Background: Sorafenib and lenvatinib have been widely adopted to treat radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). However, limited data exists regarding a direct comparison of these tyrosine kinase inhibitors (TKIs). We aimed to evaluate the clinical efficacy and safety of two TKIs as first-line therapy in patients with distant metastatic or locally advanced, progressive, radioactive iodine (RAI)-refractory DTC in real-world practice. Methods: In this multicenter, retrospective cohort study, we evaluated 136 patients with progressive, distant metastatic or locally advanced, progressive, RAI-refractory DTC who received first-line sorafenib or lenvatinib treatment. The primary outcome was progression-free survival (PFS). We also evaluated the objective response rate, disease-control rate, clinical benefit rate, and safety. Results: The median age of the patients was 68 years, and 35% (47/136) were male. Eighty and fifty-six patients were included in the sorafenib and lenvatinib groups, respectively. The median PFS was 13.3 months (95% confidence interval [CI], 9.9–18.1 months) in the sorafenib group and 35.3 months (95% CI, 18.2 months-upper limit not reported as the median was not reached) in the lenvatinib group (p=0.001). A significantly prolonged PFS was observed in the lenvatinib group (compared with the sorafenib group) after adjusting for age, sex, pathology, disease-related symptom, lung-only metastasis, cumulative RAI dose, time from diagnosis, treatment duration and longest diameter of the target lesion (HR=0.34, 95% CI, 0.19–0.60, p<0.001). The partial response rate was 24% and 59% in the sorafenib and lenvatinib groups, respectively (p<0.001). More common grade 3-4 adverse events were hypertension (16%, 9/56 vs 1%, 1/80, p=0.002), proteinuria (32%, 18/56 vs 0%, p<0.001) in lenvatinib group, and hand-foot skin reaction (24%, 19/80 vs 4%, 2/56, p=0.001) in the sorafenib group. Conclusion: In our study of Asian patients, first-line lenvatanib treatment of metastatic or locally advanced, progressive, RAI-refractory DTC was associated with a longer PFS compared to sorafenib. However, severe hypertension and proteinuria were observed more frequently after lenvatinib treatment than after sorafenib treatment.

Background: Advanced thyroid cancers, including differentiated thyroid carcinoma (DTC) with distant metastasis, and anaplastic thyroid carcinoma (ATC), are associated with poor clinical outcomes and limited treatment options. This study aimed to determine the immune profiles of advanced thyroid cancers using fluorescent multiplex immunohistochemistry (F-MIHC) and multispectral imaging (MSI). Methods: Twenty-eight tissue samples were collected from 12 patients who had DTC with distant metastasis and from 16 with ATC. The samples were assessed using F-MIHC and MSI with antibodies against the cell surface molecules, cluster of differentiation (CD)4, CD8, programmed cell death-1 (PD-1), PD ligand 1 (PD-L1), forkhead box protein 3, and cytokeratin (CK). The expression of PD-L1 was evaluated using tumor proportion score (TPS) and combined positive score (CPS). Results: Significantly, more PD-L1-positive tumor cells (CK ⁺ PD-L1 ⁺ ) per mm ² were found in ATC samples than in DTC samples (183.5 vs. 0.03, p < 0.001). Lymphocyte infiltration was significantly increased in ATC compared with DTC, with significantly more PD-L1- or PD-1-positive lymphocytes in ATC samples than in DTC samples. The TPS and CPS for PD-L1 expression were negative in all DTC samples but positive in 81% and 94% of ATC samples, respectively. Conclusions: Immune profiling revealed significant differences between advanced DTC and ATC, particularly in terms of PD-L1 expression and lymphocyte infiltration. Therefore, immune profiling using F-MIHC and MSI can provide invaluable information regarding tumor microenvironments, which could help select candidates for immunotherapy.

Background: Some papillary thyroid microcarcinomas (PTMCs) may progress with tumor enlargement or development of new lymph node (LN) metastasis during active surveillance (AS). This study evaluated the relevant predictors of disease progression, especially new cervical LN metastasis. Methods: This was a long-term follow-up study conducted using a previous multicenter cohort of AS in Korea. After excluding 54 (14.2%) patients with a short follow-up duration, 326 PTMC patients were evaluated for tumor kinetics, including changes in tumor volume (TV) and TV doubling time (TVDT). Results: During a median follow-up duration of 4.9 years, 17 (5.2%, 95% confidence intervals [CI] 2.7%–7.6%) patients showed a maximal diameter increase of ≥3 mm after a median 4.0 years of follow-up, while 9 (2.8%, 95% CI 1.0%–4.5%) showed newly developed LN metastasis after a median 2.2 years of follow-up. New cervical LN metastasis occurred exclusively of a maximal diameter increase of ≥3 mm. The prevalence of new development of LN metastasis was higher in patients with TVDT <5 years (7.4%) than in those with TV ≥50% (3.2%). Furthermore, only TVDT <5 years was significantly associated with LN metastasis (P = 0.002). In univariate and multivariate analyses, TVDT <5 years was an independent risk factor for disease progression with respect to new development of LN metastasis (hazard ratio [HR] = 6.51, CI 1.73–24.50; P = 0.002) and tumor enlargement (HR = 20.89, CI 5.78–75.48; P < 0.001). Finally, 86 (22.6%) patients underwent delayed surgery, and the most common reason was anxiety. Conclusions: TVDT <5 years is the best predictor of disease progression during AS in terms of new LN metastasis development as well as tumor enlargement. Determination of TVDT in the early phase of AS could help in predicting disease progression for the precise tailoring of the follow-up intensity of AS and in determining if early surgical intervention is needed.

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.

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 radioactive iodine therapy. Approximately 30% were still on ATD therapy for recurrent disease or prolonged low-dose maintenance. Younger age (<45 years), male sex, and fluctuating or smoldering of TRAb levels were independent risk factors of the first recurrence after ATD treatment. Conclusions: ATD treatment is an acceptable option for the initial treatment of Graves’ hyperthyroidism as well as for recurrent disease. The optimal treatment period for ATD treatment needs to be determined using the individual risk factors of recurrence.

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 benign 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 tumors than in normal tissues (P < 0.001). When we classified thyroid cancer into high and low groups according to SHMT2 mRNA expression levels, the thyroid differentiation score for the high SHMT2 group was significantly lower than that of the low SHMT2 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 outcomes. Thus, SHMT2 might be useful as a diagnostic and prognostic marker for thyroid cancer.