondylosis (LE). Under ultrasound guidance, allo-ASCs mixed with fibrin glue were injected into the hypoechoic common extensor tendon lesions of 12 participants with chronic LE; 6 subjects each were administered 106 or 107 cells in 1 ml. Safety was evaluated at day 3 and weeks 2, 6, 12, 26, and 52 post-injection. Efficacy was assessed by measuring patients’ visual analog scale (VAS) score for elbow pain, modified Mayo clinic performance index for the elbow, and by evaluating longitudinal and transverse ultrasound images of tendon defect areas after 6, 12, 26, and 52 weeks. No significant adverse effects of allo-ASC injection were observed through 52 weeks of follow-up. From baseline through 52 weeks of periodic follow-up, VAS scores progressively decreased from 66.8 ± 14.5 mm to 14.8 ± 13.1 mm and elbow performance scores improved from 64.0 ± 13.5 to 90.6 ± 5.8. Tendon defects also significantly decreased through this period. Allo-ASC therapy was thus safe and effective in improving elbow pain, performance, and structural defects for 52 weeks. This clinical study is the first to reveal therapeutic value of mesenchymal stem cell injection for treating chronic tendinopathy. Stem Cells 2015;33:2995–3005

Background Tightening and contracture of the joint capsule are hallmarks of adhesive capsulitis of the shoulder (ACS). However, quantification of capsular stiffness and its relation to clinical features have not been investigated thoroughly. Objectives To quantify capsular stiffness during intra-articular hydraulic distension (IHD) and to investigate its relationships with pain severity, symptom duration, range of motion (ROM), gender, and diabetes status. Design Case series. Setting University outpatient clinic of physical medicine and rehabilitation. Participants A total of 107 consecutive patients with ACS who underwent IHD. Methods Pressure-volume monitoring data during IHD, pain severity, symptom duration, shoulder ROM, and diabetes status were obtained by retrospective chart review. Capsular stiffness ( K cap ) was measured by calculating the slope of the elastic phase in pressure-volume curves. ROM was evaluated in 3 directions (flexion, abduction, and external rotation) with a goniometer, and the sum of the 3 ROMs was calculated. Main Outcome Measurements Pearson correlation coefficients and comparisons of averages were used to analyze the relationships between K cap and clinical features. Results The mean K cap of the total group of participants was 26.0 ± 14.2 mmHg/mL. Shoulder pain in motion or rest did not correlate with K cap . Patients with stiffer capsules had smaller sums of ROMs ( r = −.298, P = .002), with distinct limitations in external rotation and abduction ( r = −.278, P = .004 and r = −.313, P = .001, respectively). Women had significantly stiffer capsules than men (29.5 ± 14.3 versus 20.2 ± 12.1 mmHg/mL, P = .001). Diabetes status had no significant effect on capsular stiffness. Conclusions Capsular stiffness of the glenohumeral joint significantly correlated with limitation in shoulder ROM, especially in the abduction and external rotation directions, whereas there were no meaningful relationships with shoulder pain during motion or rest. This is the first study to reveal the relationships between in vivo quantified capsular stiffness and shoulder ROM limitations.

Measurement of thyroglobulin (Tg) in the washout fluid of fine-needle aspirates (FNA-Tg) is useful for diagnosis of lymph node (LN) metastasis in papillary thyroid carcinoma (PTC). However, the cutoff value of FNA-Tg in the preoperative state is not defined clearly. This study aimed to evaluate the optimal cutoff value of preoperative FNA-Tg according to serum Tg level.FNA-Tg was measured in 135 PTC patients (160 LNs) for preoperative diagnosis of cervical LN metastasis.Of the 160 LNs, 119 (74%) were surgically removed and 110 (69%) were diagnosed as malignant. When we adopted a FNA-Tg of 1.0 μg/L as the cutoff value, the sensitivity and specificity were 99% and 76%, respectively. FNA-Tg levels were correlated with serum Tg levels (Pearson's coefficient 0.42, p=0.002) and the FNA-Tg levels of 12 of the 50 benign LNs were above 1.0 μg/L. We classified the LNs into two groups according to serum Tg level regardless of anti-Tg antibody status: a low Tg group (≤1.0 μg/L, n=22, 14%) and a high Tg group (1.0 μg/L, n=138, 86%). In the low Tg group, the sensitivity and specificity of the FNA-Tg cutoff value of 1.0 μg/L were 93% and 100%, respectively. In the high Tg group, the sensitivity and specificity of the FNA-Tg cutoff value of 19.0 μg/L were 93% and 100%, respectively. A Tg ratio (FNA-Tg level divided by serum Tg level) of 0.5 gave an improved diagnostic performance (sensitivity, 98%; specificity, 98%) in the high Tg group.FNA-Tg levels in the preoperative state are affected by serum Tg levels when they exceeded 1.0 μg/L. For the preoperative diagnosis of metastatic cervical LNs, it seems reasonable to employ different cutoff values of FNA-Tg depending on serum Tg levels. We propose the use of an optimal cutoff value of FNA-Tg of 1.0 μg/L in patients with low serum Tg levels and a Tg ratio of 0.5 in those with high serum Tg levels irrespective of thyroglobulin antibody status.

Type 2 diabetes is known to increase the risk and progression of certain types of cancer. Metformin treatment of diabetic patients is reported to have beneficial effects on some cancers. We evaluated the clinical outcome of diabetic patients with differentiated thyroid cancer (DTC) according to metformin treatment.We reviewed 943 patients diagnosed with DTC after total thyroidectomy between 1995 and 2005 in a tertiary hospital. The study involved 60 diabetic patients and 210 control patients matched for age, sex, body mass index (BMI), and tumor size.There were no differences in the clinicopathological features and disease-free survival (DFS) between diabetic patients and the control group over 8.9 years of follow-up. Of the diabetic patients with DTC, 35 patients (58%) were treated with metformin. There were no differences in age, sex, BMI, tumor size, antidiabetic medication, glycated hemoglobin, or C-peptide levels in metformin and nonmetformin groups. However, cervical lymph node (LN) metastasis was more prevalent in the metformin group than in the nonmetformin group (OR 3.52, p = 0.035). Among diabetic patients with cervical LN metastasis of DTC, the metformin subgroup (17.1 years) was associated with longer DFS than the nonmetformin subgroup (8.6 years) (HR 0.16, p = 0.021); metformin treatment was also associated with longer DFS in this subgroup in multivariate analysis after adjusting age, BMI, duration of diabetes, presence of tumor at resection margin, and serum thyroglobulin level at ablation (HR 0.03, p = 0.035).Metformin treatment is associated with low recurrence in diabetic patients with cervical LN metastasis of DTC.

OBJECTIVE The follicular variant of papillary thyroid carcinoma (FVPTC) has multiple histological subtypes. Clinical outcomes of FVPTC are variable depending on the subtypes. This study evaluated the association of pre-operative ultrasonographic (US) findings and clinico-pathological features of FVPTC. PATIENTS This retrospective study enrolled patients with FVPTC (n = 70), size-matched classical variant of papillary thyroid carcinoma (CPTC, n = 328), follicular carcinoma (n = 85) and follicular adenoma (FA, n = 120). We defined the histological subtypes of FVPTC as infiltrative (I-FVPTC; n = 19) or encapsulated (E-FVPTC; n = 51) according to the presence of a fibrous capsule. Pre-operative US was reviewed using a US scoring system and classified into low US score (n = 42) and high US score (n = 28). RESULTS The median US score for FVPTC was lower than CPTC (2 vs 7, P < 0·001), but higher than FA (2 vs 0, P < 0·001). The median US score for I-FVPTC was significantly higher than E-FVPTC (4 vs 2, P = 0·009). I-FVPTC was more likely to be diagnosed as a malignancy or suspicious for malignancy on cytology than E-FVPTC (P = 0·002). The cumulative risks of cervical lymph node (LN) or distant metastasis according to tumour size were significantly higher in I-FVPTC than E-FVPTC (all P < 0·001). The cumulative risks for cervical LN metastasis or capsular invasion according to tumour size were significantly higher in FVPTC with high US score than FVPTC with low US score (P = 0·005, P < 0·001, respectively). CONCLUSIONS Pre-operative US findings of thyroid nodules were associated with not only histological subtypes, but also the clinical behaviour in FVPTC.

Background The prevalence of thyroid cancer has increased very rapidly in Korea. However, there is no published report focusing on thyroid cancer mortality in Korea. In this study, we aimed to evaluate standardized thyroid cancer mortality using data from Statistics Korea (the Statistical Office of Korea). Methods Population and mortality data from 1985 to 2010 were obtained from Statistics Korea. Age-standardized rates of thyroid cancer mortality were calculated according to the standard population of Korea, as well as World Health Organization (WHO) standard population and International Cancer Survival Standard (ICSS) population weights. Results The crude thyroid cancer mortality rate increased from 0.1 to 0.7 per 100,000 between 1985 and 2010. The pattern was the same for both sexes. The age-standardized mortality rate (ASMR) for thyroid cancer for Korean resident registration population increased from 0.19 to 0.67 between 1985 and 2000. However, it decreased slightly, from 0.67 to 0.55, between 2000 and 2010. When mortality was adjusted using the WHO standard population and ICSS population weights, the ASMR similarly increased until 2000, and then decreased between 2000 and 2010. Conclusion Thyroid cancer mortality increased until 2000 in Korea. It started to decrease from 2000.

Data on the risk stratification of pediatric differentiated thyroid cancer (DTC) remain scarce. This study aimed to evaluate the predictors of structural persistent/recurrent disease and revise an initial risk-stratification system in pediatric DTC patients.This retrospective cohort study included 203 patients (aged20 years) from two tertiary referral centers in Korea. The extent of cervical lymph node (LN) metastasis was classified based on the location or number of metastatic LNs.During a median follow-up duration of 5.5 years, structural persistent/recurrent disease was observed in 51 (25%) patients, including 22 (11%) with distant metastases. The presence of extrathyroidal extension (ETE) and lateral cervical LN metastases or more than five metastatic LNs were independent predictors for structural persistent/recurrent disease. The presence of bilateral lateral cervical LN metastases or10 metastatic LNs were independent predictors for distant metastasis. A total of 67 (33%), 72 (35%), and 64 (32%) patients were classified into the low-, intermediate-, and high-risk groups, respectively, based on the presence of ETE and the extent of cervical LN metastases. Compared to the low-risk group, the intermediate- and high-risk groups had a significantly greater risk of structural persistent/recurrent disease (hazard ratio = 7.32, p = 0.008, and hazard ratio = 24.28, p 0.001, respectively).This revised initial risk-stratification system based on the presence of ETE and the extent of cervical LN metastasis is useful for predicting the clinical outcomes of pediatric DTC patients. The findings could facilitate the practical use of a risk-stratification system.

Recent compelling epidemiological studies indicate a strong association of obesity with thyroid cancer. Obesity has been shown to promote thyroid cancer progression and exacerbate poor outcome in thyroid cancer patients. However, the molecular mechanisms by which obesity increases thyroid cancer risk and facilitates cancer progression are not completely understood. Obesity induces complex pathological changes including hyperglycemia, hyperinsulinemia, hyperlipidemia, oxidative stress, adipokines, and inflammatory responses. These changes can affect the development and progression of cancer through highly complex interactions in vivo. The deleterious effect of obesity may differ according to the different cancer types. In view of the increased incidence of thyroid cancer in parallel with the widespread occurrence of obesity in the past decades, it is imperative to clarify how obesity affects thyroid carcinogenesis. This review focuses on molecular mechanisms by which obesity aggravates thyroid carcinogenesis as elucidated by mouse models of thyroid cancer.

Purpose: Drugs that blockade interaction between programmed cell-death protein 1 (PD-1) and its ligand (PD-L1) are promising. Immune-related adverse events (irAEs) might be associated with favorable clinical outcomes, and thyroid dysfunction is one of the most common irAE. We evaluated the association of thyroid dysfunction during PD-1 blockade with the treatment efficacy in patients with non-small cell lung cancer (NSCLC). Experimental Design: A total 58 patients with stage IV NSCLC treated with PD-1 blockade were enrolled. Patients were categorized into thyroid dysfunction and euthyroid groups. Overall survival (OS) and progression-free survival (PFS) of the two groups were compared. Patients, tumor, and medication factors were adjusted using Cox proportional hazard modeling. Objective response rate (RR) and durable control rate were assessed according to the severity of thyroid dysfunction. Results: OS [median 118.0 (73.0-267.0) vs. 71.0 (28.0-160.0) days, log-rank P = 0.025] and PFS [118.0 (73.0-267.0) vs. 61.0 (28.0-130.0), log-rank P = 0.014] were longer in the thyroid dysfunction group. After adjustment, thyroid dysfunction was an independent predictive factor for favorable outcome [adjusted HR = 0.11 (95% CI) 0.01-0.92 for overall death; 0.38 (0.17-0.85) for disease progression]. The severity of thyroid dysfunction was associated with durable control rate (P for trend = 0.008). Conclusions: Thyroid dysfunction during PD-1 blockade is associated with treatment response and could provide supplementary information for immune monitoring in patients with advanced NSCLC.

Large-volume lymph node metastasis (LNM) is associated with poor clinical outcomes in papillary thyroid microcarcinoma (PTMC) patients. However, sensitivity in the detection of central neck LNM on preoperative neck ultrasonography (US) is believed to be low. The aim of this study is to investigate the preoperative clinical factors associated with large-volume LNM in clinical N0 PTMC patients.In all, 2329 clinical N0 PTMC patients who underwent total thyroidectomy with prophylactic central lymph node (LN) dissection were evaluated. The LNM status of these patients was divided into three groups by the number of metastatic nodes: no LNM, small-volume LNM (≤5 metastatic LNs), and large-volume LNM (5 metastatic LNs). The correlations between age, sex, and other clinical factors and large-volume LNM were evaluated.Large-volume LNM was found in 94 (4.0%) patients. Young (40 years old) and male patients tended to have large-volume LNM (p for trend0.001). Young age (odds ratio [OR] = 2.69 [confidence interval (CI) 1.64-4.32], p 0.001) and male sex (OR = 5.79 [CI 3.67-9.10], p 0.001) were independent risk factors for large-volume LNM in multivariate analyses. The prevalence of large-volume LNM ranged from 24% in male patients40 years of age to only 2% in female patients aged ≥40 years. Multifocal tumors and presence of extrathyroidal extension were also considered risk factors for large-volume LNM.Large-volume LNM was more frequently found in young (40 years) and male patients. These findings support the notion that surgery rather than observation may be favored in young and male clinically LN negative PTMC patients as a primary therapeutic option.

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.

To evaluate the efficacy and prognostic validity for disease-specific survival (DSS) of the eighth edition American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis (TNM) staging system (TNM-8) compared to the seventh edition (TNM-7) in patients with differentiated thyroid carcinoma (DTC).The seventh and eighth editions of the TNM staging system were applied to 1613 DTC patients who underwent thyroid surgery between 1996 and 2003. The proportion of variation explained and Harrell's c-index were evaluated to compare the predictive capability of DSS.The mean age of the patients was 44.7 years, and the median follow-up period was 11.2 years. When TNM-8 was applied, 63% of T3 and 3% of N1b DTCs were downgraded to T1/T2 and N1a, respectively. About 38% of patients were downstaged according to TNM-8. The 10-year DSS rates in TNM-7 stages I, II, III, and IV were 99.7%, 98.2%, 98.8%, and 83.2%, respectively. Those in TNM-8 stages I, II, III, and IV were 99.6%, 95.4%, 72.3%, and 48.6%, respectively. The proportion of variation explained values of TNM-7 and TNM-8 were 6.0% and 7.0%, respectively. The Harrell's c-index of TNM-7 was 0.86 and that of TNM-8 was 0.88.A significant number of patients were reclassified to lower stages with the application of TNM-8 compared to TNM-7. Applying TNM-8 could improve the accuracy of the staging system for predicting DSS in patients with DTC.

Background and Objectives Clinical outcomes in patients with the follicular variant of papillary thyroid carcinoma (FVPTC) tend to vary according to the pathological subtypes. We aimed to evaluate the clinicopathological characteristics including preoperative radiological and cytopathological diagnoses in patients with solitary encapsulated FVPTCs (EFVPTCs) to prove the preoperative assessment dilemma. Methods Patients with solitary FVPTCs who underwent thyroid surgery were included. Results Of 271 patients, 194 patients (72%) had EFVPTCs, whereas 77 patients (28%) had infiltrative FVPTCs (IFVPTCs). EFVPTCs had larger tumor sizes (P

Thyroid cancer is increasing all over the world. The exact cause of this increase is still debated and there are conflicting reports. Sophisticated molecular studies suggest that environmental chemicals may have effects of thyroid carcinogenesis. The development of powerful molecular biology techniques has enabled targeted next-generation sequencing for detection of mutations in thyroid cancer, and this technique can make a specific diagnosis of thyroid cancer in cytologically indeterminate cases. The initial treatment of well-differentiated thyroid cancer (DTC) is surgery followed by radioiodine remnant ablation. However, further studies are needed to determine the optimal dosage of radioactive iodine for DTC patients with lateral neck metastasis. DTC is an indolent tumor and may cause death even decades later. Thus, long-term follow-up is mandatory. Recently, dynamic risk stratification (DRS) has begun to use stimulated thyroglobulin level at 1 year after the initial treatment and restratified the risk in accordance with the response to the initial treatment. This DRS strategy accurately predicts disease free survival and can be widely used in daily clinical settings. For the iodine refractory metastatic disease, redifferentiation therapy and targeted therapy are two promising alternative treatments. Sorafenib is the first approved agent for the treatment of progressive iodine refractory advanced thyroid cancer in Korea and may be very helpful for radioactive-refractory locally advanced or metastatic DTC. Selumetinib may be an effective redifferentiating agent and could be used within several years.

SummaryObjective Serum calcitonin (CT) level is used to detect medullary thyroid carcinoma (MTC), but the cut-off level is unclear. We aimed at identifying the optimal cut-off value of basal serum CT levels for detecting MTC. Design and patients We retrospectively enrolled patients with hypercalcitoninemia (≥2·9 pmol/l) who had undergone thyroid ultrasonography (US) and subsequent work-up between 2001 and 2013 at Asan Medical Center. We divided patients into four groups: proven MTC (group 1, n = 93), pathologically proven non-MTC after surgery (group 2, n = 57), benign single nodule by cytology (group 3, n = 68) and patients without nodules on US (group 4, n = 24). Measurement Basal serum CT levels were evaluated. Results The median CT level of group 1 (119·5 pmol/l) was significantly higher than those of other groups (4·0, 3·8 and 3·8 pmol/l, P

Low serum vitamin D levels have been associated with several autoimmune diseases, but their association with thyroid autoimmunity is unclear. We evaluated the association of serum vitamin D levels with the prevalence of autoimmune thyroid disease (AITD).Our cross-sectional study included subjects who underwent routine health checkups, which included assays of serum 25-hydroxy vitamin D3 [25(OH)D3] and anti-thyroid peroxidase antibody (TPO-Ab), as well as thyroid ultrasonography (US) between 2008 and 2012 at the Asan Medical Center. We defined AITD according to the levels of TPO-Ab and US findings.A total of 6685 subjects (58% male; 42% female) were enrolled for this study. Overall prevalence of TPO-Ab positivity and both TPO-Ab/US positivity were 10.1% (6.3% male; 15.3% female) and 5.4% (2.3% male; 9.7% female) respectively. In female subjects, mean serum 25(OH)D3 levels were significantly lower in the TPO-Ab(+) (22.0 vs. 23.5 ng/mL, p=0.030) and TPO-Ab(+)/US(+) groups (21.6 vs. 23.4 ng/mL, p=0.027) compared with the control group, respectively. According to the levels of serum 25(OH)D3, the prevalence of TPO-Ab positivity (21.2%, 15.5%, and 12.6% in deficient, insufficient, and sufficient group, respectively; p=0.001) and both TPO-Ab and US positivity (14.7%, 9.9%, and 7.1% in deficient, insufficient, and sufficient group, respectively; p0.001) decreased in female subjects. Interestingly, this pattern was significant only in pre-menopausal women (p=0.003 and p0.001; respectively), but not in postmenopausal women. Multivariate analysis indicated that the adjusted odds ratios (OR) for AITD among those in the 25(OH)D3-deficient [TPO-Ab(+): OR 1.95, p=0.001; TPO-Ab(+)/US(+): OR 2.36, p0.001] and -insufficient groups [TPO-Ab(+): OR 1.31, p=0.043; TPO-Ab(+)/US(+): OR 1.50, p=0.017] were significantly increased when compared with the sufficient group.The levels of serum vitamin D were significantly lower in pre-menopausal women with AITD. Vitamin D deficiency and insufficiency were significantly associated with AITD in pre-menopausal women.

Previous studies showed a close association between several types of human cancers and somatic mutations of thyroid hormone receptor β (TRβ) and reduced expression of TRβ due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TRβ could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TRβ could function to inhibit tumorigenesis are less well understood.We used the human follicular thyroid cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TRβ on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models.Expression of TRβ in FTC-133 cells, as compared with control FTC cells without TRβ, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70 S6K pathway. TRβ expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models. Importantly, new vessel formation was significantly suppressed in tumors induced by FTC cells expressing TRβ compared with control FTC cells without TRβ. The decrease in vessel formation was mediated by the downregulation of vascular endothelial growth factor in FTC cells expressing TRβ.These findings indicate that TRβ acts as a tumor suppressor through downregulation of the AKT-mTOR-p70 S6K pathway and decreased vascular endothelial growth factor expression in FTC cells. The present results raise the possibility that TRβ could be considered as a potential therapeutic target for thyroid cancer.

Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for use in patients with iodine-131-refractory thyroid cancer. The common adverse events of lenvatinib include hypertension, proteinuria, fatigue, and diarrhea. To date, no report on Pneumocystis pneumonia (PCP) in patients receiving lenvatinib has been published. Here, we present a case of severe PCP that led to the death of a 79-year-old woman who was diagnosed with poorly differentiated thyroid cancer and received lenvatinib. The development of PCP should be considered when patients taking lenvatinib show clinical symptoms of pneumonia, and regular chest X-ray follow-up is needed for patients receiving lenvatinib.

Background We previously reported the frequent neurofibromatosis 2 (NF2) gene mutations in anaplastic thyroid cancers in association with the BRAFV600E mutation. We aimed to investigate the role of NF2 in thyroid cancer with BRAF mutation. Methods To identify the function of NF2 in thyroid cancers, we investigated the changes in cell proliferation, colon formation, migration and invasion of thyroid cancer cells (8505C, BHT101, and KTC-1) with BRAFV600E mutation after overexpression and knock-down of NF2. We also examined how cell proliferation changed when NF2 was mutagenized. Human NF2 expression in papillary thyroid carcinoma (PTC) was analyzed using the The Cancer Genome Atlas (TCGA) data. Results First, NF2 was overexpressed in 8505C and KTC-1 cells. Compared to control, NF2 overexpressed group of both thyroid cancer cells showed significant inhibition in cell proliferation and colony formation. These results were also confirmed by cell migration and invasion assay. After knock-down of NF2 in 8505C cells, there were no significant changes in cell proliferation and colony formation, compared with the control group. However, after mutagenized S288* and Q470* sites of NF2 gene, the cell proliferation increased compared to NF2 overexpression group. In the analysis of TCGA data, the mRNA expression of NF2 was significantly decreased in PTCs with lateral cervical lymph node (LN) metastasis compared with PTCs without LN metastasis. Conclusion Our study suggests that NF2 might play a role as a tumor suppressor in thyroid cancer with BRAF mutation. More studies are needed to elucidate the mechanism how NF2 acts in thyroid cancer with BRAF mutation.

Objective To investigate the relationship between the rotator cuff tear (RCT) and the muscle strength in hemiplegic side, and the effects of paralysis on the affected shoulders in hemiplegic patients. Methods A cross-sectional observational study performed in a university hospital was presented. The study enrolled 55 participants with hemiplegia of diverse degree of motor paresis, excluding those with bilateral lesions, history of major trauma or other co-existing musculoskeletal disorders of the shoulder. The main outcome measurements were muscle strength of the affected upper extremity (based on Medical Research Council scale), RCTs of the bilateral shoulders (by ultrasonography), and presence of shoulder pain, subluxation of the glenohumeral joint, passive range of motions, and subacromial spurs. Results Comparing each side of the shoulders, the prevalence of shoulder pain and supraspinatus muscle tear was higher (p

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in development, growth, and differentiation. The THRA and THRB genes encode several TR isoforms that express in a tissue- and development-dependent manner. In the past decades, a significant advance has been made in the understanding of TR actions in maintaining normal cellular functions. However, the roles of TRs in human cancer are less well understood. The reduced expression of TRs because of hypermethylation, or deletion of TR genes found in human cancers suggests that TRs could function as tumor suppressors. A close association of somatic mutations of TRs with human cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation.In line with the findings from association studies in human cancers, mice deficient in total functional TRs (Thra1(-/-)Thrb(-/-) mice) or with a targeted homozygous mutation of the Thrb gene (denoted PV; Thrb(PV/PV) mice) spontaneously develop metastatic thyroid carcinoma. This review will examine the evidence learned from these genetically engineered mice that provided strong evidence to support the critical role of TRs in human cancer.Loss of normal functions of TR by deletion or by mutations could contribute to cancer development, progression and metastasis.Novel mechanistic insights are revealed in how aberrant TR activities lead to carcinogenesis. Mouse models of thyroid cancer provide opportunities to identify molecular targets as potential treatment modalities. This article is part of a Special Issue entitled Thyroid hormone signalling.

That a knock-in mouse harboring a dominant-negative thyroid hormone receptor (TR)-β (Thrb) mutation develops metastatic thyroid cancer strongly suggests the involvement of TRβ in carcinogenesis. Epigenetic silencing of the THRB gene is common in human cancers. The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer (DTC) and how reexpression of the THRB gene attenuated the cancer phenotypes. We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues. Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5′-aza-2′-deoxycytidine (5′-aza-CdR) and zebularine to evaluate their impact on the cancer cell phenotypes. THRB mRNA expression in DTC was 90% lower than in normal controls, and this decrease was associated with a higher tumor/lymph node staging. The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene. Treatment of FTC-236 cells with 5′-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration. FTC-236 cells stably expressing TRβ exhibited lower cell proliferation and migration through inhibition of β-catenin signaling pathways compared with FTC-236 without TRβ. 5′-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies. These finding indicate that TRβ is a tumor suppressor and could be tested as a potential therapeutic target.

Thyroid cancers arising from a thyroglossal duct cyst (TGDC) are rarely reported. No clear consensus exists regarding optimal management. In this light, TGDC carcinomas recently treated at Asan Medical Center, as well as previously reported cases in the literature, were reviewed. There were ten patients who were diagnosed with TGDC carcinoma at our institution. All patients underwent pre-operative fine-needle aspiration biopsy (FNAB). Nine patients were suspected of having papillary carcinoma following cytology. The Sistrunk operation (SO) was performed in four patients, SO with total thyroidectomy (SO/TT) was performed in three patients, and SO/TT with neck dissection was performed in three patients. Six patients who received total thyroidectomy underwent radioactive iodine (RAI) therapy and T4 suppression. With a median follow-up period of 28.5 months, two patients showed recurrence and one of them died of the disease. We analyzed 163 cases from 1990 to 2012 with three or more cases TGDC carcinoma, including the present study. Among 48 patients who underwent FNAB, 75% had papillary thyroid carcinoma (PTC). SO, SO/TT, or SO/TT with neck dissection was performed in 27%, 41%, and 32% of patients, respectively. Among 119 patients who received total thyroidectomy, 36% had concomitant PTC in the thyroid. Among 52 patients who received neck dissection, 69% had cervical nodal involvement. The results of our review suggest that when TGDC carcinoma is suspected, ultrasonography and, if necessary, FNAB should be performed. If these tests reveal a suspected lesion in the thyroid or lymph node, SO/TT and lymph node dissection should be performed.

Increased incidence of small differentiated thyroid cancer (DTC) has emphasized the need for risk stratification and individualized disease management for these low risk DTCs. The aim of this study was to validate a new dynamic risk stratification (DRS) system for the prediction of structural recurrent/persistent disease in patients with DTC treated without radioactive iodine (RAI) remnant ablation therapy.This historical cohort study included 357 patients with DTC treated with lobectomy or total thyroidectomy without RAI therapy. We stratified patient response to initial treatment as excellent, indeterminate, biochemical incomplete, and structural incomplete according to the DRS system.During a median follow-up of 8.6 years, 3.6% patients had structural recurrent DTC. The response was excellent in 71.7% patients, indeterminate in 18.5%, biochemical incomplete in 8.4%, and structural incomplete in 1.4%. There were significant differences in DFS among the DRS groups (p 0.001). The hazard ratio (HR) of recurrent/persistent disease was significantly higher in the biochemical incomplete group (HR = 20.8, p 0.001) and structural incomplete group (HR = 243.3, p 0.001) compared with the excellent group. However, the Tumor Node Metastasis staging system and the American Thyroid Association initial risk classification did not effectively predict recurrence of DTC.The new DRS system was effective for predicting risk of recurrent/persistent disease in patients with DTC who underwent lobectomy or total thyroidectomy without RAI remnant ablation.