Thyroid最新文献

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: Iodine deficiency disorders (IDDs) remain a public health concern, especially in pregnancy, despite universal salt iodization (USI) programs. Iran has sustained iodine sufficiency since the 1990s through national USI, but recent evidence suggests recurrent iodine insufficiency among pregnant women. This study reports findings from the sixth National Monitoring Survey (2022-2023) to reassess iodine status in schoolchildren and pregnant women in Iran.

Methods: This cross-sectional survey included 11,221 schoolchildren aged 8-10 years and 2929 pregnant women from all 31 provinces. Multistage cluster sampling ensured national representativeness for children. At the same time, pregnant women were recruited from health centers by equal provincial quotas (60 per province, not population-weighted), and their individual intake of iodide along with folic acid supplements was documented. Urinary iodine concentration (UIC) was measured using the Sandell-Kolthoff method, and salt iodine content was assessed by iodometric titration at production and household levels. Data were analyzed with descriptive and nonparametric statistical methods.

Results: The median UIC in schoolchildren was 133 µg/L (interquartile range [IQR]: 88-183), within the World Health Organization (WHO)-recommended range, with 67.7% having UIC ≥100 µg/L. However, 22.8% had a UIC of 50-100 µg/L and 9.5% <50 µg/L. In pregnant women, the median UIC was 128 µg/L (IQR: 84-187), below the WHO threshold of 150 µg/L, with 61.2% having UIC <150 µg/L and 34.4% <100 µg/L. 73.7% of pregnant women used iodide + folic acid supplement, with wide provincial variation of 38-84%. Household salt median iodine content was 32 ppm, but 30.6% of samples were <20 ppm, and only 54% were stored properly. Production-level salt had a median iodine content of 33.8 ppm.

Conclusions: Although Iran has maintained iodine sufficiency in the general population during the last three decades, mild iodine deficiency has reappeared among pregnant women due to incomplete usage of iodide folic acid supplementation. Strengthened monitoring, stricter quality assurance in salt production, improved adherence to iodine supplementation in pregnant women, and targeted provincial interventions are needed to sustain IDD elimination.

Background: Familial nonmedullary thyroid carcinoma (FNMTC) occurs when three or more family members are affected by usually papillary thyroid carcinoma (PTC), the most common form of NMTC. While the heritability to NMTC is among the highest of all cancers, the genetic determinants among NMTC families are not well understood. Here, we aim to understand the contribution of rare noncoding germline variants in the etiology of FNMTC.

Methods: We previously reported whole-genome sequencing (WGS) and linkage analysis in 17 PTC families and reported on 41 protein-coding variants in 40 genes that cosegregated with PTC in 11 of the families. Herein, we further leveraged our WGS data to include noncoding variants in our analysis for all 17 families. We hypothesized that most of the pathogenic noncoding variants would be located in theoretical or empirically determined regulatory regions that demonstrate at a minimum, basal thyroid expression, a positive family linkage score, and co-segregation among PTC-affected individuals. To test this hypothesis, we adopted a unique filtering strategy to identify variants that occurred in known DNA elements and transcription factor binding sites, near regions known to impact on gene expression or splicing in thyroid tissue, and/or in characterized thyroid enhancers. We annotated variants using two analyses (ENCODE and transcription factor binding site) within the BasePlayer software. We separately analyzed (1) expression quantitative trait loci, (2) splicing quantitative trait loci, and (3) thyroid enhancers. We then ranked variants according to predicted pathogenicity and performed Sanger sequencing in all individuals of each family.

Results: In total, 121 variants were selected based on in-silico prediction and our custom ranking analysis in each pedigree. Of these, 56 variants showed cosegregation among all PTC-affected individuals and were absent from unaffected individuals. This included candidate variants from five of the six PTC families for whom no protein-coding variants were previously found.

Conclusion: Our data suggest that noncoding variants are important in the etiology of FNMTC and provide a framework for identifying noncoding germline variants using a novel approach. Further studies are needed to functionally characterize these variants to better understand the molecular mechanism of their pathogenicity.

Background: One of the challenges in tumor molecular profiling for therapeutic decisions is the unavailability of tumor tissue or its inadequacy to provide high-quality nucleic acids. Although tissue biopsy remains the "gold-standard," analysis of circulating tumor DNA (ctDNA) may offer an alternative to characterize mutations necessary to initiate systemic therapy with selective inhibitors in eligible patients. This study aimed to identify cases of sporadic medullary thyroid carcinoma (sMTC) in which plasma ctDNA analysis may be useful for RET gene testing when tumor tissue is unavailable.

Methods: We conducted a retrospective cohort study analyzing plasma from 36 patients affected by RET-mutated sMTC. Patients were divided into three cohorts (1) 18 patients with progressive sMTC; (2) nine patients with stable disease under treatment with a multikinase inhibitor; and (3) nine patients with metastatic but stable disease without treatment. For patients in cohort 1, we studied plasma collected at the time of progression just before the initiation of systemic therapy, while in cohorts 2 and 3, we studied last plasma available at follow-up. The RET driver mutation was analyzed in ctDNA using specific digital droplet PCR assays.

Results: The RET driver mutation was detected in 16/36 (44.4%, CI 27.9-61.9) ctDNA samples, with a statistically significant difference among the three cohorts 16/18 (88.9%, CI 65.3-98.6) in cohort 1 and 0/9 (0%, CI 0-33.6) in cohorts 2 and 3 (p < 0.001) with a mean variant allele frequency of 5.4%. The presence of detectable RET-mutated ctDNA was associated with disease progression (p < 0.001), higher percentage of metastatic sites with > five lesions (i.e., tumor burden; p = 0.001), and higher levels of serum calcitonin (Ct) (p = 0.009), and carcinoembryonic antigen (p = 0.038).

Conclusions: Our study demonstrates that ctDNA analysis may be a valid approach to genotype sMTC patients. Thus, liquid biopsy-based RET mutation profiling may be beneficial in advanced and progressive sMTC cases when primary tumor tissue is unavailable or inadequate for high-quality nucleic acid extraction, enabling RET-inhibitor therapy, if needed, according to specific indications. However, to obtain reliable results, ctDNA molecular profiling should be performed when tumor burden is high and the disease is progressing.

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: The risk of hypothyroidism after hemithyroidectomy is not well defined in the pediatric population. We sought to determine the incidence of hypothyroidism after hemithyroidectomy in children and the clinical factors associated with this risk. Methods: This is a retrospective cohort study of consecutive pediatric patients (<19 years of age) who underwent hemithyroidectomy in a pediatric thyroid center between 1998 and 2023, with data available on postoperative thyroid function and/or levothyroxine (LT4) treatment. The primary outcome was the composite of persistent hypothyroidism (thyrotropin [TSH] ≥ 5 mIU/L) or LT4 treatment (PersHypo/LT4). Secondary outcomes were persistent hypothyroidism and transient hypothyroidism. Univariable and multivariable survival analysis and logistic regression were used to evaluate associations of these outcomes with clinical characteristics. Results: A total of 136 eligible patients (85% female) underwent hemithyroidectomy at a median (range) age of 15.4 (0.14-19.0) years. The median (interquartile range) postsurgical follow-up was 1.10 (0.15-3.2) years for thyroid function and 1.76 (0.38-4.3) years for LT4 treatment status. PersHypo/LT4 occurred in 27/136 patients (20%), with an estimated risk of 18.1% [CI: 12.1-26.6%] at 1 year and 27.5% [CI: 18.7-39.2%] at 5 years. PersHypo/LT4 occurred within 12 months in 21/27 cases (78%) and after 12 months in 6/27 (22%). PersHypo/LT4 was associated with preoperative TSH (hazard ratio 1.89, [CI: 1.31-2.74], p = 0.001), and preoperative TSH ≥ 2 mIU/L optimally distinguished patients with high (58.8%) versus low (12.8%) 5-year risk of PersHypo/LT4 (receiver operator characteristic AUC 0.73, [CI: 0.60-0.85]). The presence of thyroperoxidase (TPO) antibodies was independently associated with increased risk of PersHypo/LT4 (OR: 7.37, [CI: 1.09-49.9], p = 0.041). Persistent hypothyroidism occurred in 14/128 patients (11%), with an estimated 5-year risk of 12.9% [CI: 7.7-21.1%]. Severe hypothyroidism occurred in 5/136 patients (3.7%), and transient hypothyroidism occurred in 22/136 patients (16%). Conclusions: Persistent hypothyroidism or LT4 treatment occurs in 27.5% of children within 5 years after hemithyroidectomy, usually in the first postoperative year. Preoperative TSH < 2 mIU/L may identify children at low risk, whereas preoperative TSH ≥ 2 mIU/L, particularly in conjunction with TPO antibodies, may identify children at high risk. Transient hypothyroidism also occurs commonly but may not require treatment. These data should inform preoperative counseling and postoperative monitoring around hemithyroidectomy in children.

Background: The prognostic value of unstimulated serum thyroglobulin (Tg) levels for structural recurrence in patients with low- to intermediate-risk differentiated thyroid cancer (DTC) who underwent total thyroidectomy but did not receive radioactive iodine (RAI) therapy remains unclear. This study aimed to determine Tg cutoff values and evaluate the role of dynamic Tg monitoring in risk stratification in these patients. Methods: We retrospectively analyzed 9753 patients with low- to intermediate-risk DTC who underwent total thyroidectomy without RAI at 11 Korean tertiary hospitals. Serum Tg levels were measured under thyrotropin suppression (<2 mIU/L) at 6, 12, and 24 months postoperatively using high-sensitive assays (functional sensitivity, <0.2 ng/mL). Optimal Tg cutoffs were determined by receiver operating characteristic curves and survival analyses. Results: Higher postoperative unstimulated Tg levels consistently predicted structural recurrence, with an optimal cutoff of 0.3 ng/mL (area under the curve: 0.815, 0.772, and 0.816 at 6, 12, and 24 months, respectively). A Tg ≥ 0.2 ng/mL, the Korean Thyroid Association (KTA) guideline cutoff for biochemical remission (excellent response), showed high sensitivity for recurrence. Tg ≥ 5.0 ng/mL at 6 months, a KTA-defined threshold for a biochemical incomplete response, independently predicted an elevated recurrence risk. Kaplan-Meier curves showed stepwise declines in recurrence-free survival with increasing Tg levels. Notably, even Tg < 0.2 or < 0.3 ng/mL were associated with recurrence if levels rose over time. Conclusion: Unstimulated Tg levels are strongly associated with the risk of structural recurrence in patients with DTC who have undergone total thyroidectomy without RAI. The current cutoff values of 0.2 ng/mL and 5.0 ng/mL were clinically relevant, and Tg kinetics over time further improved risk stratification. These findings provide the first large-scale evidence from an East Asian cohort and underscore the importance of early, serial Tg assessment in this growing patient population.

Background: RASAL1 is a prominent tumor suppressor gene through inactivating RAS, whose functional loss has been widely found to play an important role in thyroid cancer and occurs usually through its genetic and epigenetic inactivation. In this study, we intended to explore aberrant alternative splicing (AS) as an important novel mechanism for the oncogenic inactivation of RASAL1 in thyroid cancer. Methods: We used comprehensive bioinformatic and molecular experimental approaches to identify and characterize aberrant alternative splice variants of RASAL1. This included structural and functional investigation of the potentially oncogenic splice variants of RASAL1, with a focus on exploring the molecular mechanisms and clinical impacts on thyroid cancer. Results: We identified an aberrant alternative splice variant of RASAL1, known as RASAL1-004, that commonly compromised the function of RASAL1 in thyroid cancer. Specifically, we found common skipping of exon 18.1 in RASAL1, leading to the abundant formation of transcript RASAL1-004 in cancer, which was significantly associated with poor survival of patients with thyroid cancer. Mechanistically, Argonaute2 regulates exon 18.1 splicing by binding to the response element in exon 17 containing CCAGCC motif, promoting RASAL1-004 formation. The exon 18.1 skipping caused a conformational change in the RNA structure of RASAL1-004 at the junction of exons 17 and 18, resulting in ribosome stalling, halting RASAL1 translation. This reduced RAS GTPase-activating-like protein 1 (RASAL1 protein) synthesis, consequently leading to the functional loss of RASAL1. Compared with RASAL1-001, the canonical wild-type RASAL1 transcript, the absence of exon 18.1 in RASAL1-004 also conformationally altered the pleckstrin homology domain of RASAL1 protein, which, as we demonstrated, led to the loss of the ability of RASAL1 to localize with cell membrane, thereby impairing its RAS-inactivating function. We further demonstrated that compared with RASAL1-001, RASAL1-004 displayed impaired RAS-signaling pathway-suppressing and cancer cell-suppressing functions. Conclusions: This study identified a novel RASAL1-impairing mechanism, alternative to the classically known genetic and epigenetic mechanisms, for the inactivation of the tumor suppressor gene RASAL1 through aberrant AS to form RASAL1-004 with impaired protein translation. This represents a new oncogenic mechanism in thyroid cancer, with novel cancer biological, prognostic, and therapeutic-targeting implications in thyroid cancer.

Background: Bile acid sequestrants have been reported to reduce serum thyroid hormone levels by binding T4 and T3 excreted into the intestinal lumen, preventing their reabsorption into the systemic circulation and interrupting the enterohepatic circulation of these hormones. This meta-analysis evaluates whether adjunctive bile acid sequestrants accelerate reductions in serum iodothyronine when added to standard hyperthyroidism therapy. Methods: A systematic review and meta-analysis were conducted and registered in PROSPERO (CRD42025643217). MEDLINE, Embase, Web of Science, and Cochrane databases were searched from March 1971 to September 2025 for randomized controlled trials (RCTs) assessing adult non-critically ill patients with hyperthyroidism treated with standard therapy (thionamides and beta-blocker) plus adjunctive bile acid sequestrants (cholestyramine or colestipol) versus standard therapy alone. Primary outcomes included a reduction in serum-free T4 and total T3. The secondary outcome was adverse effect frequency. Results: Initial search yielded 705 results. After removal of duplicates and title/abstract screening, 17 full-text articles were reviewed, and five RCTs met the inclusion criteria, totaling 173 adult patients: 93 (53.75%) received adjunctive therapy, and 80 (46.25%) were controls. Causes for thyrotoxicosis included Graves' disease, toxic adenoma, and multinodular goiter. Doses ranged from cholestyramine 1 g twice a day to 4 g four times a day, and colestipol 20 g daily. At 2 weeks of treatment, bile acid sequestrants showed a non-significant reduction in serum total T3 (mean difference [MD] -0.44 nmol/L, 95% confidence interval [CI]: -1.2 to +0.32) and free T4 level (MD -0.55 ng/dL, CI: -1.15 to +0.04). At 4 weeks, there was a statistically significant reduction in total T3 (MD -1.59 nmol/L, CI: -2.90 to -0.27) and free T4 level (MD -1 ng/dL, CI: -1.74 to -0.25). Conclusions: Adjunctive bile acid sequestrants with standard hyperthyroidism therapy appear to enhance reductions in serum total T3 and free T4 at the mark of four weeks and were well tolerated. However, due to considerable heterogeneity and low quality of evidence, our results should be interpreted with caution. Larger, high-quality RCTs are needed to strengthen the evidence regarding the efficacy of adjunctive bile acid sequestrant therapy.