Thyroid最新文献

Background: Decreased expression of thyroid peroxidase (TPO) is frequently observed in thyroid cancer, but the underlying regulatory mechanism remains largely unknown. This study aimed to elucidate the epigenetic basis of TPO silencing and assess its potential value for the diagnosis of thyroid cancer.

Methods: DNA methylation and expression levels of TPO were analyzed using the Infinium HumanMethylation450 array and transcriptome data from The Cancer Genome Atlas thyroid cancer dataset and validated in clinical tissue samples by bisulfite sequencing polymerase chain reaction (PCR) and quantitative PCR (qPCR). Thyroid cancer cell lines MDA-T41, KTC-1, CAL62, and TTA1 were treated with the demethylating drug decitabine and subjected to DNA methylation and mRNA expression analyses. Potential regulatory proteins were identified through DNA pull-down coupled with LC-MS/MS and validated by chromatin immunoprecipitation, luciferase reporter assay, and qPCR. A pyrosequencing assay was designed to quantify the methylation level of TPO.

Results: TPO expression was markedly downregulated in thyroid cancer and showed a strong inverse correlation with DNA methylation level at TPO differentially methylated region (DMR). Treatment of thyroid cancer cells with decitabine induced significantly decreased methylation level of TPO DMR and increased expression of TPO. Mechanistic analyses demonstrated that DNA hypermethylation suppressed TPO expression by recruiting methyl-CpG binding domain protein 2 (MBD2). Moreover, a pyrosequencing-based method for quantifying TPO methylation level was developed, and a remarkable difference between malignant and benign thyroid nodules (BTNs) was observed. Two CpG sites within TPO DMR achieved diagnostic performance with areas under the receiver operating characteristic curves of 0.927 (95% confidence interval [CI]: 0.864-0.989) and 0.916 (95% CI: 0.846-0.987), respectively.

Conclusions: DNA hypermethylation suppresses TPO transcription by recruiting MBD2 in thyroid cancer. Quantitative assessment of TPO methylation by pyrosequencing offers a promising molecular diagnostic approach to distinguish malignant cancer from BTN. Further studies are warranted to ascertain the clinical diagnostic utility of these findings.

Background: Approximately 80% of post-thyroidectomy patients suffer from swallowing disorders even in the absence of definite laryngeal nerve injury. This study aimed to evaluate the efficacy of a standardized postoperative neck and orofacial rehabilitation exercise in enhancing quality of life (QoL), particular swallowing-related QoL, among post-thyroidectomy patients without definite laryngeal nerve injury during surgery.

Methods: This was a single-center, open-label randomized controlled trial. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2500097960). Participants were randomized 1:1 to rehabilitation exercise group (RE group) and control group. The RE group performed a standardized postoperative neck and orofacial rehabilitation exercise, which included neck extension, swallowing, and voice training, while the control group received only general advice to move their necks freely. The rehabilitation exercise program duration is 3 months. The QoL of participants was evaluated at 1 week, 1 month, 3 months, and 6 months postoperatively. The primary outcome was swallowing-related QoL evaluated by the MD Anderson Dysphagia Inventory (MDADI) at 1 month after surgery. Secondary outcomes included swallowing-related QoL at other follow-up time points, the thyroid cancer-specific QoL, scar assessment, and safety endpoints defined by postoperative drainage, pain scores, and adverse events.

Results: A total of 374 patients were recruited, and 356 participants were included in final analysis, including 176 in RE group and 180 in control group. The swallowing-related QoL in the RE group was significantly better than that in the control group at 1 month (MDADI total score 97.4 [80.3, 100] vs. 88.9 [75.8, 99.7], p = 0.004) and 6 months (MDADI total score 100 [96.8, 100] vs. 98.9 [85.5, 100], p = 0.020) postoperatively. The RE group reported higher pain levels at 1 week after surgery (p = 0.013) but no significant differences at subsequent time points. No statistically significant differences between groups were observed in other outcomes. No severe adverse event occurred during rehabilitation exercise.

Conclusions: The standardized postoperative neck and orofacial rehabilitation exercise was an effective and safe approach for accelerating the recovery of the swallowing-related QoL in post-thyroidectomy patients without definite laryngeal nerve injury during surgery.

Background: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with a 10-year mortality rate up to 50%. Current therapies for metastatic MTC comprise various tyrosine-kinase inhibitors, but resistance often appears due to the need for lifelong treatments. Like in other tumors, genetic, epigenetic, post-transcriptional, post-translational, and cell-cell interaction events influence drug response. However, progress in understanding MTC biology is limited by the lack of reliable in vivo and in vitro models. This study aims to develop a patient-derived model faithfully reproducing the microenvironmental alterations present in MTC.

Methods: We applied a two-step protocol consisting of a first phase in which primary cells are cultivated as multicellular spheroids and a second phase in which they are switched to adherent cultures. After evaluation of the genetic background by targeted Next Generation Sequencing, we characterized our cells phenotype by examining a panel of stem/progenitor-related markers, the secretory abilities by ELISAs, the drug response by proliferation assays, the in vivo angiogenic and invasiveness by the use of zebrafish model, the in vitro invasivity by Matrigel Dome assays and the spatial variation of stem/progenitor marker in both 3D cell models and tissue samples by confocal microscopy.

Results: Our model allowed the establishment of eight MTC patient-derived cell lines with different genetic backgrounds. The cultures faithfully reproduced the changes in stem and progenitor markers that we detected in our cohort of MTC tissue samples and could be successfully xenotransplanted in zebrafish model, showing both angiogenetic and invasive properties. Drug screening assays revealed the potential of our model for the study of patient-specific responses, as we were able to identify different candidate regulators of the sensitivity to currently available therapies for MTC.

Conclusions: Our two-step protocol successfully generated primary MTC lines that maintain high plasticity, can be cultivated for several passages, and recreate the heterogeneity observed in patients' tissues. Our model will offer a robust platform for preclinical drug testing and mechanistic studies, addressing a longstanding gap in MTC research. It enables exploration of tumor microenvironment interactions and personalized therapeutic responses, supporting progress beyond current genomic-driven frameworks.

Background: Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive malignancy. Dabrafenib plus trametinib has shown efficacy in BRAF^V600E-mutant ATC, but effective therapies remain limited for patients without this mutation. This study aimed to evaluate the efficacy and safety of anlotinib plus sintilimab in BRAF^V600E-negative ATC.

Methods: In this phase 2 trial, patients with BRAF^V600E-negative unresectable or metastatic ATC received anlotinib (12 mg orally once daily on days 1-14 of a 21-day cycle) plus sintilimab (200 mg intravenously on day 1). The primary endpoint was investigator-assessed objective response rate (ORR). This study is registered at www.chictr.org.cn, ChiCTR2200067045.

Results: From December 27, 2022, to June 11, 2025, 21 patients were enrolled. One (4.8%) patient achieved complete response, and nine (42.9%) patients achieved partial response. The ORR and disease control rate were 47.6% (10/21) and 85.7% (18/21), respectively. After median follow-up of 9.97 months (confidence interval [CI] 6.10 to NA), 61.9% (13/21) of patients had discontinued treatment, mainly due to disease progression (7/21, 33.3%), adverse events (AEs) (2/21, 9.5%), and other reasons (4/21, 19.0%). Median progression-free survival (PFS) was 9.63 months (CI 4.03 to NA), with eight (38.1%) patients were still on treatment. Subgroup analysis showed longer PFS in patients with neutrophil-lymphocyte ratio <3.06 (18.43 vs. 3.67 months; p = 0.010) and <5 (14.23 vs. 2.67 months; p = 0.002). Median overall survival was not reached (CI 13.90 to NA), 15 (71.4%) patients remained alive. AEs occurred in 66.7% (14/21) of patients, including grade 3 AEs in 19.0% (4/21). The most common were aspartate aminotransferase (AST) increased (6/21, 28.6%) and alanine aminotransferase (ALT) increased (5/21, 23.8%). Grade 3 immune-related AEs occurred in three patients, including AST/ALT increased, diarrhea, hypertension, and hypertriglyceridemia.

Conclusions: Anlotinib plus sintilimab showed favorable efficacy and manageable safety in BRAF^V600E-negative unresectable or metastatic ATC, supporting further investigation.

Background: Chronic hypoparathyroidism (hypoPT) is associated with various systemic morbidities; however, its impact in thyroid cancer patients following thyroidectomy remains unclear. This study evaluated the risk of long-term morbidities in thyroid cancer patients who developed permanent postoperative hypoparathyroidism (PO-hypoPT), compared to those with preserved parathyroid function.

Methods: This was a retrospective cohort study using South Korea's nationwide claims data encoded in the Observational Medical Outcomes Partnership Common Data Model. Among 217,156 thyroid cancer patients who underwent thyroidectomy from 2013 to 2020, 15,592 patients with PO-hypoPT and 27,906 matched controls with preserved parathyroid function were identified after 1:2 propensity score (PS) matching. Long-term morbidities associated with hypoPT included nephrolithiasis, renal insufficiency, major adverse cardiac events (MACE), seizures, infections, cataracts, and depression. Hazard ratios (HRs) for these morbidities were estimated using Cox proportional hazards regression analysis after large-scale PS matching.

Results: The median follow-up duration in both groups was approximately 5 years. Patients with PO-hypoPT had a significantly higher risk of nephrolithiasis (HR 1.17, confidence interval [CI] 1.04-1.30), renal insufficiency (HR 1.75, [CI 1.50-2.03]), and MACE (HR 1.10, [CI 1.01-1.19]) compared to those with preserved parathyroid function. However, the risks of other long-term morbidities, including seizures, infections, cataracts, and depression, were not significantly different between the two groups. The association between PO-hypoPT and renal insufficiency remained consistent across all subgroups stratified by sex, age, and duration of calcium supplementation.

Conclusions: PO-hypoPT in thyroid cancer patients is associated with increased long-term morbidity, particularly renal and cardiovascular complications. Long-term monitoring of renal function and cardiovascular health is warranted in this population.

Background: Thyroid cancer survivors experience distinctive, persistent burdens that diminish health-related quality of life (HRQoL). Utilities from patient preference-based measures are needed for quality-adjusted life-year estimation and decision-making. Generic instruments lack thyroid-specific content, limiting applicability in this population. We sought to develop a thyroid-cancer-specific utility measure, Thyroid Cancer Quality of Life Index (TCQOLI) to support clinical research, cost-effectiveness analyses, and policy applications.

Methods: We conducted a multicenter, multiphase, mixed-method, cross-sectional study. Phase 1 defined the TCQOLI domains and items using input from multidisciplinary experts and patients with thyroid cancer. Phase 2 evaluated the instrument via cognitive interviews (n = 50) and a mailed/phone-assisted psychometric survey in adults with thyroid cancer (n = 163), followed by confirmatory factor analysis (CFA) and reliability/validity analyses. Phase 3 valued health states in a separate sample (n = 103) using interviewer-administered visual analog scales (VAS; 0-100) and standard gamble (SG). Levels of morbidity in each health domain with VAS and SG were used for assessing preferences for three clinical marker states. We derived a weighted dead-to-full-health lower VAS anchor, estimated a VAS to SG power mapping solution to apply to the model overall, and constructed additive, multiplicative, and unweighted indices. Agreement of the indices with direct VAS was summarized by Pearson r, mean absolute error (MAE), overall standard deviation (OSD) of differences, and intraclass correlation (ICC).

Results: Ten candidate domains were finalized; because one domain, reproduction concern, had the weakest psychometrics and the lowest model weight, the primary instrument uses nine domains (a 10-domain version was also evaluated). CFA supported a general HRQoL factor plus a voice/swallow factor with acceptable composite reliability and model fit. The instrument-level ceiling effect was low (3.8%) with no floor effect. The 9-domain additive multiattribute utility theory index correlated with direct VAS (r ≈ 0.74-0.75) and showed the best agreement. MAE/OSD was 0.045/0.095 after SG mapping and a good to excellent ICC of 0.74.

Conclusions: TCQOLI is a psychometrically robust, thyroid-cancer-specific, preference-based measure with patient-anchored valuation, suitable for health-economic evaluations. This concise index supports comparative-effectiveness research in thyroid cancer and informs resource allocation across clinical and policy settings.

Background: Neonatal fragment crystallizable receptor (FcRn) blockers selectively inhibit FcRn-mediated IgG recycling, resulting in degradation of IgG autoantibodies, including thyrotropin receptor autoantibodies (TSH-R-Ab).

Methods: We describe a case involving a 55-year-old woman with a 17-month history of Graves' disease (GD) who was hyperthyroid despite 15 months on methimazole (MMI) 15-25 mg/day. She received the investigational FcRn blocker batoclimab in a clinical study and was subsequently followed in clinic.

Results: Within 1 week of starting weekly subcutaneous batoclimab, serum free triiodothyronine (FT3) and thyroxine (FT4) were normalized. Thyrotropin (TSH) was normal within 4 weeks. MMI was discontinued by study week 6. Twenty-three months after stopping batoclimab, the patient remained off MMI, with normal FT3, FT4, and TSH. Total IgG returned to approximate baseline levels 18 months post discontinuation of batoclimab, whereas TSH-R-Ab, which was elevated at baseline, remained below the upper limit of normal 23 months post batoclimab discontinuation.

Conclusions: FcRn blockade may be an effective and potentially disease-modifying treatment for GD.

Background: The coexistence of BRAF^V600E and telomerase reverse transcriptase (TERT) promoter alterations has been reported to cooperatively upregulate TERT expression and is well recognized as a biomarker for aggressive thyroid cancer. However, the mechanism underlying their synergistic effect remains elusive.

Methods: TERT-interacting proteins were identified via immunoprecipitation (IP) and mass spectrometry and validated by Co-IP. DDX21 expression was detected in 60 paired thyroid cancer and adjacent normal tissues, and the function of DDX21 in thyroid cancer was explored in vitro and in vivo. Integrated analyses of RNA-seq, ChIP-seq, and Ribo-seq assays were conducted to elucidate the molecular mechanisms. BRAF/MEK inhibitors and BRAF^V600E overexpression were used to investigate the regulation of DDX21 by BRAF mutation. In silico analysis, ChIP, and luciferase reporter assays were used to identify the transcription factors binding to DDX21 promoter.

Results: DDX21 interacted with TERT to regulate ribosomal RNA (rRNA) transcription by affecting the binding of Pol I to rDNA. DDX21 is upregulated in thyroid cancer, and DDX21 knockdown decreased the expression of multiple cancer hallmark genes and suppressed cell proliferation, colony formation, cell migration, and invasion of thyroid cancer cells. GABPA bound to the promoter of DDX21, and knockdown of GABPA or GABPB1 suppressed DDX21 promoter activity and transcription. Pharmacological inhibition of the MAPK pathway in BRAF-mutant cancer cells decreased the expression of GABPA, GABPB1, and DDX21.

Conclusions: BRAF^V600E upregulates expression of DDX21 through the MEK/ERK/GABP axis. DDX21, in turn, interacts with TERT to promote rRNA transcription and modulate the expression of multiple cancer hallmark genes, driving the malignant progression of thyroid cancer. These findings suggest that DDX21 acts as a mediator to bridge the crosstalk between BRAF^V600E and TERT and may serve as a therapeutic target for patients with thyroid cancer harboring BRAF and TERT alterations.

Background: Preparation for radioiodine (RAI) therapy in differentiated thyroid cancer (DTC) often requires thyroid hormone withdrawal (THW) to achieve thyrotropin (TSH) stimulation. Current guidelines recommend TSH ≥30 mIU/L, a target that prolongs hypothyroidism and worsens quality of life, yet rests on limited evidence.

Objective: To evaluate the association between pre-RAI TSH levels and oncologic outcomes in adults with DTC prepared by THW.

Methods: We conducted a systematic review and meta-analysis of studies comparing outcomes across pre-RAI TSH thresholds (<30 vs. ≥30, <60 vs. ≥60, and <90 vs. ≥90 mIU/L) in adults with DTC prepared by THW. Primary outcomes included disease-specific mortality, recurrence, and response to therapy. Searches in MEDLINE, Embase, Cochrane, and Scopus (inception to March 2025) identified eligible studies. Risk of bias was assessed using the CLARITY tool and certainty of evidence using GRADE. Pooled relative risks (RRs) were calculated using random-effects models. This systematic review was registered in PROSPERO (CRD42020158354).

Results: This meta-analysis included eight retrospective cohort studies comprising a total of 4651 DTC patients, predominantly women (68.5%) with a mean age of 46 years. All patients underwent THW before RAI. Across all TSH thresholds examined (<30, <60, and <90 mIU/L), higher pre-RAI TSH levels were not associated with better treatment response, lower recurrence, or reduced mortality. Specifically, patients with higher pre-RAI TSH levels (≥30 mIU/L) did not have better oncologic outcomes compared with those with lower levels (<30 mIU/L). At 2- and 3-year follow-up, no significant differences were observed in excellent (pooled RR = 0.87; confidence interval [CI] 0.68-1.11) or indeterminate (RR = 1.28; CI 0.72-2.27) response rates. Similarly, recurrence rates did not differ (RR = 1.45; CI 0.83-2.55), and no study demonstrated a difference in disease-specific mortality across follow-up periods extending up to 10 years. The certainty of evidence for all outcomes was rated very low due to risk of bias, heterogeneity, and imprecision.

Conclusions: The current evidence base is insufficient to support or refute the routine use of a specific TSH threshold before RAI administration. These findings question the recommendation to achieve TSH ≥30 mIU/L before RAI and highlight the need for trials to define the minimal effective level of TSH stimulation.