European Thyroid Journal最新文献

Objective: To analyse at our institution the criteria for selecting a first-line therapy for patients with advanced radioiodine-refractory thyroid cancer and their clinical responses, safety and survival outcomes.

Patients and methods: We extracted data from 69 consecutive patients referred to Federico II University Hospital from September 2016 to September 2024, among whom 44 patients were treated with TKIs as first-line treatment and outside any clinical trial, and form the basis of this report.

Results: Thirty-one (71%) patients were treated with the antiangiogenesis inhibitor lenvatinib and 13 (29%) were treated with selective tyrosine kinase inhibitors (s-TKIs). Among the latter, eight patients were treated with dabrafenib + trametinib (DT), two patients were treated with selpercatinib because of contraindications to lenvatinib, and three patients received DT as redifferentiation therapy. A RECIST partial response was observed in 28% of patients treated with lenvatinib, in 63% of those treated with DT and in one of the two patients treated with selpercatinib. Grade ≥3 adverse events occurred in 13 (42%) patients treated with lenvatinib and only in 1 (9%) patient treated with DT. Progression-free survival (PFS) and overall survival rates at 1 year were 72% and 83% in lenvatinib-treated patients and 69% and 83% in DT-treated patients, respectively. In both selpercatinib-treated patients, the PFS at data cut-off was 10 months. No treatment-related deaths were observed.

Conclusion: S-TKIs permitted tailoring systemic treatment based on disease location, tumour volume and patient comorbidities, achieving satisfactory tolerance and outcomes in selected patients with an actionable driver mutation and with contraindications to angiogenesis inhibitors or candidates for redifferentiation therapy.

Background: In relapsing differentiated thyroid cancer (DTC), the in vivo evaluation of natrium-iodide symporter (NIS) expression is pivotal in the therapeutic planning and is achieved by 131/123Iodine (131/123I) whole body scan. However, these approaches have low sensitivity due to the low resolution of SPECT. 18F-Tetrafluoroborate (TFB) has been proposed as a viable alternative, which could outperform 131/123I scans owing to the superior PET resolution. We have reviewed the literature to collect the available data on TFB diagnostic performance and compare it with the standard methods.

Methods: Two authors searched PubMed, CENTRAL, Scopus, Web of Science and the web for studies evaluating the biodistribution and dosimetry of TFB in patients with DTC. General characteristics, technical parameters, procedures' sensitivities and standards of reference were extracted from the selected studies. The risk of bias was evaluated with the QUADAS-2 scoring system.

Results: Five studies were included in the review. Two analysed TFB's biodistribution and dosimetry, while the other three assessed its diagnostic performance. The diagnostic comparators were 18F-FDG PET/CT (all cases), 124I-PET/CT (one study) and diagnostic/therapeutic 131I-SPECT/CT (one study each). TFB performed better than 131I; the TFB and 18F-FDG PET/CT combination achieved the best sensitivity. TFB delivered significantly less dose than the other NIS tracers.

Conclusion: TFB is a promising tracer in relapsing DTC, showing higher sensitivity and less radiation exposure than the standard methods. The TFB and 18F-FDG combination appears particularly intriguing, especially when disease heterogeneity is suspected. However, data are still sparse and need to be confirmed by further investigations.

Objective: Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) cause Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with muscle hypoplasia and spastic paraplegia as key symptoms. These abnormalities have been attributed to impaired TH transport across brain barriers and into neural cells, thereby affecting brain development and function. Likewise, Mct8/Oatp1c1 (organic anion-transporting polypeptide 1c1) double knockout (M/Odko) mice, a well-established murine AHDS model, display a strongly reduced TH passage into the brain as well as locomotor abnormalities. To which extent the peripheral nervous system is affected by combined MCT8/OATP1C1 deficiency has not been addressed.

Methods: Using the sciatic nerve as a model, we studied the spatiotemporal expression of TH transporters as well as the sciatic thyroidal state, sciatic nerve myelination and function in M/Odko mice by immunofluorescence, qPCR, Western blotting and electrophysiology.

Results: We detected MCT8 protein expression in sciatic nerve axons, whereas OATP1C1 expression was observed in a subset of endothelial cells early in postnatal development. The absence of MCT8 and OATP1C1 did not alter the thyroidal state of isolated nerves at P12. Moreover, electrophysiological studies did not disclose any significant alteration in sciatic nerve signal propagation parameters in adult M/Odko mice. Although Schwann cell numbers were similar, Western blot analysis showed a mild form of hypermyelination in adult M/Odko mice.

Conclusions: Altogether, our data point to a largely unaffected sciatic nerve structure and function in the absence of MCT8 and OATP1C1.

Background: Thyroid eye disease (TED) is the most prevalent extrathyroidal manifestation of Graves' disease (GD). Emerging evidence suggests a relationship between elevated total and low-density lipoprotein (LDL) cholesterol levels and TED. This study aimed to investigate this correlation in the Brazilian population by analyzing data from two tertiary care centers.

Methods: Data were collected from GD patients treated with methimazole between 1999 and 2021, excluding those receiving other treatments. Laboratory results and information on smoking habits, statin use and medications affecting lipid profiles during the euthyroid state were analyzed.

Results: Smoking and elevated LDL cholesterol levels were significantly associated with TED activity and severity. Logistic regression revealed correlations between higher LDL cholesterol, total cholesterol and increased clinical activity score (P < 0.01, OR: 1.012, 95% CI: 1.003-1.021; P < 0.01, OR: 1.010, 95% CI: 1.002-1.018). These were also associated with more severe disease forms as defined by EUGOGO (P < 0.01, OR: 1.015, 95% CI: 1.006-1.024; P < 0.005, OR: 1.011, 95% CI: 1.004-1.019). Multiple regression confirmed that TED activity was significantly correlated with LDL cholesterol (P < 0.01) and smoking status (P < 0.01). Disease severity was associated with reduced HDL cholesterol (P < 0.05, OR: 0.973, 95% CI: 0.948-0.999), elevated LDL cholesterol (P < 0.005, OR: 1.013, 95% CI: 1.004-1.023) and active smoking (P < 0.05, OR: 2.881, 95% CI: 1.190-6.971).

Conclusion: Elevated LDL cholesterol may serve as a potential indicator of TED. Further research is needed to determine whether lipid-lowering interventions could reduce TED risk or improve its management.

Objective: Thyroid hormones control a variety of processes in the central nervous system and influence its response to different stimuli, such as ischemic stroke. Post-stroke administration of 3,3',5-triiodo-L-thyronine (T3) has been reported to substantially improve outcomes, but the optimal dosage and time window remain elusive.

Methods: Stroke was induced in mice by transient middle cerebral artery occlusion (tMCAO), and T3 was administered at different doses and time points before and after stroke.

Results: We demonstrated a dose-dependent protective effect of T3 reducing infarct volumes with an optimal T3 dosage of 25 μg/kg. In addition, we observed a time-dependent effectiveness that was most profound when T3 was administered 1 h after tMCAO (P < 0.001), with a gradual reduction in efficacy at 4.5 h (P = 0.066), and no reduction in infarct volumes when T3 was injected with an 8-h delay (P > 0.999). The protective effect of acute T3 treatment persisted for 72 h post-tMCAO (P < 0.01) and accelerated the recovery of motor function by day 3 (P < 0.05). In-depth investigations further revealed reduced cerebral edema and diminished blood-brain barrier leakage, indicated by reduced extravasation of Evans blue and diminished aquaporin-4 expression.

Conclusion: Our findings suggest that T3 may be a promising intervention for ischemic stroke in the acute phase.

Background: Congenital hypothyroidism (CH) is a preventable cause of neurodevelopmental delay in children, detectable by newborn screening (NBS) programs for CH. Since NBS for CH was started in Canada in 1974, numerous countries have successfully implemented this public health strategy. However, in 2014, only 29.3% of newborns worldwide were screened by NBS for CH.

Objective: This study aimed to assess the implementation of new NBS programs for CH over the past decade, and screening methods and coverage rates of current programs. In addition, it sought to update the worldwide iodine status.

Methods: We reviewed literature data on NBS programs for CH and their coverage rates for each country, using PubMed, Embase and Google searches.

Results: Currently, 29.6% of children worldwide are screened for CH. Europe, North America, Oceania, China, Japan and Israel have efficient programs with optimal coverage. Recently, some countries of Central and Western Asia have implemented NBS programs for CH, and coverage has increased in several Asian countries. South America has also seen substantial improvements in coverage. In contrast, almost none of the African countries has widespread screening programs, but some attempts with pilot studies and local initiatives have been witnessed. Global iodine sufficiency has improved, with 149 of 193 countries achieving adequate iodine levels by 2023.

Conclusions: Over the past decades, several countries have launched NBS programs for CH or conducted pilot studies, and the coverage of most existing NBS programs has increased. Nevertheless, approximately 70% of newborns worldwide still lack access to NBS for CH, predominantly in African and Asian countries, accounting for a significant part of annual births.

Objective: Pleural metastasis (PM) is rare in patients with differentiated thyroid cancer (DTC). Radioiodine (131I) therapy has been the main treatment for postoperative metastasis and recurrence of DTC. However, clinical data on PM from DTC are limited. This study investigated the clinicopathological characteristics of patients with PM from DTC that were treated surgically and with 131I therapy and evaluated their long-term prognosis and prognostic factors.

Methods: A review of the Shanghai Sixth People's Hospital medical records from 2010 to 2023 identified PM in 27 of 14,473 patients with DTC. Overall survival (OS) was assessed by the Kaplan-Meier method.

Results: The prevalence of PM in DTC was 1.87‰ (27/14,473). The median age at the time of initial diagnosis of PM was 59 years (range: 34-79). At the end of follow-up, eight patients (29.63%) had disease progression (PD), four (14.81%) had a partial response, and the remainder had stable disease; no patient achieved complete response. Twelve patients (44.44%) died, and 15 (55.56%) survived. Thirteen patients (48.15%) did not show 131I avidity, and 16 (59.26%) had radioiodine-refractory DTC (RR-DTC). Twenty patients (74.07%) had malignant pleural effusion (MPE), which was large in 11 cases (40.74%) and moderate in two. More-than-moderate MPE (P = 0.031), lack of 131I avidity (P = 0.041) and RR-DTC (P = 0.030) were significantly associated with worse 5-year OS in patients with PM of DTC.

Conclusions: PM is rare in DTC. Lack of 131I avidity, RR-DTC and more-than-moderate MPE are associated with poor OS in patients with DTC and PM.

Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs), with thyroid irAEs being the most common endocrine-related irAEs. The incidence of overt thyroid irAEs was in the range of 8.9-22.2% in real-world settings, typically triggered by antibodies against PD-1 and PD-L1 and rarely by anti-CTLA-4 antibodies alone. The representative clinical course involves biphasic changes in thyroid function: transient thyrotoxicosis and subsequent persistent hypothyroidism. The identified risk factors for thyroid irAEs include the presence of thyroid autoantibodies, thyroid uptake on 18F-FDG-PET, prior use of tyrosine kinase inhibitors (TKIs), high BMI and high thyroid-stimulating hormone levels. There is evidence that overt thyroid irAEs are associated with good prognosis, at least in non-small cell lung cancer. Although the clinical features have been well clarified, the management strategies require further refinement. Routine monitoring of thyroid function every 4-6 weeks during ICI therapy is recommended for early detection of thyroid irAEs. While thyrotoxicosis generally requires observation only, hypothyroidism should be promptly treated with levothyroxine replacement. Continuation of ICI therapy is typically feasible in patients with thyroid irAEs, provided their overall health remains stable. However, these strategies were largely based on clinical experience with monotherapy. As combination ICI therapies have been developed as first-line treatments, antitumor agents may modify the clinical features of thyroid irAEs. For example, cytotoxic agents can delay the onset of thyroid irAEs, while TKIs are often linked to early-onset hypothyroidism, independent of ICI use. Given the increasing diversity and complexity of cancer immunotherapy, it is essential to vigilantly screen for thyroid irAEs.

Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point mutations (50.4%), particularly HRAS (70.3%), compared with other PTC drivers (9.3%), supporting the conclusion that 22qDEL is unlikely to be a solitary driver of PTC but possibly an important co-factor in carcinogenesis, particularly in PTCs with RAS driver mutations. Differential RNA expression analyses revealed downregulation of most genes located on chromosome 22 in cases with 22qDEL compared to those without 22qDEL. Many differentially expressed genes are drawn from immune response and regulation pathways. These findings highlight the value of further investigations into the contributions of 22qDEL events to PTC, perhaps mediated through immune perturbations.

Objective: Fine-needle aspiration (FNA) cytological analysis fails to confirm the benignity or malignancy of Bethesda III, IV and V thyroid nodules. Molecular tests performed on FNA samples have demonstrated interesting results in improving the diagnosis of these nodules. The aim of this study was to assess the performance of a large next-generation sequencing (NGS) panel in thyroid nodules with indeterminate cytology (Bethesda III, IV and V).

Methods: Retrospective, monocentric study including 121 patients with cytologically indeterminate thyroid nodules (Bethesda III, IV and V) who underwent a routine FNA procedure for molecular testing using the AmpliSeq general cancer NGS panel, with an available final histological diagnosis. The main objective was to estimate the negative predictive value (NPV) of malignancy of the AmpliSeq panel in Bethesda III and IV thyroid nodules. Performance assessment (sensitivity, specificity, positive predictive value (PPV) and NPV) was carried out in the grouped categories III and IV, in the overall cohort and in each Bethesda category. The final histological diagnosis was used as the designated gold standard.

Results: Histologically, 86 nodules were benign and 35 nodules were malignant. Molecular analysis yielded a positive result in 40 nodules. Panel performances assessed in the grouped categories Bethesda III and IV demonstrated a 55.0% (95% CI: 31.5; 76.9) sensitivity, a 76.9% (95% CI: 66.0; 85.7) specificity, a 37.9% (95% CI: 25.7; 51.9) PPV and an 87.0% (95% CI: 80.2; 91.7) NPV, considering a 20% prevalence of malignancy.

Conclusions: The performances of the AmpliSeq panel are promising; however, the NPV is not sufficient to avoid diagnostic surgery in cytologically indeterminate thyroid nodules.

Significance statement: Different ancillary molecular tests have been marketed in the USA and are integrated into the management of thyroid nodules with indeterminate cytology. Unfortunately, none of these molecular tests are currently available in France and clinicians lack effective tools for the management of these nodules. The aim of this work was to assess the performance of a large general-cancer targeted NGS panel in a series of thyroid nodules with indeterminate cytology (i.e. Bethesda III and IV categories and, to some extent, the Bethesda V category), managed in a French university medical center referral for thyroid tumors.