Thyroid最新文献

Background: Mice lacking the thyroid hormone (TH) transporters monocarboxylate transporter 8 (Mct8) and organic anion transporter 1c1 (Oatp1c1) exhibit a strongly perturbed brain maturation, thereby replicating symptoms of patients with MCT8 deficiency. Mct8/Oatp1c1 double knockout (DKO) mice show a strongly diminished TH brain content, indicating a compromised TH passage across blood-brain barrier (BBB) endothelial cells that may represent a major pathogenic event causing CNS abnormalities. Here, we tested this hypothesis by generating mice that lack Mct8 and Oatp1c1 in endothelial cells only. Methods: Adult conditional Mct8/Oatp1c1 mice expressing a constitutively active Tek-driven Cre recombinase (Endo del mice) and control littermates were characterized regarding their hypothalamus-pituitary-thyroid axis, brain morphology as well as peripheral and central TH signaling. For comparison, age-matched DKO mice were included. Immunofluorescence (IF) studies were conducted to examine neural maturation. Fluorescence in situ hybridization (FISH) experiments and qPCR analysis were performed to determine transcript levels of TH-regulated genes in different brain regions. TH tissue content in dissected brain areas was quantified by LC-MS/MS analysis. Results: Analysis of different brain parameters by IF staining revealed a compromised maturation of cortical GABAergic interneurons and hypomyelination in Endo del mice, although the observed alterations were less profound than in DKO mice. TH content determination, FISH, and qPCR studies disclosed significantly reduced TH concentrations and, consequently, decreased TH signaling in several brain areas. Surprisingly, hippocampal T3 content and transcript levels of TH-regulated genes were found to be only mildly altered in Endo del mice compared with DKO animals. Conclusions: Deficiency of Mct8 and Oatp1c1 in endothelial cells results in reduced murine brain TH content and TH action, thereby underscoring the major function of BBB endothelial Mct8/Oatp1c1 in facilitating TH uptake into the CNS. Yet, the degree of central TH deficiency and neural impairments in Endo del mice are not as profound as in DKO mice. Particularly, unaltered hippocampal T3 signaling suggests a sufficient T3 supply of this brain area, possibly via the cerebrospinal fluid (CSF). These findings infer that apart from the BBB, additional Mct8/Oatp1c1-facilitated TH transmembrane passages (for instance, TH transport across the blood-CSF barrier) are required for proper mouse brain development and function.

Background: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the endocrine system. BRAF mutations occur in 40-60%, panRAS mutations in 10-15%, and different gene fusion events such as RET fusions in 7-35% of these neoplasms. Artificial intelligence (AI) methods could be used to predict genetic changes from conventional histopathological slides. Methods: In this retrospective study, we used two independent cohorts of patients with PTC, totaling 662 cases for the establishment of our AI pipeline. The Cancer Genome Atlas cohort (496 cases) served as the developmental cohort, while the Mainz cohort (166 cases) served as an independent external test cohort. BRAF, panRAS, and fusion status was determined for all of these patients as target variables. Vision Transformer was trained on digitized annotated hematoxylin and eosin-stained slides for the presence of these alterations. Highest probability image tiles were used to identify new morphological criteria associated with the genetic changes. Results: The trained model resulted in an area under the receiver operating characteristic curve of 0.882 (confidence interval 0.829-0.931) for BRAF, 0.876 (0.822-0.927) for panRAS, and 0.858 (0.801-0.912) for gene fusions. Accuracy was 79.3% (72.7-85.8%) for BRAF, 89.3% (84.2-94.0%) for panRAS, and 84.7% (78.8-90.2%) for gene fusions. The performance on the validation set was almost identical to that on the test set. Analyzing the highest predictive tiles, novel morphological criteria for fusion-associated PTC could be discovered. Conclusions: Our study demonstrates that predicting genetic alterations in digitized histopathological slides using AI is feasible in patients with PTC. Our model showed high accuracy in predicting these changes, making it potentially suitable for pre-screening. Explainability approaches uncovered previously undescribed morphological patterns associated with certain genotypes. Providing pathologists with these AI-based features could improve their accuracy. Assuming further positive prospective validation, this discovery could contribute to a deeper understanding of PTC.

Background: Thyroid cancer is the most common endocrine malignancy, with papillary thyroid cancer (PTC) accounting for ∼80% of all cases. DNA methylation alterations and gene expression changes in cancer, offer valuable insights into tumor biology and serve as potential clinical biomarkers. However, the functional implications of DNA methylation changes in PTC patients, particularly based on multiomics analysis in the Chinese population, remain insufficiently explored. This study aims to investigate the epigenetic signatures of thyroid cancer and identify the DNA methylation biomarkers for diagnosing PTC in Chinese patients. Methods: Thyroid cancer tissues (n = 40) and benign thyroid nodule tissues (n = 31) were collected from Chinese patients for global DNA methylation analysis. Gene expression profiles and H3K27ac modifications were also investigated to understand the impacts of epigenetic changes on gene expression. Genome-wide methylation profiling and machine learning methods were employed to differentiate PTC from control samples. Results: Genome-wide DNA methylation maps revealed significant methylome changes in Chinese PTC tissues. By integrating our data with The Cancer Genome Atlas thyroid cancer methylation profiles, we identified unique hypomethylation patterns associated with thyroid hormone synthesis specifically in Chinese PTC patients. RNA sequencing and H3K27ac modification analysis, along with functional assays, showed that the dysregulated genes in PTC patients are critical for the proliferation, migration, and invasion of thyroid cancer. Conclusions: Our study provides a comprehensive view of the multi-omics-based, function-guided DNA methylation landscape for Chinese PTC patients. We identified seven functional differentially methylated regions with high sensitivity and specificity for diagnosing thyroid cancer in Chinese patients. Additionally, DHRS3 is highlighted as a key player in PTC pathogenesis and shows promise as a valuable biomarker for predicting patient outcomes. This research advances our understanding of DNA methylation in thyroid cancer and underscores the importance of developing population-specific diagnostic tools to improve patient outcomes. However, further validation in larger, independent cohorts is needed to confirm their diagnostic value.

Background: Anaplastic thyroid cancer (ATC) has historically been almost uniformly fatal. In patients with the loco-regional disease (stage IVB), multimodal therapy (upfront surgery when feasible, radiation +/- concurrent chemotherapy) followed by observation is the current standard of care. Methods: Stage IVB ATC patients treated with multimodal therapy, followed by adjuvant pembrolizumab were studied. Data were combined from a prospective, phase 2 trial that closed early due to poor accrual, and a retrospective cohort of consecutive patients who received adjuvant pembrolizumab, mirroring the trial eligibility criteria. Patients received adjuvant pembrolizumab starting within 6 weeks after completion of radiation. An age and treatment-matched control arm treated with multimodal therapy without adjuvant pembrolizumab was selected for comparison. The primary objectives included median progression-free survival (PFS) and recurrence rate, and the secondary objective was median overall survival (OS). Results: Sixteen patients were included in each arm. The median age in both groups was 59 years. The median PDL1 score in the adjuvant pembrolizumab arm was 50% (range, 0-95%). The majority (88%) had upfront surgery in both groups. The median follow-up time was 24.3 months in the adjuvant arm and 56.7 months in the control arm. The median PFS in the adjuvant and control arm was not reached, and 5.4 months [CI: 2.04-16.20], respectively (p = 0.006; HR 0.24 [CI: 0.08, 0.73]). The median OS was not reached in the adjuvant pembrolizumab group. In the control group, the median OS was 31 months [CI: 13.9, NA] (p = 0.009; HR 0.11 [CI: 0.01, 0.83]). The 12-and 24-month survival rates were 80% [CI: 0.51-0.93] and 52% [CI: 0.25-0.74], respectively, in the control arm, whereas all patients in the adjuvant arm were still alive at 1- and 2-years. Conclusion: Adjuvant pembrolizumab appears to be a safe and effective strategy to prevent recurrences and prolong survival in stage IVB ATC patients following multimodal therapy. Confirmatory studies are needed.

Background: The management of indeterminate thyroid nodules (ITNs), classified as Bethesda III and IV, is challenging due to biopsy limitations in distinguishing benign from malignant nodules. While diagnostic lobectomy is the standard, thermal ablation (TA) is increasingly considered for patients ineligible or unwilling to undergo surgery. This systematic review and meta-analysis therefore evaluate the efficacy and safety of TA for ITNs. Methods: A comprehensive search of MEDLINE, EMBASE, and COCHRANE databases was conducted through May 11, 2025, for studies on ITNs treated with TA, with ≥12 months of follow-up and reported clinical or safety outcomes. Case reports, abstracts, and reviews were excluded. Two radiologists independently performed data extraction and quality assessment. Outcomes included volume reduction rate (VRR), regrowth, delayed surgeries, malignancy detection, and complications. The Risk of Bias for Nonrandomized Studies (RoBANS) tool was used for quality assessment. A random-effects model synthesized pooled estimates, with heterogeneity quantified by Higgins' I². Results: A total of 15 studies with 1149 nodules were analyzed, showing progressive VRR increase, plateauing at 48 months. The pooled 12-month VRR was 81.0% (confidence interval: 76.0-85.9%). Hydrodissection significantly improved VRR at 6 months (p = 0.03), while larger nodules were more prone to regrowth. Major complications occurred in 1.8% (21/1149), with no reported metastasis. Regrowth and delayed surgery occurred in 2.3% (26/1149) and 0.3% (4/1149), respectively, with three malignancies upon delayed surgery. Conclusions: TA may be considered a minimally invasive alternative for ITNs who are not candidates for or decline surgery, demonstrating favorable efficacy and safety. However, study limitations, short follow-up, and residual malignancy risk necessitate careful follow-up, particularly for larger nodules. Advanced TA techniques such as hydrodissection may enhance outcomes by increasing the likelihood of complete ablation. Long-term prospective studies and randomized trials are needed to confirm TA's role in clinical practice.

Purpose: Artificial intelligence (AI) models have shown promise in predicting malignant thyroid nodules in adults; however, research on deep learning (DL) for pediatric cases is limited. We evaluated the applicability of a DL-based model for assessing thyroid nodules in children. Methods: We retrospectively identified two pediatric cohorts (n = 128; mean age 15.5 ± 2.4 years; 103 girls) who had thyroid nodule ultrasonography (US) with histological confirmation at two institutions. The AI-Thyroid DL model, originally trained on adult data, was tested on pediatric nodules in three scenarios axial US images, longitudinal US images, and both. We conducted a subgroup analysis based on the two pediatric cohorts and age groups (≥14 years vs. < 14 years) and compared the model's performance with radiologist interpretations using the Thyroid Imaging Reporting and Data System (TIRADS). Results: Out of 156 nodules analyzed, 47 (30.1%) were malignant. AI-Thyroid demonstrated respective area under the receiver operating characteristic (AUROC), sensitivity, and specificity values of 0.913-0.929, 78.7-89.4%, and 79.8-91.7%, respectively. The AUROC values did not significantly differ across the image planes (all p > 0.05) and between the two pediatric cohorts (p = 0.804). No significant differences were observed between age groups in terms of sensitivity and specificity (all p > 0.05) while the AUROC values were higher for patients aged <14 years compared to those aged ≥14 years (all p < 0.01). AI-Thyroid yielded the highest AUROC values, followed by ACR-TIRADS and K-TIRADS (p = 0.016 and p < 0.001, respectively). Conclusion: AI-Thyroid demonstrated high performance in diagnosing pediatric thyroid cancer. Future research should focus on optimizing AI-Thyroid for pediatric use and exploring its role alongside tissue sampling in clinical practice.

Background: Familial non-medullary thyroid carcinoma (FNMTC) accounts for approximately 9% of differentiated thyroid cancer (DTC). There is conflicting data on the FNMTC aggressiveness compared with sporadic DTC (sDTC), leading to usually more extensive therapy applied for FNMTC, given its autosomal dominant genetic background. This study aimed to compare the progression-free survival (PFS) in patients with FNMTC and sDTC treated with standard therapy. Methods: This longitudinal retrospective cohort study included patients with FNMTC, defined as at least two first-degree relatives affected by DTC. FNMTC patients were matched with sDTC in a 1:3 ratio based on age, sex, American Thyroid Association recurrence risk stratification (ATA-R), extent of initial surgery, and diagnosis date. The primary outcome was PFS. Kaplan-Meier curves were used to compare PFS between the groups, and the Cox proportional hazards model was used to assess confounders. Results: From 95 affected FNMTC patients, 30 were excluded due to lack of follow-up data. The study population consisted of 65 FNMTC and 170 sDTC patients, with a median follow-up of 4.73 (2.87-10.27) years for FNMTC and 5.83 (2.33-10.79) years for sDTC (p = 0.76). There was 100% matching for ATA-R, sex, surgery type, and year of surgery and a satisfactory matching for age (43.12 ± 15.11 vs. 42.76 ± 12.46 years, p = 0.85). FNMTC exhibited a smaller tumor size (1.20 ± 0.96 vs. 1.89 ± 1.51 cm, p < 0.01) and fewer positive lymph nodes (range 0-13 vs. 0-38, p = 0.009) at presentation. The rate of repeated neck surgeries for persistent/recurrent disease was comparable between the groups: 13.8% (9/65) for FNMTC vs. 17.7% (30/170) for sDTC (p = 0.48). There was no difference in radioactive iodine (RAI) therapy dosage between the groups (104 [100-149] vs. 106 [76-160] mCi, p = 0.82). During follow-up, 15.4% of FNMTC and 18.2% of sDTC patients experienced disease progression (p = 0.61). PFS was non-different between groups (p = 0.56) and was associated with ATA-R (high vs. low hazard ratio [HR]: 9.2, confidence interval [CI]: 2.67-31.85, p < 0.001) and sex (male vs. female, HR: 2.5, CI: 1.11-5.6, p = 0.026). Conclusions: No difference in PFS between FNMTC and sDTC patients suggests comparable responsiveness to standard therapy. Therefore, the management of FNMTC should align with the standard of care for DTC to avoid overtreatment of FNMTC.

Background: Over the past several decades, there have been indications of potential shifts in the diagnostic strategies and treatment of patients with Graves' disease (GD) and thyroid eye disease (TED). The objective of this study was to evaluate current practices in managing GD when complicated by moderate-to-severe TED worldwide. Methods: We recently reported results from a global online survey of endocrinologists comparing the management of GD in different scenarios. The current analysis focuses on regional differences in the diagnosis and treatment of GD when complicated by TED. Results: A total of 1252 respondents from 85 countries completed the survey. Regarding the initial diagnostic and treatment measures, there were no differences among the various geographical regions. Regarding the treatment of moderate-to-severe TED, the use of sodium selenite was higher in Europe (66.5%) and Oceania (60%) compared to other regions (p < 0.001). North American respondents were more likely to recommend teprotumumab and less likely to use glucocorticoids (p < 0.001). When comparing the treatment options for GD in patients with TED, although prolonged use of antithyroid drugs (ATD) remained the first choice in all regions, respondents from Europe, North America, and Oceania were more likely to recommend thyroidectomy than those from other regions (p < 0.001). Ophthalmologists, rather than endocrinologists, would more often be responsible for prescribing advanced medical therapy for TED in North America, Oceania, and Africa, while endocrinologists would have primary responsibility in other regions of the globe. Conclusions: Although there are regional differences, respondents generally employ the recommended diagnostic tools, treatments, and a multidisciplinary approach suggested by current clinical practice guidelines. However, there were examples of deviations from current guidance from professional societies.