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Background: Advanced thyroid cancers, including differentiated thyroid carcinoma (DTC) with distant metastasis, and anaplastic thyroid carcinoma (ATC), are associated with poor clinical outcomes an...

Background: Active surveillance (AS) is recommended as an alternative to immediate surgery in patients with papillary thyroid microcarcinoma (PTMC), but the impact of AS on quality of life has not ...

Background: The lymphocyte-to-monocyte ratio (LMR), which reflects the tumor-infiltrating immune cell status and host immunity, has been reported as a prognostic marker in various cancers. The aim ...

Although several studies have shown that obesity affects low back pain (LBP), the relationship between degenerative lumbar spine (LSD) and obesity has not been fully investigated. This study evaluated whether obesity is independently associated with LSD in the general population.This cross-sectional study used public data from the Fifth Korean National Health and Nutrition Examination Survey (2010-2012). Subjects aged ≥50 years who had completed surveys were included (3668 men and 4966 women). Obesity was classified based on the body mass index, and LSD was assessed by lumbar spine radiographs. Independent associations of obesity with LSD or LBP were determined using odds ratios (OR) adjusted by two regression models.The prevalence of obesity was more frequent in women than in men (38.27% vs. 33.97%, P 0.001). Compared with normal weight women, the risk of LSD was increased in overweight and obese women following adjustments [OR = 1.227, 95% confidence interval (CI): 1.019-1.477; OR = 1.217, 95% CI: 1.024-1.446, respectively]. When obesity was subdivided, the obese II group showed higher odds for LSD in women (OR = 1.797, 95% CI: 1.287-2.510). However, obesity was not correlated with LSD in men. There was no significant association between obesity and LBP in either men or women.Compared with normal weight women, LSD risk was higher in overweight and obese women, especially those in the obese II subgroup. These findings suggest that maintaining normal body weight may be a preventative factor of LSD.

The concept of a dynamic risk-stratification scheme has been suggested for individualized management of patients with papillary thyroid carcinoma (PTC). However, there is no specified follow-up strategy for patients with an indeterminate response.This study evaluated 403 PTC patients who had an indeterminate response during the first 12-24 months after initial therapy. All patients underwent total thyroidectomy with radioactive iodine remnant ablation. Patients were further classified into three groups based on risk of structural persistence/recurrence: a Tg+ group (detectable thyroglobulin [Tg], regardless of antithyroglobulin antibody [TgAb] or imaging findings; 196 patients), a TgAb+ group (positive results for TgAb with undetectable Tg, regardless of imaging findings; 46 patients), and an Image+ group (nonspecific findings on neck ultrasonography or faint uptake in the thyroid bed on whole-body scan, with undetectable Tg and negative results for TgAb; 161 patients).With a median of 9.6 years (interquartile range 7.7-11.2 years) of follow-up, 56 (14%) PTC patients had structural persistent/recurrent disease: 50 (89%) at locoregional sites and six (11%) at distant sites. The recurrence rate in Tg+, TgAb+, and Image + groups were 26.5%, 8.7%, and 0%, respectively. The median time to detection of structural persistent/recurrent disease from the initial thyroid surgery was 3.7 years (interquartile range 2.5-6.3 years). The optimal cutoff stimulated Tg level to predict structural persistent/recurrent disease was 3.1 ng/mL in the Tg+ group. This classification system revealed higher predictability of structural persistent/recurrent disease than the tumor-node-metastasis staging system and American Thyroid Association risk stratification (proportion of variation explained: 15.7% vs. 2.4% and 0.9%, respectively). Six (3%) patients with distant metastatic disease were all classified in the Tg+ group, and all had lung metastasis.The findings suggest a more individualized follow-up strategy for patients with an indeterminate response. More careful evaluation, including early evaluation of distant metastasis, is necessary in patients with elevated Tg levels. However, for patients testing positive for TgAb or those with only nonspecific imaging findings, regular follow-ups of Tg and TgAb levels and neck ultrasonography are sufficient.

The recently published eighth edition of the American Joint Committee on Cancer (AJCC) staging system has emphasized the importance of gross extrathyroidal extension (gETE) while classifying the tumor (T) stage in differentiated thyroid carcinoma (DTC). However, the clinical impact of gETE invading only the strap muscles or the recurrent laryngeal nerve (RLN) remains unclear due to scarce and conflicting data.A retrospective cohort study was carried out in patients with DTC who underwent thyroid surgery from 1996 to 2005. In total, 3104 patients were included, and disease-specific survival (DSS) was compared according to the degree of gETE, with a median follow-up duration of 10 years.Patients with gETE invading only the strap muscles and with a tumor size ≤4 cm (T3b [≤4 cm]) showed no difference in DSS compared to patients with T2 stage disease (hazard ratio [HR] = 0.81 [confidence interval (CI) 0.24-2.77]; p = 0.737) but rather showed a better DSS than patients with T3a disease (HR = 0.19 [CI 0.05-0.72]; p = 0.014). Conversely, patients with gETE invading to the posterior direction showed significantly poorer DSS than patients with T3 stage disease, even when only the RLN was invaded (HR = 7.78 [CI 3.41-17.75]; p 0.001). However, there was no difference in DSS between gETE invading only the RLN and that invading other posterior organs beyond the RLN (p = 0.563). A modified T classification was suggested to downgrade patients with T3b (≤4 cm) disease to the T2 stage, which revealed higher predictability of survival than the T classification according to the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (proportion of variation explained: 3.6% vs. 2.65%).gETE invading only the strap muscles did not significantly affect DSS, while that invading the posterior organs significantly affected DSS, even when only the RLN was invaded. The data support the applicability of downgrading patients with T3b (≤4 cm) disease to the T2 stage for a better predictability of survival.

It is unknown whether the growth of thyroid nodules with a Bethesda category III cytology (atypia of undetermined significance [AUS]) is predictive of malignancy, especially in cases with architectural atypia (AUS-A). This study evaluated whether tumor growth rates can help distinguish malignant from benign nodules in the AUS-A subcategory.This retrospective, single-center cohort study included 172 patients who underwent diagnostic thyroid surgery because of a nodule with a cytological diagnosis of AUS-A. The growth kinetics of nodules was assessed by serial preoperative neck ultrasonography over a median follow-up of 52.6 months (range 12.7-198.3 months).Pathologic examinations showed that 112 (65%) and 60 (35%) patients had benign and malignant nodules, respectively. The largest diameter and volume of both benign and malignant nodules increased gradually (p 0.001). However, there was no significant difference in the growth rates of benign and malignant nodules based on the largest diameter (p = 0.132) and volume (p = 0.200). The time to tumor growth curves and estimated median time to significant tumor growth from baseline were not significantly different in malignant nodules compared to benign nodules (p = 0.458 and p = 0.568, respectively). The relative risk (RR) of malignancy of growing and stable nodules did not differ significantly based on the largest diameter (RR = 0.5; p = 0.064) and volume (RR = 0.9; p = 0.748).The size of thyroid nodules classified as AUS-A increased linearly, regardless whether these nodules were benign or malignant. These results suggest that growth kinetics on serial preoperative neck ultrasonography cannot predict malignancy in the AUS-A subcategory.

Active surveillance has been introduced as a management option for low-risk papillary thyroid microcarcinoma (PTMC) due to its mostly indolent course.This was a multicenter study of 370 PTMC patients who underwent active surveillance more than one year. The changes in volume and maximum diameter between initial and last ultrasonography were evaluated to identify the natural course of PTMC during active surveillance.Patients' age at diagnosis was 51 ± 12 years, and 110 (30%) patients were45 years of age. The initial maximum diameter and volume of PTMCs were 5.9 ± 1.7 mm and 81.0 ± 77.7 mmA significant number of PTMCs grow during active surveillance, and tumor volume change is a more sensitive means of evaluating tumor growth. Active surveillance can be carefully applied for selected patients. Although it is not contraindicated, it should be applied more cautiously for younger patients.

Recent studies have reported improved survival in patients with thyroid cancer. This study evaluated the changes in disease-specific survival (DSS) of patients with differentiated thyroid cancer (DTC) in association with clinicopathologic characteristics from 1996 to 2005 in Korea.This was a retrospective, multicenter cohort study. A total of 4398 DTC patients were included, and they were classified according to the year of initial surgery: 1996-2000 (period 1), 2001-2003 (period 2), and 2004-2005 (period 3).During the study period, patient age and the proportion of papillary thyroid cancer increased gradually. Primary tumors became smaller (2.3 ± 1.4 cm at period 1 to 1.5 ± 1.2 cm at period 3; p 0.001). The proportion of high-volume lymph node metastases decreased significantly (20% at period 1 to 13% at period 3; p for trend0.001). DSS differed significantly according to period during the median 10 years follow-up (p = 0.002). The 10-year DSS rates were 98.0%, 98.7%, and 99.2% in periods 1, 2, and 3, respectively. After adjusting for various characteristics, the disease-specific mortality risk was significantly lower during period 2 (hazard ratio = 0.49 [confidence interval CI 0.25-0.90], p = 0.021) and period 3 (hazard ratio = 0.40 [confidence interval 0.21-0.77], p = 0.006) compared to that of period 1. This trend was also significant in a subgroup analysis of low (I-II) and high (III-IV) TNM stages.The disease-specific mortality of patients with DTC in Korea decreased over time. Earlier detection of small DTCs with less extensive disease and standardization of treatment may be associated with this phenomenon.

Objective: The aims of this study were to stratify the risk of malignancy in thyroid incidentalomas detected on 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG...

Background Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor previously known as noninvasive subtype of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). The absence of BRAFV600E mutations has been considered characteristic of NIFTPs. However, a recent study from Korea found that 28.6% of NIFTPs harbored a BRAF mutation. This study evaluated BRAF and RAS mutations in NIFTPs and invasive subtype of EFVPTCs. Methods This study enrolled 32 patients with NIFTP and 48 with invasive EFVPTC. BRAF, NRAS, HRAS, and KRAS mutations were evaluated by direct sequencing using DNA from fresh-frozen tissues and formalin-fixed, paraffin-embedded tissue samples. Results The primary tumor size of NIFTP was smaller than that of invasive EFVPTC (median 2.8 cm vs. 3.2 cm; p = 0.03). Cervical lymph node metastases were found in only four (8%) patients with invasive EFVPTC. There was no BRAF mutation in NIFTPs, whereas invasive EFVPTCs had three (6%) BRAFV600E mutations and one (2%) BRAFK601E mutation. RAS mutations were detected in 15 (47%) NIFTPs and 22 (46%) invasive EFVPTCs. NRAS mutations in codon 61 were the most common mutations in NIFTPs (34%) and invasive EFVPTCs (27%). There was no significant difference in the frequency of RAS mutations between the two groups. Conclusions There was no BRAF mutation in any of the NIFTPs. RAS mutations, particularly mutations in codon 61 of NRAS, were the most common mutations in both NIFTPs and invasive EFVPTCs. The presence of a RAS mutation is not helpful for preoperative differentiation between NIFTPs and invasive EFVPTCs.

Regional lymph node metastases (LNM) have prognostic significance in differentiated thyroid cancer (DTC). However, there was no distinction between N1a and N1b in the final staging classification in the eighth edition of the tumor-node-metastasis (TNM) staging system. This study aimed to evaluate the prognostic implication of N1b classification for predicting disease-specific survival (DSS) in DTC patients with stage I/II disease.A total of 3089 patients with stage I/II DTC who underwent thyroid surgery between 1996 and 2005 were included. DSS was evaluated according to N classification and number of LNM. A modification of the TNM was assessed that classified N1b cases in patients aged ≥55 years as stage IIB and the remaining cases as stage IIA.The mean patient age was 45.6 years, and the median follow-up period was 10.0 years. In patients aged ≥55 years, patients with N1b had significantly poorer DSS compared to those with N0 (hazard ratio [HR] = 11.0; p 0.001) and N1a (HR = 4.2; p = 0.013). The large-volume LNM group had significantly poorer DSS compared to the N0 (HR = 10.1; p 0.001) and small-volume LNM (HR = 3.9; p = 0.019) groups. When patients were reclassified using the modified TNM staging system, DSS was significantly poorer in stage IIB patients than in stage IIA patients (HR = 2.9; p = 0.030).N1b classification has a significant prognostic implication in patients with stage I/II DTC, especially in older patients. Modified TNM staging employing N1b classification could be more useful for the prediction of DSS.

The risk of recurrence in patients with differentiated thyroid cancer (DTC) can be estimated based on their response to initial therapy. The aim of this study was to evaluate an adequate follow-up strategy for DTC patients with an excellent response by assessing the characteristics of structural recurrence.This historical cohort study included 1359 DTC patients who had excellent response to total thyroidectomy with radioactive iodine remnant ablation.Among 1359 patients, 703 (54%) patients were classified as stage I according to the seventh tumor node metastasis staging system, and 987 (73%) patients were classified as intermediate risk according to the American Thyroid Association's risk stratification after initial therapy. During a median of 8.7 years of follow-up, only 13 (1%) patients were confirmed to have structural recurrence. All of the recurrences were locoregional disease, and there were no distant metastases. Recurrences were detected late at a median of 5.5 years after the initial surgery (range 3.6-10.7 years). All structural recurrences were detected on neck ultrasonography. Non-stimulated serum thyroglobulin (Tg) was detectable (≥0.2 ng/mL) in four (31%) patients, and serum anti-Tg antibodies were positive in one (8%) patient. However, non-stimulated serum Tg levels were stably low (0.2 ng/mL) in eight (62%) patients when recurrences were detected. In addition to these 13 patients, 14 patients also presented with biochemical persistent disease at the end of follow-up.Recurrences of DTC in patients with an excellent response to initial therapy were detected relatively late. The intensity and frequency of follow-up of neck ultrasonography as well as serum Tg and anti-Tg antibody measurements should be reduced, especially within five years of the initial therapy, in DTC patients who have an excellent response.

This study validated the dynamic risk stratification (DRS) system with regard to its association with structural recurrence and risk factors associated with non-excellent responses in patients45 years with stage I classical papillary thyroid cancer (PTC).This historical cohort study included 598 patients with stage I classical PTC45 years of age treated with total thyroidectomy followed by radioactive iodine remnant ablation (n = 440), total thyroidectomy without radioactive iodine remnant ablation (n = 23), and thyroid lobectomy alone (n = 135).The median follow-up period was 123 months. Structural recurrence occurred in 4.2% (n = 18/432) of the patients with an excellent response, 17.1% (18/105) of patients with an indeterminate response, 44.7% (17/38) of patients with a biochemically incomplete response, and 82.6% (19/23) of patients with a structurally incomplete response (p 0.001) during the follow-up. The disease-free survival curves of each response showed significant differences (p 0.001). Extensive extrathyroidal extension and extranodal extension were the independent risk factors associated with non-excellent response (p 0.05).DRS may reduce unnecessary additional treatments by reclassifying initial risk estimates of structural recurrence. Furthermore, applying the risk factors associated with non-excellent response to initial therapy may be a more useful and viable surrogate of the risk for structural recurrence in stage I PTC patients45 years of age.

Thyrotropin (TSH) suppression has improved the clinical outcomes of patients with differentiated thyroid cancer (DTC). However, the efficacy of TSH suppressive therapy (TST) is unclear in patients with low-risk DTC. This study aimed to evaluate the efficacy of TST and optimal TSH levels of patients with low-risk DTC.This retrospective propensity score-matched cohort study included DTC patients (n = 446) who underwent lobectomy from 2002 to 2008 with or without TST (TST group and No-TST group). Disease-free survival (DFS) and dynamic risk stratification were compared between both groups using serum TSH levels.Approximately 74% of TST patients and 11% of No-TST patients had suppressed serum TSH levels (2 mIU/L). The median follow-up period was 8.6 years. During follow-up, the disease recurred in 10 (2.7%) patients, with no significant difference in DFS between the groups (p = 0.63). The proportion of patients with excellent treatment response was similar between the TST (65.2%) and No-TST (64.4%) groups. Incomplete biochemical response was noted in 17.2% of the TST group patients and 9.4% of the No-TST group patients. No significant difference was observed in the DFS between both groups by comparing serum TSH level (p = 0.57).TST did not improve clinical outcomes, and serum TSH levels were not associated with recurrence in patients with low-risk small DTC. No clinical benefits were shown for TSH suppression in low-risk patients who underwent lobectomy. Thus, levothyroxine is not necessary for patients without evidence of hypothyroidism.

The clinical course of patients with lung metastases of differentiated thyroid carcinoma (DTC) vary, and cancer-specific survival (CSS) can be associated with tumor burden. This study evaluated the growth kinetics of lung metastases from DTC using serial chest computed tomography for Response Evaluation Criteria in Solid Tumors assessment and its prognostic implications.Forty-four patients with macronodular lung metastases (≥1 cm) of DTC were included. The time intervals to disease progression of lung metastases were measured and compared to CSS rates.On the basis of the time to progression, 15 (34%), 17 (39%), and 12 (27%) patients were classified into the slow (≥3 years), moderate (1-3 years), and rapid groups (1 year), respectively. The growth kinetics of lung metastases exhibited a linear pattern in the three groups. The doubling time of tumor burden was 1.8 years (RThis is the first study to demonstrate objectively that tumor growth kinetics within the first year are an independent predictor of CSS in patients with macronodular lung metastases. Performing chest computed tomography at least twice a year in the early phase of the disease in patients with macronodular lung metastases may be helpful for identifying high-risk patients who are eligible for treatment with tyrosine kinase inhibitors.

For patients with lung metastases of differentiated thyroid carcinoma (DTC), there is no consensus on the maximal size of metastatic lesions to use when determining the intensity of follow-up and additional therapeutic options. This study evaluated the clinical outcomes and survival of patients with metastatic DTC confined to the lung, using the maximal diameter of lung lesions in the initial computed tomography.This retrospective cohort study included 112 DTC patients with metastases confined to the lung. The clinical responses were evaluated according to changes in the serum levels of stimulated thyroglobulin or antithyroglobulin antibody, disease status was evaluated according to radiological findings, progression-free survival (PFS), and cancer-specific survival (CSS).Macronodular lung metastases (≥1 cm) were observed in 27 (24%) patients, and these patients had significantly poor biochemical responses and disease status (p 0.001, and p 0.001, respectively), irrespective of radioactive iodine (RAI) avidity. After adjusting for age, sex, primary tumor size, extrathyroidal invasion, cervical lymph node metastasis, time of lung metastasis, and RAI avidity, the macronodular group also had shorter PFS and CSS (p = 0.009 and p = 0.03, respectively) than the micronodular group. From the multivariate analyses, RAI avidity was not an independent prognostic factor predicting PFS and CSS. In the subgroup analyses, RAI avidity was a significant prognostic factor associated with better PFS and CSS (p = 0.013 and p = 0.021, respectively) in the micronodular group only.The initial largest diameter of metastatic lesions is the most important prognostic factor for predicting poor clinical outcomes and survival in patients with metastatic DTC confined to the lung.

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.

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.

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.

Measurement of the serum thyroglobulin (Tg) level with TSH stimulation (sTg) is the cornerstone of monitoring for the recurrence or persistence of differentiated thyroid cancer (DTC) in patients who have undergone surgery and remnant ablation. However, there have been several reports that an undetectable sTg could not predict the absence of future recurrence. The aim of this study was to evaluate the long-term outcome of DTC patients who achieved biochemical remission (BR, defined as sTg1 ng/mL) after initial treatment, and to determine the role of repeated sTg measurement in detecting a clinical recurrence.This is a retrospective observational cohort study in a tertiary referral hospital. There were 1010 DTC patients who achieved BR at 12 months after the initial treatment (surgery and ablation), and they were eligible for analysis. Among them, 787 patients had values of repeated sTg.Thirteen out of 1010 (1.3%) patients had clinical recurrences during a median 84 months of follow-up. All of the clinical recurrences were limited to the cervical lymph nodes without clinical evidence of distant metastasis. Among 787 patients with available repeated sTg, 10 had clinical recurrences (5 out of 750 patients with repeated sTg1 ng/mL and 5 out of 37 patients with repeated sTg ≥ 1 ng/mL). Patients with repeated sTg ≥ 1 ng/mL had a much greater chance of disease recurrence (log-rank statistics=43.7, df=1, p0.001).About 1% of DTC patients who had sTg1 ng/mL 12 months after initial treatment had a clinical recurrence. All of clinical recurrences were loco-regional recurrences. Although repeated sTg measurement can be helpful to predict recurrence, we could not recommend it for surveillance in patients with BR due to its very low yield.