Thyroid最新文献

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.

Background: Mutations in the promoter region of TERT (TERTp) in thyroid nodules with indeterminate cytology are quoted to confer a high (∼80-95%) probability for thyroid carcinoma when detected on genomic classifier (GC) ThyroSeq. TERTp mutations may also occur in benign and low-risk thyroid neoplasms, and the risk of malignancy (ROM) in nodules harboring TERTp mutations without BRAF^V600E is unknown. We analyzed the ROM and the surgical diagnosis in a retrospective cohort of thyroid nodules with TERTp treated at two academic medical centers. Methods: From 2323 patients with ThyroSeq GC performed on preoperative fine needle aspiration samples, 52 cases (2.3%) were identified harboring TERTp mutations without coexisting BRAF^V600E. Results: The surgical diagnosis was obtained from resection (n = 51) or biopsy (n = 1, anaplastic thyroid carcinoma). The ROM was 65%. The reviewed diagnoses were benign/low-risk neoplasms in 18 (35%), carcinoma-American Thyroid Association (ATA) low/intermediate-risk in 14 (27%), and carcinoma-ATA high-risk in 20 (38.5%). All 18 benign or low-risk neoplasms had their tumor capsule submitted entirely, and 78% underwent total thyroidectomy. The molecular alterations were substratified into four groups: TERTp alone (n = 21, 40%), TERTp + RAS (n = 18, 35%), TERTp + other non-RAS mutation (n = 8, 15%), and TERTp + RAS + other alterations (n = 5, 10%), and the ROM for each group was 57%, 78%, 50%, and 80%, respectively. The frequency of a high-risk malignancy, which would often lead to a recommendation for total thyroidectomy, was 9.5%, 44.5%, 37.5%, and 80%, respectively. The frequency of high-risk carcinomas was significantly higher when a nodule harbored TERTp and other concomitant alterations (48%) compared with TERTp alone (9.5%; p = 0.006). Conclusions: Thirty five percent of TERTp nodules without BRAF^V600E are benign/low-risk thyroid neoplasms, leading to their overtreatment. The incidence of high-risk carcinomas increases in TERTp-mutated nodules with the presence of additional mutations. If the indolent histology found in these lesions is confirmed at the behavior level, lobectomy may be sufficient for the initial management of TERTp thyroid nodules without BRAF^V600E as long as there is no aggressive clinical or imaging feature. This will spare many patients from the side effects of total thyroidectomy.

Introduction: Hyperthyroidism can be treated with antithyroid drugs (ATD), radioactive iodine (RAI), or surgery. We aimed to evaluate the long-term outcomes of these treatments through a systematic review and network meta-analysis (NMA). Methods: A systematic literature search of PubMed, EMBASE, Web of Science, and the Cochrane Library (from inception to March 7, 2025) was conducted to identify studies comparing the risks of all-cause mortality, cardiovascular mortality, major adverse cardiovascular events (MACE), and cancer mortality among patients with hyperthyroidism treated with ATD, RAI, or surgery. Pooled effect estimates were expressed as hazard ratios (HR) with confidence intervals (CI) using a random-effects model. The study was registered with PROSPERO (CRD420250543380) and adhered to the PRISMA-NMA guidelines. Results: Of the 8163 studies screened, 12 observational studies with an overall moderate risk of bias, comprising 192,208 patients were included in this NMA. Most patients received ATD (n = 142,622), followed by RAI (n = 19,303) and surgery (n = 10,360). Surgery was associated with decreased risks of all-cause mortality and cardiovascular mortality compared with both ATD and RAI. For all-cause mortality, the pooled HRs (CI, p-values) were 0.58 (0.45-0.75, p < 0.0001) for surgery versus ATD and 0.68 (0.56-0.84, p = 0.0004) for surgery versus RAI. For cardiovascular mortality, the pooled HR (CI, p-values) were 0.43 (0.19-0.98, p = 0.0445) for surgery versus ATD and 0.55 (0.33-0.93, p = 0.0269) for surgery versus RAI. No significant differences were observed in MACE or cancer mortality across the treatment groups. Conclusions: In patients with hyperthyroidism, surgery was associated with significantly decreased risks of all-cause mortality and cardiovascular mortality compared with ATD and RAI. Risks of MACE and cancer mortality did not differ by type of hyperthyroidism treatment. However, these findings should be interpreted with caution due to inherent methodological limitations of observational studies, including, but not limited to heterogeneity and potential selection bias.

Background: TERT promoter mutations in thyroid cancer are associated with aggressive disease, including recurrence, distant metastasis, and disease-related mortality. We aim to assess histological and disease-related outcomes when TERT mutation is detected alone or with other alterations during preoperative testing. Methods: A retrospective, single-institution study was performed, including all adult patients undergoing initial diagnostic thyroid nodule evaluation with TERT promoter mutation (C228T/C250T) detected in preoperative thyroid fine needle aspiration samples using TSv3 testing. Results: Of 70 thyroid nodules, 18 (26%) were isolated (iTERT), and 52 (74%) were associated with ≥1 concurrently detected mutation (TERT+). The most common additional abnormalities were BRAF^V600E (23, 44%), RAS (19, 37%), and copy number alterations (CNA; 15, 29%). Patients with iTERT were older than those with TERT+ nodules (p = 0.007). While nodule size was similar between the two groups (mean size 3.2 cm, p = 0.18), Bethesda III/IV cytology was more likely with iTERT (94% vs. Bethesda V/VI 56%, p = 0.007). Histology was available for 9 (50%) iTERT and 51 (98%) TERT+ nodules and malignancy was higher with preoperative detection of TERT+ compared with iTERT (96% vs. 67%, p = 0.02). Poorly differentiated or anaplastic cancers were diagnosed in 33% of the malignancies at an equivalent rate in both cohorts. At median follow-up of 13.1 months (interquartile range 26.2, 7.2-33.4), distant metastasis occurred in 32.7% of patients including 17% (1/6) with iTERT versus 33% of patients with TERT+ (p = 0.65). None of the iTERT patients had locoregional recurrence as compared with 25% of TERT+ patients (p = 0.31). Conclusions: When preoperatively detected, TERT promoter mutations are more often seen in association with additional driver mutations or other genetic alterations such as CNA, but when present, carries a very high risk of malignancy (93%). Up to 1/3 are poorly differentiated or anaplastic thyroid cancer, and this likelihood is equivalent when TERT is present in isolation or in combination with other mutation. Thus, surgery should be strongly considered in iTERT nodules, and total thyroidectomy should be favored when TERT+ is identified.

Background: Anaplastic thyroid cancer (ATC) is an aggressive malignancy with a median survival of six months. While immunotherapy (IT) has improved outcomes in other solid tumors, its role in ATC remains unclear. This study evaluated whether receipt of IT was associated with improved overall survival (OS) in the initial treatment of patients with newly diagnosed ATC. Methods: We performed a retrospective study of patients with metastatic and nonmetastatic ATC from the National Cancer Database (2008-2020) treated with surgery, radiation, chemotherapy, or a combination. Patient outcomes were stratified between those who received IT at any point in their treatment compared with those who did not. The primary outcome was OS, compared between cohorts receiving IT and those who did not. Survival analyses were performed using Kaplan-Meier estimates, long-rank tests, and multivariable models. Results: Among 3318 patients with ATC, 87 (2.6%) received IT. Rates of surgical resection (46%) and radiation therapy (64% vs. 57%, p = 0.133) were similar across groups. IT recipients were younger (mean = 66.7 vs. 70.2 years, p = 0.005), more often diagnosed in recent years (2017-2019 vs. 2008-2016, p = 0.0001), and more frequently received chemotherapy (65.5% vs. 46.3%, p = 0.0007). Charlson Comorbidity Index scores were similar (p = 0.551). Median OS was 9.1 months (confidence interval [CI] 7.06-14.9) for those receiving IT versus 3.78 months (CI: 3.52-4.01) for those who did not (p < 0.005). Five-year OS was 18% (CI: 5-36%) with IT versus 9% (CI: 8-10%) without (p < 0.0001). Among 23 patients who received trimodality therapy (surgery, IT, and radiation), 5-year OS was 35% (CI: 16-55%) versus 9% in patients who did not. Conclusions: IT was associated with prolonged survival in patients with ATC, although confounding factors, such as the retrospective design of the study, lack of detailed IT drug details, and sequencing of therapy, preclude definitive conclusions on its efficacy. The efficacy of IT for ATC as a stand-alone treatment is uncertain. Further studies could indicate which combination of therapies best increases OS in patients with ATC.

Background: Dysthyroid optic neuropathy (DON) is a rare but serious complication of Graves' orbitopathy (GO) that can lead to permanent vision loss. In a previous study, medical and surgical treatment of DON according to EUGOGO guidelines resulted in partial or no recovery in 30% of patients. Insulin growth factor-1 receptor inhibitor teprotumumab has shown significant improvement of GO symptoms, but little is known about its effect on DON. The aim of this study was to evaluate the efficacy of teprotumumab in treating steroid- and surgery-resistant DON. Methods: This retrospective case series included 6 patients (8 eyes; median age 58 years) with confirmed DON resistant to steroids and orbital decompression (median duration of DON 2 months, interquartile range [IQR 2.0-6.5]) treated at the Hospices Civils de Lyon. Median time from the end of first-line treatment was 34.5 days (IQR: 8.0-61.7). The treatment protocol was 8 intravenous infusions of teprotumumab administered every 3 weeks. Definition of DON recovery was based on changes in best-corrected visual acuity (BCVA) and visual field mean deviation (VF-MD). Results: At the end of teprotumumab treatment, DON recovered in 7/8 (87.5%) of affected eyes, with BCVA improvement in all patients (median 0.30 logMAR [0.24-0.42], p = 0.004) and a median VF-MD improvement of 66% (46-90) (p = 0.024). In 3/6 patients, DON improved after one infusion. All patients showed improvements in clinical activity score and proptosis. Improvements persisted over the follow-up (median from first infusion, 73.8 weeks), with no DON relapse but inflammatory relapse in two patients. Due to adverse events, two patients did not complete all infusions. Conclusions: The data suggest teprotumumab as a promising treatment for steroid- and surgery-resistant DON with rapid symptom improvement and long-lasting recovery. However, these only preliminary results need to be better evaluated by specific clinical trials.

Background: The use of multikinase inhibitors (MKIs) in thyroid cancer has been established to downsize and facilitate resection of poorly differentiated, differentiated high-grade, anaplastic, and medullary thyroid cancer. Case reports and case series have suggested the potential use of MKIs as neoadjuvant therapies for locally advanced differentiated thyroid cancer (DTC). Our objective was to review available studies and assess if neoadjuvant therapy with MKI can improve surgical and oncological outcomes in patients with locally advanced DTC. Methods: A systematic search of four different databases (PubMed, Cochrane Library, Scopus, and EMBASE) with no time restrictions was performed to identify relevant observational studies evaluating patients with locally advanced DTC who received neoadjuvant therapy before surgery with MKI (PROSPERO ID: CRD420251012812). Results: A total of 119 participants from 23 observational studies (12 case reports, 9 case series, and 2 prospective phase II studies) were included. Lenvatinib was the most frequently used MKI, followed by sorafenib. Tumor volume reduction ranged from 25% to 87%, and partial response rates ranged between 33.3% and 76.9%, whereas progressive disease was described only in seven cases. Of 114 patients with inoperable or potentially resectable tumors with associated high perioperative morbidity, 95 (83.3%) were able to undergo surgery. Conclusions: Neoadjuvant MKIs in locally advanced DTC may improve resection rates. The overall low quality of evidence prompts further prospective studies to confirm these findings.

Background: Thyroglobulin (Tg), stimulated or unstimulated by recombinant human thyrotropin (TSH), is a static marker of recurrent or persistent disease, and the Tg-doubling rate (Tg-DR) is a dynamic prognostic factor. This study evaluated the prognostic value of an unstimulated Tg (uTg) and Tg-DR papillary thyroid carcinoma (PTC). Methods: This retrospective study included 1818 Tg antibody (Tg-Ab)-negative patients who underwent curative intent total thyroidectomy for PTC without distant metastasis. The uTg was measured 1-3 months post-surgery under TSH suppression (<0.1 mIU/mL). We calculated the Tg-DR for patients, of whom postoperative Tg levels could be measured three or more times under TSH suppression. Results: Eighty-eight (4.8%) and 32 (1.8%) patients had respective local and distant recurrences (median follow-up period, 7.2 years; 25th percentile 4.7 years, 75th percentile 9.8 years). Of 1818 patients, 131 had a uTg ≥3 ng/mL and were more likely to display local and distant recurrences in univariate and multivariable analyses (p < 0.001). We divided 1212 patients with no adjuvant radioactive iodine treatment, of whom uTg and Tg-DR data were available, into four categories A, uTg ≥3 ng/mL and Tg-DR ≥0.33/year; B, uTg <3 ng/mL and Tg-DR ≥0.33/year; C, uTg ≥3 ng/mL and Tg-DR <0.33/year; and D, uTg <3 ng/mL and Tg-DR <0.33/year. The lymph node recurrence-free survival rate was significantly worse from category A to D (A vs. B, p < 0.001, hazard ratio or HR [CI]: 5.083 [1.994-12.955]; B vs. C, p = 0.001, HR [CI]: 2.654 [1.462-4.824]; C vs. D, p < 0.001, HR [CI]: 27.420 [15.100-4.980]). The distant recurrence-free survival rate (DR-FS) of category B did not differ from that of category C (p = 0.419), but DR-FS of category D was better (p < 0.001) than those of B and C, and that of category A tended to be worse (p = 0.087) compared with those of B and C. Patients in category A, categories B and C, and category D could thus be classified as high-risk, intermediate-risk, and low-risk for distant recurrence, respectively. Conclusions: This study demonstrates the prognostic value of postoperative uTg and Tg-DR in Tg-Ab-negative patients with PTC under TSH suppression after total thyroidectomy. Prospective studies are needed to confirm these findings.

Background: Statin use is associated with a reduced risk of Graves' orbitopathy (GO). However, whether the timing of initiating statin treatment after the diagnosis of Graves' disease (GD) affects the association between statin and GO risk remains unclear. This study aims to evaluate the risk of GO based on varying intervals of statin initiation following GD diagnosis. Materials and Methods: This nationwide, population-based retrospective cohort study used data of all beneficiaries aged >40 years diagnosed with GD from Taiwan's National Health Insurance Research Database (2009-2019). We excluded patients with incomplete data, follow-up <6 months, with a diagnosis of GO, or on medication for hyperlipidemia before GD diagnosis. We performed 1:4 matching based on age, sex, and the duration between GD diagnosis and the index day for statin users and nonusers. GO patients were further classified as having mild or moderate-to-severe GO according to the type of treatment received. Results: A total of 47,424 patients were categorized into Group A (<1 year, 4649 statin users; 18,584 nonusers), Group B (1-2 years, 3060 statin users; 12,349 nonusers), and Group C (2-3 years, 1752 statin users; 7030 nonusers) by the duration between GD diagnosis and the index date. Cox regression showed that statin users in Group A had a significantly lower risk of total GO (adjusted hazard ratio [HR]: 0.66, confidence interval [CI]: 0.47-0.94, p = 0.023) and moderate-to-severe GO (adjusted HR: 0.39, CI: 0.19-0.80, p = 0.010), but not mild GO (adjusted HR: 0.84, CI: 0.56-1.25, p = 0.385) than nonusers. However, no significant associations were found in Groups B and C. The risk of GO was not statistically different among users of various types or intensities of statins in any group. Conclusion: Initiating statin treatment within one year after being diagnosed with GD was associated with 34% and 61% reduction in total and moderate-to-severe GO risk, respectively. For patients whose treatment was initiated more than one year after GD was diagnosed, statin use was not related to the risk of total, mild, and moderate-to-severe GO. These findings suggest that the timing of statin initiation may influence the risk of GO, which warrants further confirmation through prospective studies.

Background: Primary thyroid lymphoma (PTL) is a rare malignancy, comprising less than 5% of all thyroid cancers and about 2.5% of lymphomas. Historically, treatment with surgery and radiation yielded poor outcomes. The advent of combined chemotherapy and radiation has improved survival, but long-term trends and prognostic factors remain underexplored. This study aimed to characterize the clinical and demographic features of PTL, evaluate changes in survival over time, and identify factors independently associated with survival. Methods: A retrospective cohort study was conducted using Surveillance, Epidemiology, and End Results data from PTL patients aged ≥20 years, diagnosed between 1975 and 2021. Variables analyzed included age, sex, race/ethnicity, lymphoma subtype, stage, and treatment modality. Survival outcomes were estimated using Kaplan-Meier curves, and Cox proportional hazards models were used to identify factors associated with survival. Treatment was categorized as chemotherapy plus radiation (with or without surgery), chemotherapy alone, radiation alone, or no treatment. Results: A total of 2465 patients were included; 76% (n = 1,874) were diagnosed from 2001 to 2021. Median age at diagnosis was 67 years (interquartile range [IQR]: 56-77); 69.9% (n = 1723) were female, and 88.8% (n = 2189) were White. The most common subtype was diffuse large B-cell lymphoma (62.5%, n = 1540). Median follow-up was 83 months (IQR: 24-156). Median overall survival (OS) was 150 months, with 1-, 5-, and 10-year OS rates of 84.9%, 72.9%, and 57.7%, respectively. Disease-specific survival (DSS) rates at the same time points were 89.1%, 83.7%, and 80.5%. Survival significantly improved for patients diagnosed after 2000 (p < 0.001). Variables associated with poorer DSS survival included age ≥70 years (hazard ratio [HR] = 5.77; confidence interval [CI] 2.71-12.32, p < 0.001), regional metastatic disease (HR = 1.45; CI 1.04-2.02; p = 0.03) and distant metastatic disease (HR = 1.53; CI 1.17-1.99; p = 0.002). The highest 10-year DSS (86.6%) was seen in those receiving combined chemotherapy and radiation, outperforming chemotherapy alone (77.2%), radiation alone (77.0%), and no treatment (68.2%). Conclusion: PTL survival has significantly improved in recent decades, which may reflect both advances in treatment, particularly the combined use of chemotherapy and radiation, and shifts in disease presentation, including earlier diagnosis and changes in stage distribution.