European Thyroid Journal最新文献

This review explores the role of BRAF V600E in thyroid cancer with emphasis on its debated prognostic value, notable molecular heterogeneity, and opportunities as a therapeutic target. BRAF V600E, the most common oncogenic driver in papillary thyroid carcinoma, activates the MAPK pathway and suppresses genes involved in iodine metabolism and differentiation. While linked to adverse features and outcomes such as extrathyroidal extension, lymph node metastasis, recurrence, and mortality, its utility as an independent prognostic marker remains controversial. In solitary intrathyroidal tumors (1-4 cm) and low-risk microcarcinomas, BRAF V600E testing may help refine surgical decisions, though evidence is inconsistent, particularly for tumors <2 cm. The mutation also contributes to radioactive iodine (RAI) refractoriness, but not all BRAF-mutant tumors behave similarly. Transcriptomic and genomic heterogeneity - including differences in thyroid differentiation score, genetic co-alterations and miRNA signatures - modulates treatment response. Targeting BRAF V600E has led to novel therapeutic strategies. Selective BRAF and MEK inhibitors - including vemurafenib, dabrafenib, and selumetinib - have demonstrated efficacy in advanced thyroid cancers. The combination of dabrafenib and trametinib is FDA approved for BRAF V600E-mutant anaplastic thyroid carcinoma based on its significant survival benefits. Moreover, due to its histology-agnostic approval for solid tumors with BRAF V600E mutations, this regimen is now also indicated for papillary and poorly differentiated thyroid cancers. In addition, redifferentiation strategies using MAPK inhibitors to restore RAI avidity have shown promise, particularly in selected patients. These advances highlight the need to contextualize BRAF mutation status within a broader molecular and clinical framework to guide personalized, effective treatment strategies.

Introduction: Thermal ablation (TA), including radiofrequency (RFA) and microwave ablation (MWA), is a widely used, minimally invasive alternative to surgery for benign thyroid nodules. While transient, self-limited thyrotoxicosis is a recognized effect of the procedure, the onset of Graves' disease (GD) post-TA remains exceedingly rare and poorly characterized.

Case reports: We report three cases of new-onset GD occurring 3-10 months after RFA or MWA, identified among more than 500 patients treated at our tertiary care Endocrinology Unit. All patients were female and had undergone TA for cytologically benign nodules. Two had a documented history of thyroid autoimmunity. At diagnosis, all three exhibited suppressed TSH, elevated thyroid hormone levels, and positive anti-TSH receptor antibodies (TRAb). None had been tested for TRAb before treatment. One case occurred during pregnancy and was managed with propylthiouracil; the others received antithyroid treatment with methimazole.

Conclusion: Although rare, GD may develop following TA, likely through immune activation triggered by thyroid tissue injury in genetically predisposed individuals. Routine TRAb screening before TA is not currently justified; however, clinical awareness is essential to distinguish transient post-ablation thyrotoxicosis from true GD and to ensure timely initiation of antithyroid therapy when appropriate. Despite these rare cases, the overall incidence remains very low, confirming the excellent safety profile of TA for benign thyroid nodules.

Objective: Dysthyroid optic neuropathy (DON) is a severe complication of thyroid eye disease (TED) with limited early detection methods. This study aimed to investigate the clinical characteristics of patients with TED who developed DON and to establish a predictive model for early identification of high-risk cases.

Methods: Herein, 257 TED patients were prospectively included, of whom 68 (26.5%) developed DON. All patients were divided into derivation and validation cohorts, and Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression analyses were applied to identify clinical factors and construct a prediction model.

Results: In the derivation cohort (185 TED patients), 49 (26.5%) developed DON. DON patients showed significantly higher prevalence of pretibial myxedema (PTM) (22.4 vs 5.9%, P = 0.001), diabetes mellitus (18.4 vs 7.4%, P = 0.029), older age (58.04 ± 11.30 years vs 47.99 ± 10.65 years, P < 0.001), higher CAS (5 vs 4, P < 0.001), elevated triglyceride (TG) levels (1.44 mmol/L vs 1.15 mmol/L, P = 0.042), and lower visual functioning (VF) (43.75 vs 62.50, P < 0.001). LASSO regression analysis identified age, PTM, TG, VF, and CAS as independent predictors of DON. The developed nomogram presented AUCs of 0.853 (95% CI: 0.792-0.914) and 0.856 (95% CI: 0.762-0.950) in the derivation and validation cohorts, respectively.

Conclusions: Altogether, the findings of this study identify advanced age, elevated CAS, increased TG, lower VF, and PTM as significant predictors of DON in patients with TED. The proposed nomogram offers a practical clinical tool for risk stratification, providing clinicians with an approach for individualized risk assessment and timely therapeutic intervention.

Introduction: Thyroid nodules are common, affecting approximately 50% of individuals. These nodules are often discovered incidentally and exhibit benign characteristics. Following a suspicious ultrasound, a fine-needle aspiration biopsy (FNAB) is performed to assess the risk of malignancy. However, approximately 30% of cases are classified as indeterminate by cytology. In response, the development of molecular tests has refined malignancy risk assessment and reduced the need for diagnostic surgeries.

Objective: To independently evaluate the real-world clinical utility and the diagnostic performance of a microRNA-based molecular test (mir-THYpe full) in improving diagnostic accuracy and avoiding unnecessary surgeries in indeterminate thyroid nodules.

Methods: This is the first external, independent, prospective, real-world, observational, and non-interventional validation study of this molecular classifier. A total of 256 patients with nodules classified as Bethesda III/IV were analyzed.

Results: The test was positive for malignancy in 90 patients, 79 (90%) of whom underwent surgery. Of the 158 test-negative nodules, 7 (4.4%) underwent thyroidectomy. The test demonstrated a sensitivity of 83.0%, a specificity of 83.5%, a positive predictive value of 62.8%, and a negative predictive value of 93.6%.

Conclusions: The mir-THYpe full molecular test supported 95.5% of clinical decisions when negative and 89.8% when positive, reducing surgery rates by 79.5%. Therefore, the integration of this microRNA-based classifier into clinical practice represents a valuable tool in managing indeterminate thyroid nodules, reducing unnecessary thyroidectomies, and conserving valuable healthcare resources.

Objective: To compare the diagnostic test accuracy of Afirma GSC and ThyroSeq v3 in cytologically indeterminate thyroid nodules.

Methods: PubMed, Embase, Cochrane Library, Medline, and the Web of Science were searched from the date of inception to May 9, 2025. Two independent reviewers screened articles for eligibility. Studies assessing Afirma gene sequencing classifier (GSC) or ThyroSeq v3 for indeterminate thyroid nodules were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis reporting guidelines were followed. Statistical analysis was performed using R.

Results: A total of 26 studies met the eligibility criteria. For surgically confirmed Afirma GSC results, the sensitivity, specificity, and negative predictive value (NPV) were 94, 42, and 96%, respectively. For unoperated negative cases, the values were 96, 86, and 99%. For ThyroSeq v3, the sensitivity, specificity, and NPV for surgically confirmed cases were 96, 40, and 93%, respectively, and for unoperated negative cases, they were 97, 83, and 99%.

Conclusion: Both molecular tests demonstrate high NPV but low specificity; neither is clearly superior. Future research should prioritise randomised controlled trials, long-term follow-up of unoperated nodules, and direct comparisons of molecular tests.

Objective: This study aims to analyze the genes that influence PTC progression and investigate the role of MAPK13 in PTC.

Methods: Differentially expressed genes (DEGs) in Gene Expression Omnibus (GEO): GSE3467, GSE3678, GSE33630, and GSE58545 were analyzed between PTC and normal thyroid tissues. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were performed on the DEGs using The Cancer Genome Atlas (TGCA) Program data. MAPK13 was subsequently identified as promoting progression in PTC. The association between MAPK13 expression and clinicopathological features was analyzed using data from public database and the collected cohort. The CCK-8 assay, EdU assay, wound healing assay, transwell assay, flow cytometry, GSEA enrichment analysis, and xenograft model were used to investigate the function of MAPK13 in PTC.

Results: Higher expression of MAPK13 was associated with poorer progression-free survival, higher tumor pathologic stage, extrathyroidal extension, lymph node metastasis, multifocal tumors, American Thyroid Association (ATA) stratification system level, and BRAF V600E mutation. Overexpression of MAPK13 significantly promoted cell proliferation, migration, and invasion, and inhibited apoptosis of PTC. Knockdown of MAPK13 significantly inhibited cell proliferation, migration, and invasion, and promoted apoptosis of PTC. Epithelial-mesenchymal transition (EMT) was significantly enriched in GSEA analysis. Higher MAPK13 expression was related to higher N-cadherin and lower E-cadherin expression. Knockdown of MAPK13 significantly prevented tumor growth in vivo.

Conclusion: MAPK13 promotes the malignant biological behavior of PTC cells and is associated with EMT. MAPK13 may be a potential biomarker for treatment.

Background: In 2021, the European Group on Graves' orbitopathy (EUGOGO) published clinical practice guidelines for the management of GO, and in 2022, the American and European Thyroid Associations published the ATA/ETA consensus statement on the same topic.

Aims: i) To highlight similarities and differences between the two documents, ii) to suggest possible amendments for future revisions.

Results and conclusions: The two documents show a high degree of concordance as to classification, assessment, and prevention, as well as treatment of mild GO, moderate-to-severe and inactive GO, and sight-threatening GO. The major disagreement regards treatment of moderate-to-severe and active GO. The EUGOGO guidelines, written when teprotumumab was not available outside the USA, indicate intravenous glucocorticoids (IVGC) (with/without mycophenolate) as the first-line treatment, whereas the ATA/ETA consensus statement indicates teprotumumab as the first-line treatment for virtually all phenotypes of moderate-to-severe and active GO, particularly when exophthalmos is predominant. However, also in the ATA/ETA consensus statement, IVGC are the preferred treatment when the goal is GO inactivation and resolution of inflammation, and among the preferred treatments (in combination with orbital radiotherapy) when the goals are inactivation and correction of eye dysmotility. Recent developments to be considered in future revisions of the guidelines/consensus statement include the possible use of biologicals (teprotumumab and tocilizumab) for dysthyroid optic neuropathy, treatment of longstanding inactive GO with teprotumumab, reconsideration of the cautious use of radioactive iodine in patients with moderate-to-severe and active GO concomitantly treated with IVGC (with/without orbital radiotherapy), and use of statins as an adjunct therapy.

Autoimmune hypothyroidism occurs rarely before 3 years of age. Two siblings were diagnosed with autoimmune hypothyroidism at age 5 and 16 months, presenting with classic symptoms of hypothyroidism, abnormal thyroid function tests (TSH: 200 and 660 mU/L; reference range (RR): 0.73-8.4 mU/L; Free T4: 5.9 and <1.3 pmol/L; RR: 11.9-25.6 pmol/L), and high thyroid peroxidase antibody levels. Thyroxine medication alleviated their symptoms. Apart from mild infections, the siblings exhibited no other major disorders. Whole exome sequencing identified a pathogenic STAT3 gain-of-function variant, most commonly associated with infantile-onset multi-organ autoimmune disorder. Genetic testing for early-onset hypothyroidism may reveal specific etiologies, impacting follow-up and treatment.