Thyroid®

Mortality from thyroid cancer is driven by advanced forms of the disease. While second-line therapies have been approved and recognized in thyroid cancer guidelines, development of toxicity and resistance requires addition of salvage treatments.

This retrospective cohort study evaluates the utility of pemetrexed as single agent or in combination with carboplatin for advanced radioiodine refractory differentiated and anaplastic thyroid cancer (ATC) treated at Memorial Sloan Kettering Cancer Center between December, 2023, and December, 2025. Our primary outcome was best overall response, and secondary outcomes were progression-free survival and disease-specific survival.

Twenty-two patients (11 with ATC), 68% females, and 95% with distant metastatic disease, received pemetrexed single agent or in combination with carboplatin as a fourth-line therapy for a median duration of about 5 months. Median time to pemetrexed initiation was 73 months. Partial response (PR) was observed in 6/22 (27%) of all patients and in 5/11 (45%) with non-ATC. Median progression-free survival was 148 days for all tumors and 375 days for patients with non-ATC. One patient with ATC remains on pemetrexed/carboplatin with a PR to therapy.

Pemetrexed single agent or in combination with carboplatin has comparable efficacy to approved second-line therapies for advanced thyroid cancer. Prospective Phase II and III clinical trials are needed to confirm the efficacy of this salvage therapy.

Brain metastases (BMs) from nonanaplastic follicular cell–derived thyroid carcinoma (hereinafter referred to as non-ATC) are rare and not well characterized, with limited evidence guiding treatment and prognostic stratification. We aimed to describe clinical features, treatment patterns, and outcomes of patients with BMs from non-ATC and to develop and validate a disease-specific prognostic score.

This retrospective international multicenter study included adults with histologically confirmed non-ATC and radiologically documented BMs treated at 19 tertiary referral centers. Clinical, radiological, treatment, and outcome data were collected. Independent predictors of progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression, and variables identified were used to develop a disease-specific Graded Prognostic Assessment (non-ATC GPA), exploratorily assessed in an independent SEER cohort.

A total of 189 patients were included; median age at BM diagnosis was 59 years (interquartile range [IQR] 48–67). First-line BM treatments included stereotactic radiosurgery (27.0%), neurosurgery (23.8%), whole-brain radiotherapy (18.5%), and best supportive care (10.6%). Median PFS was 7.0 months (IQR: 2.9–22.4), and median OS was 15.0 months (IQR: 4.0–38.4). Independent predictors of shorter OS were age >75 years, Eastern Cooperative Oncology Group performance status ≥2, papillary histology, extracranial metastases, and ≥4 BM. The GPA stratified patients into four prognostic groups with median OS ranging from 72.6 months in the highest-score group to 3.7 months in the lowest. An exploratory SEER-based assessment showed survival differences across adapted prognostic groups (p = 0.036), although this analysis was limited by the absence of all key GPA variables.

BMs from non-ATC are associated with poor survival and marked prognostic heterogeneity. The proposed GPA may provide a useful framework for prognostic stratification, pending further validation in independent datasets to support individualized management.

Thyroid radiofrequency ablation (RFA) is a minimally invasive treatment for thyroid nodules. However, the health system costs of thyroid RFA are not well defined in the current literature. As its use expands, the objective of this study was to conduct a micro-costing analysis comparing RFA and hemithyroidectomy in outpatient and inpatient settings.

A retrospective micro-costing analysis of 112 hemithyroidectomies and 42 thyroid RFAs was performed between January 2023 and May 2025 at two tertiary hospitals in Toronto, Canada. Costs were calculated in 2025 Canadian Dollars from the perspective of a publicly funded, single-payer health care system using a bottom-up approach across a one-year patient care cycle from initial consultation to one year of follow-up. Deterministic one-way sensitivity analyses were performed to assess cost-equivalence thresholds and the impact of procedural volume, repeat ablation, and delayed future surgery.

The base-case cost of RFA was $3985.05 over a one-year care cycle, including initial consultation and follow-up. RFA procedure costs accounted for $3107.61 (78.0%), which were primarily driven by consumables and supplies ($2022.21, 50.7%). Mean hemithyroidectomy costs were $4730.48 for outpatient cases and $5739.39 for inpatient cases, with an overall mean cost of $5613.28 across a one-year care cycle. For all hemithyroidectomy cases, procedure costs were driven primarily by operating room facility fees ($2344.86, 41.8%), physician fees for the surgeon and anesthesiologist ($943.38, 16.8%), and laboratory and pathology services ($486.12, 8.7%). Sensitivity analyses demonstrated that cost equivalence between RFA and outpatient hemithyroidectomy occurred when 13.3% of patients required delayed surgery and 18.7% required repeat RFA. For inpatient hemithyroidectomy, cost equivalence was reached when 31.3% required delayed surgery and 44.0% required repeat RFA.

Over one year, the base-case cost for thyroid RFA was $1628.23 lower (29.0%) than the mean cost of all hemithyroidectomies. The cost savings of thyroid RFA are driven by eliminating the need for operating room and inpatient admission resources. Nodule regrowth requiring repeat ablation or delayed surgery is a critical factor that significantly affects the overall cost of RFA. Ultimately, proper patient selection, ablation technique, and evidence-informed implementation are needed to fully realize RFA’s clinical and economic benefits.

The optimal duration of antithyroid drug (ATD) therapy in Graves’ disease is uncertain. Although guidelines recommend 12–18 months, shorter courses may be sufficient in selected patients. We evaluated whether ATD duration <12 months is non-inferior to 12–18 months for relapse among patients with Graves’ disease and lower thyrotropin receptor antibody (TRAb) levels (>1.8 and <10.0 U/L) at diagnosis.

We analyzed real-world data from adults with Graves’ disease and baseline TRAb <10 U/L treated with ATDs at a single center. The primary endpoint was relapse within 12 months of ATD cessation. A prespecified risk-difference non-inferiority framework was used, with a primary margin of +5% and an exploratory margin of +10%. Treatment effects were estimated using unadjusted analyses, inverse-probability-of-treatment weighting (IPTW; n = 369), and 1:1 propensity-score matching (PSM; 104 matched pairs). Secondary outcomes included long-term relapse (median follow-up 58 months), TRAb levels at cessation, and restricted mean survival time (RMST) over 60 months.

At 12 months, relapse occurred in 23/134 (17.2%) patients treated <12 months and 48/235 (20.4%) treated for 12–18 months. The IPTW-adjusted risk difference was –1.5% (CI –11.0 to +8.0), meeting the 10% but not the 5% non-inferiority margin. The unadjusted estimate (–3.2%) met both margins, whereas the PSM estimate (+2.9%, CI –7.3 to +13.1) met neither because of reduced precision. Long-term outcomes were similar between groups (IPTW Cox HR 0.92 [CI 0.65–1.31]; RMST difference +3.2 months over 60 months [–2.1 to +8.4]). TRAb levels at cessation were comparable.

Among patients with Graves’ disease and lower TRAb levels, shorter ATD courses (<12 months) produced outcomes broadly comparable to 12–18 months. Although strict non-inferiority was not confirmed at a 5% margin, findings meeting an exploratory 10% threshold support TRAb-guided individualization of ATD duration and justify prospective randomized evaluation.

Over recent decades, variations have been observed in the incidence of pediatric hyperthyroidism (HT) and Graves’ disease (GD), preferred treatment modalities, and long-term outcomes. This study aimed to evaluate trends and long-term outcomes of pediatric HT across a 20-year period in a large cohort.

We conducted a retrospective study using the electronic database of a large health maintenance organization. Children aged 2–18 years who were diagnosed with HT between 2000 and 2019, received antithyroid drugs (ATDs) for at least 6 months, and were followed up through 2024 were included in the analysis.

Of 5,111,304 insured children, 518 (75% females) met the inclusion criteria. The median age at diagnosis was 15.1 (13.0–16.5) years, and the median follow-up was 10.4 (6.5–15.1) years. The median ATD treatment duration was 3.8 (1.8–6.6) years. The mean initial methimazole dose decreased from 15.8 (8.5–23.4) mg/day in 2000–2009 to 12.9 (7.3–19.4) mg/day in 2010–2019 (p = 0.030). The overall remission rate was 31.1%. Compared with children diagnosed in 2000–2009, those diagnosed in 2010–2019 were less likely to undergo definitive treatment (27.5% vs. 59.6%, p < 0.001) and had higher nonremission (19.0% vs. 3.8%, p < 0.001) and relapse rates (15.9% vs. 4.6%, p < 0.001). Among the 161 children achieving remission, the median time to remission was 2.36 years. Younger age and antithyroid peroxidase positivity were associated with later remission (p = 0.010 and p = 0.018, respectively). Higher baseline free thyroxine levels at diagnosis were found in children with late remission than in those with early remission (42.4 [26.7–61.5] vs. 32.6 [24.4–42.5] pmol/L, p = 0.014).

Over the past two decades, the management of pediatric HT has evolved toward more prolonged medical therapy and decreased reliance on definitive treatments. This change in practice appears to coincide with an increased relapse rate, underscoring the clinical implications of these changes. Future studies should focus on evaluating the influence of these treatment strategies on the long-term prognosis of children with pediatric HT.

Graves’ disease (GD) is rare in children, and methimazole (MMI) is recommended as the first-line therapy. However, data on MMI-associated neutropenia and agranulocytosis in pediatric patients remain limited. In this study, we aimed to characterize the clinical features of these adverse events and to identify their associated risk factors.

A cohort study was conducted involving 432 pediatric patients with GD treated with MMI. Clinical and biochemical data were collected retrospectively and prospectively, with follow-up 0.5, 1, 2, 3, 4, 5, 6, 7–9, and 10–12 months after treatment initiation. Multivariable logistic regression analysis was performed to identify risk factors for MMI-associated neutropenia.

During the 12-month follow-up period, 104 (24.1%) patients developed neutropenia, with 84.6% developing neutropenia within the first 3 months, 72.1% within 1 month, and 59.6% within 2 weeks. Among the affected patients, 83.7%, 13.5%, and 2.8% had mild, moderate, and severe neutropenia (agranulocytosis), respectively. All patients with moderate or severe neutropenia were asymptomatic and were identified through routine monitoring within the first month. Multivariable analysis revealed that a thyroid peroxidase antibody (TPOAb)-negative status (odds ratio [OR], 2.020; confidence interval [CI], 1.113–3.666) was associated with a higher prevalence of MMI-associated neutropenia, whereas older age (OR, 0.916; CI, 0.848–0.989) and higher baseline absolute neutrophil count (ANC; OR, 0.775; CI, 0.665–0.903) were protective factors.

ANC monitoring is recommended every 1 to 2 weeks during the first month and monthly for the first 3 months after MMI initiation. Pediatric patients with GD younger than 3 years with TPOAb-negative status or a baseline ANC < 3 × 10⁹/L may have a higher prevalence of MMI-associated neutropenia.

Maternal Graves’ disease (GD) has been linked to neonatal thyroid dysfunction, but its relationship with offspring neurodevelopment remains unclear. We examined the associations of maternal GD-related thyroid factors with neonatal thyroid function and neurodevelopment at 24 months. We also explored whether neonatal thyroid function might partly explain this association.

This single-center bidirectional cohort study included pregnant women with GD and their offspring delivered between January 1, 2019, and December 31, 2023. Maternal thyroid-related variables, including thyrotropin (TSH), free T4, thyrotropin receptor antibodies (TRAbs), and antithyroid drug exposure, were collected across pregnancy. Neonatal thyroid function was assessed at 7–14 days after birth, and neurodevelopmental screening at a corrected age of 24 months was performed using the Ages and Stages Questionnaire, Third Edition. Logistic regression was used to identify factors associated with neonatal thyroid dysfunction and abnormal neurodevelopmental screening results. Covariates were selected with guidance from a directed acyclic graph, and exploratory mediation analysis was performed using PROCESS Model 4.

Among 159 neonates, 60 (37.7%) had thyroid dysfunction, with hyperthyrotropinemia as the most common abnormality (28.9%). Higher maternal third-trimester TRAb was independently associated with neonatal thyroid dysfunction (odds ratio [OR] = 1.59 [confidence interval or CI: 1.29–1.97], p < 0.001). Of the 143 offspring with follow-up data, 23 (16.1%) had abnormal neurodevelopmental screening results at 24 months. Higher maternal third-trimester TRAb (OR = 1.15 [CI: 1.04–1.27], p = 0.005) and higher neonatal TSH (OR = 1.11 [CI: 1.02–1.20], p = 0.016) were independently associated with abnormal neurodevelopmental screening results. Exploratory mediation analysis did not support a significant mediating role of neonatal TSH.

Higher maternal third-trimester TRAb levels were associated with both neonatal thyroid dysfunction and abnormal neurodevelopmental screening results at 24 months in offspring of mothers with GD. This association with neurodevelopmental screening results may not be explained primarily by neonatal thyroid function alone.

Due to an impaired thyroid hormone (TH) transport across brain barriers, inactivation of the murine TH transporters Mct8/Oatp1c1 causes a profound TH deficiency of the CNS that greatly impacts neural development and function. Since oligodendrocyte maturation and myelination are dependent on local TH signaling, Mct8/Oatp1c1 double knockout (DKO) mice exhibit a persistent state of hypomyelination. Yet, to which extent Mct8/Oatp1c1 inactivation also affects TH transport into oligodendroglia cells has not been addressed. Here, we studied oligodendrocyte maturation and myelination in mice lacking Mct8/Oatp1c1 specifically in oligodendroglia lineage (OL) cells and compared their phenotype with that of control and DKO animals.

Conditional Mct8/Oatp1c1 mutants were crossed with mice expressing constitutively Cre-recombinase under the control of the Olig2 promoter to inactivate both transporters in OL cells (so-called OL CKO mice). Neural maturation and myelination were assessed by immunofluorescence (IF) and fluorescence in situ hybridization (FISH) studies at different postnatal time points. Oligodendrocyte precursor cells (OPCs), premyelinating, and myelinating oligodendrocytes were visualized by coimmunolabeling.

OL CKO mice exhibited normal serum TH concentrations and hypothalamic Trh transcript levels. Quantification of neuronal TH-target gene transcript levels (Rc3; Klf9; Pde10a) revealed no alterations. Abundance of myelin sheaths-related proteins Mbp and Cnp was significantly reduced in OL CKO mice at postnatal day P12 but reached normal levels at P21 and P120. Quantification of OPC, premyelinating, and myelinating oligodendrocytes disclosed a strongly reduced number of mature OL at P6 and P12, while cell numbers normalized in adult OL CKO mice.

Inactivation of murine TH transporters Mct8/Oatp1c1 in OL cells causes a delayed oligodendroglia maturation and myelination. These findings highlight a physiologically relevant function of Mct8/Oatp1c1 in developmental oligodendrogenesis and myelin formation. In contrast to the persistent myelination defect seen in central hypothyroid DKO mice, OL CKO mice exhibit only a transient oligodendrocyte differentiation impairment and transient hypomyelination. These observations indicate the presence of additional, yet unknown, TH transporters that ultimately enable cellular TH entry into oligodendroglia cells even in the absence of Mct8/Oatp1c1.

Allan–Herndon–Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type–specific pathologies underlying AHDS remain insufficiently defined.

To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell–cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope.

In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell–cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin–neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number.

Our findings provide the first single-cell–level cortical map of AHDS brain pathology, revealing cilia defects, excitation–inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.

Graves’ orbitopathy (GO) affects approximately 0.1% of the population. GO in anophthalmic patients is extremely rare and may provide insights into the pathogenesis of this disease.

We describe four cases of GO in patients with previously acquired anophthalmia in one eye.

In all cases, the anophthalmic eye showed both clinical and radiological evidence of GO. In two patients, optic nerve compression was present. In all cases, involvement of extraocular muscles was radiologically symmetrical when comparing the two orbits.

GO in anophthalmic patients is a rare combination of ocular morbidities. Early recognition and appropriate management of GO in such patients are important if visual function is to be preserved. Whether anophthalmia predisposes to GO in susceptible patients is unclear. This rare group of patients may provide unique opportunities for studying the pathogenetic mechanisms in GO.

We report a cross-sectional analysis of prevalence and distribution of goiter among commercially insured adults ages 18–64 in the United States using the 2022–2023 Merative™ MarketScan^® Commercial Claims and Encounters Database.

Cases of goiter were identified using ICD-10 diagnosis codes. Prevalence was estimated under nested case definitions and by goiter subtype. Estimates were compared across U.S. Census regions. Multivariable regression was used to model the association of demographic, clinical, and regional variables on goiter prevalence.

Among 15.2 million commercially insured adults enrolled in MarketScan on December 31, 2023, overall goiter prevalence was 12.7–24.6 per 1000 persons. Prevalence was substantially higher among women and increased steadily with age. Non-toxic multinodular goiter accounted for most cases. Prevalence varied by U.S. Census region after adjusting for age, sex, toxic status, and diagnostic intensity.

The prevalence of goiter, comprised predominantly of non-toxic multinodular goiter, is estimated to be 1.3–2.5% among working-age adults in the U.S. and varies by sex, age, and potentially by geography. Further research is needed to investigate environmental and social drivers of the goiter burden.