European Thyroid Journal最新文献

Cryo-EM studies indicate that full-length human TSH receptor (TSHR) is a monomer consisting of a leucine-rich repeat (LRR) domain (LRD), hinge region (HR) and transmembrane domain (TMD). Receptor autoantibodies (TRAb) bind to the extracellular domain (LRD plus HR). In the cell membrane, TSHR transitions between inactive and active states, involving rotation of the LRD about the HR, with the active state LRD further from the membrane. Cryo-EM structures of the TSHR in complex with different human monoclonal autoantibodies provide a detailed understanding of how they interact with the receptor. Stimulating monoclonal autoantibody M22™ binds to the entire LRD (LRR 1-11) concave surface and cannot interact with the inactive state receptor, as this would result in a clash between antibody and membrane. No clash occurs when M22™ binds the active state, and once bound, M22™ holds the receptor in the active state, resulting in prolonged activation. K1-18™, a different stimulating monoclonal autoantibody, interacts with LRR 1-11 in a similar way to M22™. Blocking type monoclonal autoantibody K1-70™ only interacts with LRR 1-7, positioning itself clear of the cell membrane when interacting with inactive or active receptor states. Once bound, binding of TSH and other TRAb is prevented. Monoclonal autoantibody 5C9™ interacts differently, binding the inactive conformation from LRR 3 to the HR. Its heavy chain CDR3 interacts with the HR, locking the receptor in the inactive state, causing inhibition of constitutive activity, activating mutation activity and blocking receptor binding by TSH and TRAb. Elucidation of the structure of the TSHR and mechanisms of its activation and inactivation by TRAb is of great importance for the development of new TSHR-specific drugs.

Background: Previous studies showed that dynamic risk stratification (DRS) was also useful in differentiated thyroid carcinoma patients with lobectomy or total thyroidectomy without radioactive iodine. The aim of this study was to evaluate the DRS system in patients with follicular thyroid carcinoma (FTC) who underwent lobectomy alone.

Methods: In total, 161 patients with FTC who were diagnosed between January 2005 and December 2014 and underwent lobectomy alone were included in this study.

Results: Of the 161 patients with FTC, the DRS system classified 159 patients (99%) as having an excellent response, and 2 (1%) as having a structural-incomplete response. The 10-year disease-free survival (DFS) rates of patients with excellent response and structural-incomplete response were 93.5% and 0%, respectively (P < 0.001). Of the 54 patients with VI ≥ 2, the 10-year DFS rates of patients with excellent response (n = 53) and structural-incomplete response (n = 1) were 83.2% and 0%, respectively (P < 0.001). Of the 53 patients with excellent response, 10 patients experienced disease recurrence. Among Of these ten patients, the duration between initial thyroid surgery and recurrence was 2-5 years in one, 5-8 years in two, 8-10 years in four, and 10 years or more in three patients, respectively.

Conclusion: Long-term follow-up may be needed in FTC patients treated with lobectomy alone even though they had an excellent response to initial thyroid surgery, especially in patients with a higher risk of recurrence.

Background: Patients with resistance to thyroid hormone β (RTHβ) show elevated thyroid hormone concentrations with non-suppressed thyroid-stimulating hormone (TSH) concentrations and large phenotypic variability. Triac therapy has been successfully applied in some patients. Mosaic mutations causing mild RTHβ have been reported three times so far.

Patient: We present a case of severe RTHβ caused by a mosaic frameshift mutation in the thyroid hormone receptor β (p.R438Lfs445X). Methimazole and Triac combination therapy was commenced at the age of 8 years, resulting in a substantial decrease in free T4 concentrations and an increase in TSH concentrations (follow-up duration of >18 months). His extreme agitation, motor restlessness, weight, and some motor and communication skills improved. The mutation was fully unresponsive to stimulation with T3 in in vitro and ex vivo analyses.

Conclusion: The p.R438Lfs445X mutation leads to a severe phenotype of RTHβ. Mosaicism might underlie a subset of patients with the clinical phenotype of RTHβ. Combined methimazole/Triac therapy had beneficial effects on several thyrotoxic features.

Objective: Thyroid hormones (TH) are well-known regulators of the immune system. However, the precise immunomodulatory mechanisms of TH action in immune cells remain elusive. In a previous study, an essential role of the TH receptor α (TRα) in regulatory T cell (Treg) immunity was demonstrated, affecting Treg activation at steady state. The present study therefore aimed to unravel the biological relevance of altered TRα action in protective immune responses during disease.

Methods: To assess the role of TRα action in immune responses, especially T cell responses, during disease, different TRα signaling mouse models (TRαKO, complete lack of TRα signaling; TRαGS, lack of canonical signaling) were challenged with influenza virus A/PR8/34, and in-depth immune phenotyping was performed.

Results: Upon influenza virus infection, TRαGS mice, which lack canonical TRα signaling, showed prolonged survival and reduced disease severity, correlating with enhanced anti-inflammatory Treg and decreased pro-inflammatory CD4 and CD8 T cell responses. The loss of TRα action in TRαKO mice was related to elevated viral titers upon influenza virus infection, which correlated with increased inflammatory monocyte responses early during infection.

Conclusion: The present study demonstrates a complex role of TRα signaling in protective immune responses during disease, with distinct effects on innate and adaptive immune cells. By exploring the understudied link between the endocrine and immune systems, this study provides novel evidence for the role of TH as modulators of immunity.

Background: Subclinical hyperthyroidism (SHT), a low serum thyroid-stimulating hormone (TSH) and normal free thyroxine (FT4) concentration, has potential health implications yet the epidemiology and factors influencing its natural course in a primary care setting remain unclear.

Objectives: To investigate the incidence and natural course of SHT in primary care and assess guideline adherence to follow-up recommendations within Dutch primary care.

Methods: Using a retrospective cohort design, in General Practitioner (GP) data from the PHARMO Data Network in the Netherlands (2012 to 2021). Patients with biochemically confirmed SHT were followed to assess progression to hyperthyroidism, recovery, or persistence. Adherence to the Dutch primary care SHT guideline was evaluated.

Results: The SHT annual incidence was approximately 200 per 100,000 person-years. Among the 11,163 SHT patients, 47% recovered, 11% persisted, and 8% progressed to overt hyperthyroidism over a median follow-up of five years. Lower TSH (<0.1 mU/L) and female sex were associated with lower odds of recovery (OR for TSH <0.1 mU/L: 0.50, 95%CI: 0.43-0.58; OR for women: 0.82, 95%CI: 0.70-0.96) and higher odds of progression to overt hyperthyroidism (OR for TSH <0.1 mU/L: 2.36, 95%CI: 1.97-2.83; OR for women: 1.69, 95%CI: 1.32-2.17). Guideline adherence evaluation showed that 33% received follow-up TSH measurement within six months, and 4% underwent TSH-receptor antibody testing.

Conclusion: This study highlights that a small subset of SHT patients progress to overt hyperthyroidism. Factors increasing the odds for progression included lower baseline TSH and female sex. Our findings indicate a need for improved guideline adherence.

Background: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are both rare and aggressive thyroid cancers. Advances in targeted therapy and immunotherapy have changed treatment strategies and improved prognosis in these patients.

Methods: This single-center cohort study included patients diagnosed with locally advanced or metastatic PDTC/ATC at Fudan University Shanghai Cancer Center (FUSCC) between 2019 and 2023. Patients were either enrolled in clinical trials or received treatment based on clinical guidelines and expert consensus. Gene testing was conducted using next-generation sequencing of clinical samples.

Results: 95 patients were analyzed (PDTC = 34, ATC = 61). Median overall survival (OS) was 19.7 months for PDTC and 9.5 months for ATC (P = 0.478). Among 82 patients who underwent gene testing, the most frequent gene alterations in PDTC were BRAF (50.0%), TERT promoter (39.3%), and TP53 (25.0%) mutations; in ATC, they were TERT promoter (55.6%), BRAF (42.6%), and TP53 (25.9%) mutations. Compared with ATC patients, PDTC patients were more likely to receive best supportive care and less likely to be enrolled in clinical trials or treated with PD-1 inhibitors. The 1-year OS rates for PDTC/ATC patients receiving neoadjuvant therapy + surgery, systemic treatment, and supportive care only were 83.3, 51.2, and 5.7%, respectively (P < 0.001). After adjusting for covariates, neoadjuvant therapy + surgery (hazard ratio = 0.216, 95% confidence interval: 0.647-0.718, P = 0.012) was an independent predictor of superior OS.

Conclusion: Despite the generally poor prognosis, aggressive treatment, particularly neoadjuvant therapy, has been shown to improve survival. Personalized treatment is crucial for optimizing treatment strategies for PDTC/ATC.

This review examines the emerging roles of DICER1 and DGCR8, key components of the miRNA biogenesis pathway, in thyroid pathogenesis, with a particular focus on their association with oncocytic morphology. Recent findings have expanded our understanding of DICER1 syndrome and DGCR8-related thyroid disorders, revealing a broader spectrum of thyroid lesions associated with mutations in these genes than previously recognised. We analyse the current literature on DICER1 and DGCR8 mutations in thyroid pathology, synthesising data from both basic science and pathological studies. The review explores recent findings on oncocytic features in some DICER1-mutated thyroid lesions, acknowledging that this association remains under investigation. The manuscript details the molecular mechanisms underlying DICER1 and DGCR8 mutations, including their impact on miRNA processing and subsequent effects on gene expression and cellular function. We discuss the diverse range of thyroid lesions associated with these mutations, from benign follicular nodular disease to aggressive carcinomas. The clinical implications of these findings are significant, as recognising DICER1 and DGCR8-related thyroid lesions can lead to improved patient management, including genetic counselling and surveillance for other associated malignancies. We propose an algorithm for identifying DICER1-related thyroid lesions, with a focus on oncocytic tumours, to aid clinicians and pathologists in recognising these entities. This emerging field promises to refine the diagnosis, management, and treatment of thyroid disorders associated with miRNA biogenesis pathway alterations, potentially leading to novel diagnostic and therapeutic approaches.

Introduction: Signal transducer and activator of transcription 3 (STAT3) is a signaling molecule that functions downstream of various cytokine and growth factor receptor signaling pathways to regulate cell growth, survival, and differentiation. Constitutive activation of STAT3 is relevant to cancer development and progression in many types of malignancies. In this study, the relationship between STAT3 activation and the prognosis of papillary thyroid carcinoma (PTC) was retrospectively examined using immunohistochemical staining with an anti-STAT3 antibody.

Materials and methods: A total of 1,132 PTC cases with M0 diagnosed between 1993 and 2012 were included. The H-score (0-300 points) was used to evaluate nuclear staining of STAT3 (n-STAT3), which reflects the activated form of STAT3. The relationship between the n-STAT3 score and recurrence-free survival (RFS) was examined.

Results: The median n-STAT3 score was 105. RFS was compared between the two groups using the Kaplan-Meier method at a cutoff of 70 points (AUC = 0.60), calculated from the ROC curve based on recurrence. Ten-year and 20-year RFS were 87.5 and 83.1% in the high n-STAT3 group (n = 764) and 77.7 and 72.6% in the low n-STAT3 group (n = 371), respectively. The high n-STAT3 group had a significantly better RFS (P < 0.0001). Age (≥55 years), tumor size (≥4 cm), extrathyroidal extension, larger maximum lymph node size (≥30 mm), and low n-STAT3 levels were associated with poor RFS on univariate and multivariate analyses.

Conclusion: n-STAT3 scores in cases with PTC were associated with favorable prognosis. Further studies are required to elucidate the mechanism.