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Objective: This study evaluated the efficacy of antithyroid drugs (ATDs) and risk factors associated with the recurrence of Graves’ hyperthyroidism using a comprehensive retrospective cohort. Methods: We included 1829 patients newly diagnosed with Graves’ hyperthyroidism, with sufficient follow-up data. Clinical outcomes of the patients and risk factors associated with recurrence-free survival, including the changes in thyrotropin receptor antibody, were evaluated. Results: The median age of the patients was 44.5 years, and 69% were female. Among the patients, 1235 had a chance to withdraw ATD after a median of 23 (interquartile range (IQR) 17.0–35.5) months of treatment. The first remission rate was 55.6% during a median of 72.7 months of follow-up. After the first recurrence, 95% of patients underwent the second course of ATD treatment for a median of 21 .1 (IQR 14.8–31.7) months, and the remission rate was 54.1%. During a median of 67 months of follow-up, 7.7% of patients underwent surgery, and 10.5% underwent radioac tive iodine therapy. Approximately 30% were still on ATD therapy for recurrent disease or prolonged lowdose maintenance. Younger age (

Background: Catabolism of serine via serine hydroxymethyltransferase2 (SHMT2) through the mitochondrial one-carbon unit pathway is important in tumorigenesis. Therefore, SHMT2 may play a role in thyroid cancer. Methods: Thyroid tissue samples and The Cancer Genome Atlas (TCGA) database were used to evaluate SHMT2 expression in thyroid tissues and the association with clinical outcomes. Results: SHMT2 protein expression was evaluated in thyroid tissues consisting of 52 benign nodules, 129 papillary thyroid carcinomas (PTC) and matched normal samples, and 20 anaplastic thyroid carcinomas (ATC). ATCs presented the highest (95.0%) positivity of SMHT2 protein expression. PTCs showed the second highest (73.6%) positivity of SHMT2 expression, which was significantly higher than that of be nign nodules (19.2%, P = 0.016) and normal thyroid tissues (0%, P < 0.001). Analysis of TCGA data showed that SHMT2 messenger RNA (mRNA) expression was significantly higher in tumo rs than in normal tissues (P < 0.001). When we classified thyroid cancer into high and low gr oups according to SHMT2 mRNA expression levels, the thyroid differentiation score for t he high SHMT2 group was significantly lower than that of the low SH MT2 group (P < 0.001). There was also a significant correlation between SHMT2 mRNA expression and the stemness index (r = 0.41, P < 0.001). The high SHMT2 group had more advanced TNM stages and shorter progression-free survival rates than the low SHMT2 group (P < 0.01 and P = 0.007, respectively). Conclusion: SHMT2 expression is higher in thyroid cancers than normal or benign tissues and is associated with de-differentiation and poor clinical outc omes. Thus, SHMT2 might be useful as a diagnostic and prognostic marker for thyroid cancer.

Dabrafenib is a BRAF kinase inhibitor approved for treatment of BRAF-mutated anaplastic thyroid carcinoma (ATC) in combination with trametin ib. Erlotinib is a tyrosine kinase inhibitor of EGF receptor (EGFR). We evaluated effects of dabrafenib and erlotinib combination treatment on ATC cells in vitro and in vivo. Cell proliferation, colony formation, apoptosis, and migration of ATC cells harbori ng a BRAF mutation (BHT101, 8505C, and SW1736) were evaluated after treatment with dabrafenib in combination with erlotinib or trametinib. The changes in act ivation of mitogen extracellular kinase (MEK) and extracellular signal-related kin ase (ERK) signaling were also evaluated by Western blot analysis. Effects of these c ombinations were also evaluated using an in vivo xenograft model. First, we detected EGFR activation in dabrafenib-resistant SW1736 cells using a phospho-receptor tyro sine kinase array. A dabrafenib and erlotinib combination synergistically inhibite d cell proliferation, colony formation, and migration, with an induction of apoptotic cell death in all three ATC cells, compared with dabrafenib or erlotinib alone. This synergistic effect was comparable with a dabrafenib and trametinib combination. The dabrafenib and erlotinib combination effectively inhibited phosphorylated (p)-M EK, p-ERK, and p-EGFR expressions compared with dabrafenib or erlotinib alone, while the dabrafenib and trametinib combination only inhibited p-MEK and p-ERK expressio ns. The dabrafenib with erlotinib or trametinib combinations also significantly sup pressed tumor growth and induced apoptosis in a BHT101 xenograft model. The dabrafen ib and erlotinib combination could be a potential novel treatment regimen to ove rcome drug resistance to dabrafenib alone in patients with BRAF-mutated ATC. [ABSTRACT FROM AUTHOR]

We previously reported that high thyroid-stimulating hormone (TSH) levels are associated with papillary thyroid microcarcinoma (PTMC) progression during active surveillance. However, validation with multicenter, long-term data, and identification of appropriate age or TSH levels are needed. This multicenter retrospective study enrolled PTMC patients under active surveillance with TSH measurements and ultrasonography. The primary outcome was PTMC progression (volume increase ≥50%, size increase ≥3 mm, or new lymph node (LN) metastasis). PTMC progression according to time-weighted average of TSH (TW-TSH) groups was compared using survival analyses in overall patients and each age subgroups (<40, 40-49, 50-59, and ≥60 years). The identification of TW-TSH cutoff point for PTMC progression and trend analysis of PTMC pro gression rate according to LT4 treatment were also performed. During 1061 person-years of follow-up, 93 of 234 patients (39.7%) showed PTMC progression (90, 17, and 5 patients for volume increase ≥50%, size increase ≥3 mm, and new LN metastasis, respectively). The highest TW-TSH group was the risk factor most strongly associated with PTMC pr ogression (hazard ratio 2.13 (1.24-3.65); P = 0.006), but the impact was significant only in patients aged <4 0 or 40-49 years (hazard ratio 30.79 (2.90-326.49; P = 0.004), 2.55 (1.00-6.47; P = 0.049)). For patients aged <50 years, TW-TSH cutoff for PTMC progression was 1.74 mU/L, and PTMC progression rates successively increased in the order of effective, no, and ineffective LT4 treatment group (P for trend = 0.034). In young PTMC patients (<50 years), sustained lownormal TSH levels during active surveillance might be helpful to prevent progression. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC) is a rapidly growing, highly metastatic cancer with limited therapeutic alternatives, thus targeted therapies need to be developed. This study aimed to examine desmoglein 2 (Dsg2) expression in ATC an d its biological role and potential as a therapeutic target in ATC. Consequently, Dsg2 was downregulated or aberrantly expressed in ATC tissues. ATC patients with low Dsg2 expression levels also presented with distant metastasis. Dsg2 depletion significantly increased cell migration and invasion, with a relatively limited effect on ATC cell proli feration in vitro and increased distant metastasis in vivo. Dsg2 knockdown induced cell motility through the hepatocyte growth factor receptor (HGFR, c-Met)/Src/Rac1 signaling axis, with no alterations in the expression of EMT-related molecules. Further, specific targeting of c-Met significantly inhibited the motility of shDsg2-depleted ATC cells. Decreased membrane Dsg2 expression increased the metastatic potential of ATC cells. These results indicate that Dsg2 plays an important role in ATC cell migration and invasive ness. Therapies targeting c-Met might be effective among ATC patients with low membrane Ds g2 expression levels, indicating that the analysis of Dsg2 expression potentially provides novel insights into treatment strategies for ATC. [ABSTRACT FROM AUTHOR]

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 fr om distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit-related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, r espectively. When the mutational status was analyzed in 15 matched pairs of thyro id tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor-metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy without effective therapeutic options to improve survival. Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator whose amplification and/or overexpression has been identified in many cancers. In this study, we explored the expression of S RC-3 in ATCs and the effects of a new class of SRC-3 inhibitor-2 (SI-2) in human ATC cells (THJ-11T and THJ-16T cells) and mouse xenograft models to assess therapeutic potential of SI-2 for the treatment of ATC. SRC-3 protein abundance was significantly higher in human ATC tissue samples and ATC cells than in differentiated thyroid carcinomas or normal controls. SI-2 treatment effectively reduced the SRC-3 expression in both ATC cells and ATC xenograft tumors induced by these cells. Cancer cell survival in ATC cell s and tumor growth in xenograft tumors were significantly reduced by SI-2 treatment through induction of cancer cell apoptosis and cell cycle arrest. SI-2 also reduced cancer stem-like cells as shown by an inhibition of tumorsphere formation, ALDH activity, and expression of stem cell markers in ATC. These findings indicate that SRC-3 is a pot ential therapeutic target for treatment of ATC patients and that SI-2 is a potent and pro mising candidate for a new therapeutic agent. [ABSTRACT FROM AUTHOR]

5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 5′-AMP-activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPKmediated growth inhibition is achieved via an action of the RAF-MEK-ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anticancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects. AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600Emutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR-induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation. [ABSTRACT FROM AUTHOR]