Thyroid最新文献

Background: Germline variants in the telomere-regulating genes (TRG) of the shelterin complex have recently been associated with long telomere length and increased risk of several tumors, including thyroid cancer (TC). We aimed to validate these findings in a different ancestral population. Patients and Methods: We conducted a cross-sectional study in a tertiary care hospital in Saudi Arabia. We included 189 patients with sporadic TC and 63 members of 26 families with at least two members with TC. Whole exome sequencing was performed on genomic DNA isolated from peripheral blood, and bioinformatics analysis focused on TRG variants. Results: In the 189 sporadic TC patients, 8 TRG variants were found in 39 patients (20.6%). These included 3 ACD variants in 30 patients (NM_001082486.2: c.22G>A, c.617A>C and c.824C>T), 2 variants in TERF1 in 4 patients (NM_003218.4: c.162_163insGAG and c.1126C>G) and 3 variants in TERT in 5 patients (NM_198253: c.769G>T, c.76A>G and c.1323_1325del). In 63 patients with a family history of TC (26 families), only two variants were found: a TERF1 variant in one patient (NM_017489.3: c.347C>T), and an ACD variant (NM_001082486.2: c.22G>A) in 2 affected members of a 4-member family with papillary TC and in another patient from an unrelated family. All the TRG variants found in this study were either variants of unknown significance or likely benign. The TRG variants described in the recent studies from the United States were absent in the current study and our local database of >18,000 exomes. Conclusions: Unlike the recently reported results from the United States, TRG variants do not seem to play a role in sporadic or familial TC samples from the Saudi Arabian population. These results suggest that the role of TRG variants may vary among different ethnic populations and call for validation of these findings in diverse populations.

Background: Under sufficient iodine supply, dual oxidase (DUOX)-dependent H₂O₂ production constitutes the limiting factor for thyroid hormone (TH) synthesis. Inherited loss-of-function mutations in related genes can trigger congenital hypothyroidism (CH). TH supplementation is not always well-tolerated and requires dose adjustments throughout life. Regenerative medicine directed at thyroid follicular cells (TFCs) could offer an alternative therapy; however, the minimal number of TFCs to be corrected remains unknown. Methods: Thyroid dyshormonogenesis in Duoxa^-/- deficient mice was rescued by conditional thyroid-specific expression of DUOXA2/DUOX2 subunits. In order to restrict reactivation in a subset of TFCs, low doses of tamoxifen (0.1-2 mg) were injected. Thyroid function was assessed by immunostaining of iodinated-thyroglobulin (iTG). Circulating serum thyrotropin (TSH) and total thyroxin (T4) were quantified, and thyroidal expression of TSH-responsive genes (Nis, Tpo, Tshr) and hepatic deiodinase type-1 (Dio1) was measured. Last, combining iTG immunostaining with Duox2 in situ hybridization, we estimated the fraction of rescued TFCs required to restore follicular TG iodination. Results: Colloidal iTG⁺ staining in more than 90% of follicles demonstrated the successful rescue of TH biogenesis in doxycycline-induced Tet:Da2D2^+/-;mTg:CreER^T2+/-;Duoxa^-/- animals (3TA). In contrast, reducing tamoxifen doses to 0.1 mg resulted in unresolved primary CH with thyroid enlargement, induction of Nis, Tpo, and Tshr, decrease of Dio1, and growth delay. Corresponding thyroid sections revealed scattered iTG⁺ colloidal lumens dispersed in histologically altered parenchyma. Nevertheless, we determined that only 11-15% of TFCs need to be reactivated within the follicle to functionally restore iodide organification. Goiter involution was also studied in 3TA following functional oxidase recovery or levothyroxine supplementation. Although thyroid enlargement was similarly reduced in both groups, expression of Nis, Tpo, Tshr, and Dio1 more rapidly normalized in genetically rescued 3TA. In these pathological conditions, around 50-70% of iTG⁺ follicles would seem sufficient to recover a healthy thyroid function until two weeks. Conclusions: Our data in Duoxa^-/- mice suggest that the percentage of TFCs to be corrected is limited to 10-15% per follicle, which could be compatible with future somatic gene therapies. Furthermore, the reconstitution of hormonogenic-competent TFCs successfully results in goiter resolution, to an extent comparable to that of gold-standard TH replacement therapy.

Background: Progression-free survival (PFS) may not fully capture the impact of treatment on patients, especially in cancers with longer natural histories and thus, could be complemented by robust measures of patient-reported tolerability (PRT). We report the use of a novel, quantifiable PRT metric as a multiplicity-controlled endpoint to support regulatory and clinical decision-making for selpercatinib use. Comparative PRT was assessed in LIBRETTO-531 (NCT04211337), a randomized phase 3 trial of selpercatinib versus vandetanib/cabozantinib (control) in advanced RET-mutant medullary thyroid cancer (MTC). Patients and Methods: Patients were self-administered the single Functional Assessment of Cancer Therapy item GP5: "I am bothered by side effects" weekly, and scores were dichotomized into "low" (0-2) and "high" (3-4) side-effect burden. PRT measured the proportion of time on treatment (PTT) with "high" side-effect burden for each patient. Comparative PRT was tested at a two-sided significance level of 0.05, conditional on achieving significance for efficacy endpoints. Complementary patient-reported outcomes included health-related quality of life (HRQoL) and symptomatic adverse events self-administered at baseline and at different intervals post-baseline during treatment period. Results: In the tolerability evaluable population (N = 242; selpercatinib n = 161 and control n = 81 [56 received cabozantinib, 25 received vandetanib]), patients on selpercatinib had significantly better PRT with lower PTT with "high side-effect burden" than control (8% vs. 24%, p < 0.0001). Post-baseline compliance rates for PRO questionnaires were generally greater than 80% in both treatment groups. Patients on selpercatinib reported significantly less PTT with HRQoL impairment across physical (36% vs. 52%), role (2% vs. 11%), cognitive (4% vs. 8%), emotional (6% vs. 11%), and social (2% vs. 8%) function (all p < 0.01); and significantly less PTT with severe diarrhea (5% vs. 38%), fatigue (6% vs. 21%), taste change (3% vs. 15%), decreased appetite (2% vs. 15%), and hand-foot syndrome (2% vs. 9%) (all p < 0.001). Conclusion: This study demonstrated superior PRT for selpercatinib compared with control in patients with RET-mutant MTC, further supporting selpercatinib use as the first-line treatment for patients with advanced RET-mutant MTC. Comparative PRT deserves further adoption as a complement to traditional endpoints in future randomized-controlled trials.

Background: Thyroid eye disease (TED) is a debilitating autoimmune disorder linked to thyroid dysfunction. There is limited knowledge of TED in Asian populations. This multicenter study characterizes the clinical features and treatment response of TED in a large Chinese cohort. Methods: A retrospective multicenter study included 4157 patients with TED from nine Chinese hospitals from February 2016 to July 2023. Disease severity and activity were evaluated according to the European Group on Graves' Orbitopathy standards. We examined associations of variables including sex, age, smoking status, I¹³¹ treatment, consultation department, and geographical region with clinical outcomes. Logistic regression and nomogram models were developed to examine associations with sight-threatening TED and, in a subgroup analysis (n = 126), patients' responsiveness to intravenous glucocorticoid (IVGC) therapy. Results: We included 4157 patients with mean age and standard deviation (SD) 45.96 ± 16.44 years. Of these, 63.6% (n = 2644) were females. Over half (55.6%, n = 2310) of participants were in the inactive phase, with a mean clinical activity score of 2.19 ± 1.61 (SD) for all patients. TED severity was categorized as mild (9.3%, n = 385), moderate-to-severe (82.5%, n = 3428), and sight-threatening (8.2%, n = 344). The average degree of exophthalmos was 20.04 ± 5.27 mm, and 48.8% (n = 2029) of patients had diplopia. Patients treated with I¹³¹ had higher disease activity (47.5%, n = 468, vs. 43.5%, n = 1379, p < 0.05). Coastal region patients exhibited more severe TED (sight-threatening cases: 10.1%, n = 195, vs. 7.2%, n = 147) and higher diplopia scores (1.00 ± 1.10 vs. 0.86 ± 1.09, p < 0.001) than inland counterparts. TED severity was also greater in patients treated in Ophthalmology departments (mild cases: 6.0%, n = 213; moderate-to-severe cases: 85.6%, n = 3055) compared with Endocrinology departments (mild cases: 29.3%, n = 172; moderate-to-severe cases: 63.5%, n = 373). Nomograms had an area under the receiver operating curve of 0.742 (confidence interval [CI] 0.716-0.768) for sight-threatening TED and 0.759 (CI 0.674-0.843) for IVGC therapy responsiveness. Conclusions: We characterized the clinical features and treatment response of TED in a large Chinese cohort. These findings offer valuable insights informing TED risk stratification in Asian patients and forming a foundation for future prospective studies.

Background: DUOX2 is a major cause of congenital hypothyroidism (CH) in Chinese patients, but clinical outcomes for those with biallelic DUOX2 mutations remain unclear. This study aimed to describe the clinical manifestations of CH due to DUOX2 defect. Methods: One hundred eighty-one patients with primary CH were recruited initially and were subjected to genetic screening. Patients with DUOX2 biallelic mutations were chosen. After 3 years of age, 28 patients underwent a prospective clinical reevaluation after levothyroxine (LT4) withdrawal. Subsequent periodic evaluation of thyroid function was executed to evaluate the necessity of LT4 retreatment. The medical histories of all patients before the age of three years were collected and analyzed. DUOX2 residual enzymatic activity was also calculated relative to clinical outcomes. Results: Twenty-eight patients who were reevaluated were divided into three groups: patients with permanent CH (PCH; 7/28 [25%]), patients with transient CH (TCH; 6/28 [21.4%]), and patients with hyperthyrotropinemia (15/28 [53.6%]). The median duration of follow-up was 17.5 months (interquartile range: 8.5, 29.25). The correlation between DUOX2 residual enzymatic activity and the clinical outcome of patients with CH with DUOX2 biallelic mutations was not clear in this study. No significant differences in laboratory findings at diagnosis were observed among the three groups. LT4 dose decreased with age in TCH but remained stable in PCH. Doses at ages 2, 3, and pre-withdrawal were significantly higher in PCH versus TCH (p = 0.027; p = 0.003; p = 0.025). After LT4 withdrawal, serum thyroglobulin levels and thyroid size increased in most patients (especially hyperthyrotropinemia group) and often persisted for months. Moreover, thyrotropin levels normalized in 44.4% of patients with hyperthyrotropinemia after more than one year off LT4. Conclusions: Some patients with CH and DUOX2 biallelic mutations may have TCH or hyperthyrotropinemia. These patients should undergo long-term follow-up to prevent excessive compensatory thyroid hyperplasia.

Background: Ultrasound (US) examination is the pivotal test to assess the risk of cancer and the indication for fine needle aspiration cytology (FNAC) in thyroid nodules (TNs). The subcapsular location of a TN may strengthen the indication for FNAC as, in TN resulting malignant at cytology may favor surgery rather than active surveillance. However, the definition of a subcapsular TN remains unclear. This study aimed to evaluate the interobserver agreement (IOA) among thyroid US experts in classifying TNs as subcapsular or not. Methods: Twelve raters received an electronic link to a file containing static US images and were asked to assess 60 TNs for subcapsular location, blinded to all other TN characteristics. The overall IOA was calculated, and the TN US features were subsequently analyzed to evaluate their potential influence on interobserver variability. The raters had high or very high thyroid US experience. Two experienced operators preliminarily selected the case series and analyzed the findings. All cases were derived from patients undergoing surgery and histological diagnosis. The IOA was calculated according to Fleiss' kappa, ranging from 0.0 (no agreement) to 1.0 (perfect agreement). Results: The overall IOA was fair (κ = 0.34), with a slightly better result in the subgroup of raters with higher experience (κ = 0.39). A higher IOA value (κ = 0.38) was observed in TNs of medium size. Following multiple sub-analyses, the highest κ value (0.46) was observed in the subgroup of TNs that were categorized as EU-TIRADS 5 and were smaller than 2 cm. Conclusions: The overall IOA among US experts when assessing TNs as subcapsular was unsatisfactory. A clear and standardized definition of subcapsular position is needed to improve clinical decision-making. Future guidelines should address this issue to ensure consistent assessment and management of subcapsular TNs.

Background: Anaplastic thyroid carcinoma (ATC) represents a rare yet highly malignant histotype of thyroid cancer. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor cell invasion, migration, and angiogenesis and present a potential target for cancer treatment. We aimed to investigate the effects of modulating specific subsets of CAFs on the proliferation, invasion, and migration of ATC. Methods: We developed nanosystems, platelet-derived growth factor receptor (PDGFR-β) targeted-polypeptide-modified poly (β-amino ester) (pBAE) (T-pBAE)/siB7-H3 nanoparticles (NPs), targeting PDGFR-β+ CAFs and featuring B7-H3 knockdown. We evaluated both the targeting efficacy and gene silencing performance of T-pBAE/siB7-H3 NPs, as well as the functional contribution of B7-H3 to CAFs-driven ATC progression. Results: T-pBAE/siB7-H3 NPs were efficiently internalized by CAFs, achieving targeted knockdown of B7-H3 expression. Silencing B7-H3 significantly suppressed the expression of cell division cycle 27 and other cell cycle-related genes, thereby inhibiting CAFs' proliferation. Consequently, CAFs-secreted cytokines (e.g., CCL1 and CCL4) were altered. Through modulation of cytokine receptor activation on ATC cells, this process reduced ATC cell proliferation, invasion, and migration. In mice ATC subcutaneous tumor models, local injection of T-pBAE/siB7-H3 NPs reduced tumor volume. Moreover, the expression of invasive proliferation-related markers (PDGFR-β, Ki-67, CD31), immune evasion-related marker CD163, and chemoresistance-related marker ATP-binding cassette subfamily G member 2 was remarkably downregulated in tumor tissues. Conclusion: This study demonstrates that PDGFR-β polypeptide-modified pBAE could successfully deliver B7-H3 siRNA to CAFs. After knockdown of B7-H3 within CAFs, ATC proliferation, invasion, and migration were inhibited. Overall, our findings revealed that B7-H3 can be a promising therapeutic target for ATC.