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Search for other papers by Megumi Fujikawa in
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Objective: As thionamide is associated with various adverse effects, we reevaluated the practical efficacy of potassium iodide (KI) therapy for Graves’ hyperthyroidism (GD).
Methods: We administered KI (mainly 100 mg/day) to 324 untreated GD patients, and added methimazole (MMI) only to those remaining thyrotoxic even at 200 mg/day. When the patient became hypothyroid, MMI if taken was stopped, then levothyroxine (LT4) was added without reducing the KI dose. Radioactive iodine (RI) therapy or thyroidectomy was performed whenever required. We evaluated the early effects of KI at 2-4 weeks, and followed patients for 2 years.
Results: At 2 weeks, serum thyroid hormone decreased in all 324 patients. At 4 weeks, fT4, fT3, and both fT4 and fT3 levels became normal or low in 74.7%, 50.6%, and 50.6%, respectively. In a cross-sectional survey over 2-years, GD was well-controlled with KI or KI+LT4 (KI-effective) in >50% of patients at all time points. Among 288 patients followed for 2 years, 42.7% remained ‘KI-effective’ throughout 2 years (KI Group), 30.9% were well-controlled with additional MMI given for 1-24 months, and 26.4% were successfully treated with ablative therapy (mainly RI). Among ‘KI-effective’ patients at 4 weeks, 76.5% were classified into KI Group. No patients experienced adverse effects of KI.
Conclusion: KI therapy was useful in the treatment of GD. A sufficient dose of KI was effective in >50% of GD patients from 4 weeks to 2 years, and 42.7% (76.5% of ‘KI effective’ patients at 4 weeks) remained ‘KI-effective’ throughout 2 years.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy
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Search for other papers by Patrice Rodien in
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Endocrine Section, Beacon Hospital, Dublin, Ireland.
School of Medicine, University College Dublin, Ireland
Endocrinology Department, St Vincent’s University Hospital, Dublin, Ireland
Search for other papers by Carla Moran in
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Search for other papers by Krishna Chatterjee in
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Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.
Search for other papers by Hyunju Park in
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Search for other papers by Jung Heo in
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Search for other papers by Tae hyuk Kim in
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Search for other papers by Sun Wook Kim in
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Search for other papers by Jae Hoon Chung in
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Objective: Previous reports suggest that a high body mass index (BMI) increases the risk of thyroid carcinoma. However, it remains unclear whether a high BMI is associated with the risk of BRAFV600E mutation. We aimed to assess whether a high BMI is associated with an increased risk of BRAFV600E mutation.
Design and Methods: We screened 6,558 PTC patients who had undergone BRAFV600E mutation testing between January 2009 and December 2017. After exclusion, 6,438 PTC patients were enrolled. We used logistic regression, and restricted cubic spline plots of the adjusted odd ratios (ORs) were illustrated to model the relationship between BMI and BRAFV600E mutation.
Results: Among the 6,438 patients, 5,102 (79.2%) had the BRAFV600E mutation, and 4,954 (76.9%) were female. The median BMI was 23.8 (21.6 – 26.2) kg/m2. The primary tumor size was ≤ 1cm in 4,226 patients (65.6 %) and > 1cm in 2,212 patients (34.4 %). The BRAFV600E mutation was significantly associated with high BMI only in patients with primary tumor size > 1cm (OR 1.034; 95% CI 1.003 – 1.065; P = 0.029), whereas no clear association was found in patients with primary tumor size ≤ 1cm (OR 1.007; 95% CI 0.984 – 1.030; P = 0.570). Gender was not a significant factor in either group.
Conclusions: Our study found that a higher BMI was positively associated with BRAFV600E mutation in patients with primary tumor size > 1cm. These results suggest that the association between BMI and BRAFV600E mutation status differs depending on primary tumor size.
Search for other papers by Hyun-Jin Lee in
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Search for other papers by Young-Sool Hah in
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Search for other papers by So Young Cheon in
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Search for other papers by Seong Jun Won in
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Search for other papers by Somi Ryu in
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Search for other papers by Jung Je Park in
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Objective: This study examined the effect of Sirtuin 4 (Sirt4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).
Methods: Data from The Cancer Genome Atlas (TCGA) were analyzed to identify Sirt4 expression in thyroid cancer. Subsequently, the correlation between Sirt4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated Sirt4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.
Results: GEO and TCGA data indicated that Sirt4 expression is lower in thyroid cancer and Sirt4 downregulation is associated with poor overall survival. In our PTC tissues, positive Sirt4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of Sirt4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. Sirt4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial–mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.
Conclusion: This study provides novel insight into the potential contribution of Sirt4 to regulation of the pathological progression of PTC. The data suggest that Sirt4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of Sirt4.
Search for other papers by Pepijn van Houten in
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Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
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Search for other papers by Martin Jaeger in
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Search for other papers by Adriana C H van Engen-van Grunsven in
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Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
Search for other papers by Romana T Netea-Maier in
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Objective
Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC.
Methods
Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies.
Results
Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial.
Conclusion
Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Search for other papers by Kenneth Ka Hei Lai in
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Department of Ophthalmology, Salmaniya Medical Complex, Government Hospitals, Bahrain
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Department of Ophthalmology, Vicente Sotto Memorial Medical Center, Cebu City, Philippines
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Search for other papers by Yingying Wei in
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Search for other papers by Elaine Yuen Ling Au in
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Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China
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Search for other papers by Wilson Wai Kuen Yip in
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Search for other papers by Alvin Lerrmann Young in
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Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China
Search for other papers by Clement Chee Yung Tham in
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Search for other papers by Chi Pui Pang in
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Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China
Search for other papers by Kelvin Kam Lung Chong in
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Purpose
This study aims to report correlations between thyroid-stimulating immunoglobulin (TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease (TED) patients.
Methods
A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the Clinical Activity Score (CAS), marginal reflex distance1 (MRD1), extraocular muscle motility restriction (EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI.
Results
A total of 255 (197 female) treatment-naive patients, with an average onset age of 50 ± 14 years (mean ± s.d.), were included. Elevated pre-treatment TSI level was observed in 223 (88%) patients. There was a weak positive correlation between TSI and CAS (r = 0.28, P = 0.000031), MRD1 (r = 0.17, P = 0.0080), and the size of the levator palpebrae superioris/superior rectus complex (r = 0.25, P = 0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67 (95% CI: 0.60–0.75) and 284% (specificity: 50%, sensitivity: 85%). In total, 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP (P = 0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level (P < 0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and did not respond to the first course of IVMP.
Conclusion
TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be warranted.
Search for other papers by Alison-Michelle Naujack in
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Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signalling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized, that epigenetic mechanisms may be involved in modulating hepatic TH action.
Methods: Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2-cells were used to validate functional binding of miRNA to predicted targets. DNA-methylation was analyzed by bisulfite-pyrosequencing.
Results: miR-34a-5p was upregulated in MASH patients and correlated positively with clinical parameters of MASH. Using in silico and in vitro analysis we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2-cells reduced the expression of THRA, THRB, DIO1 and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As additional regulatory mechanism, DNA-methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression.
Conclusion: miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB specific DNA-methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.
Search for other papers by Carla Gambale in
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Search for other papers by Alessandro Prete in
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Search for other papers by Antonio Matrone in
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Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70 years-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.
Search for other papers by Elisa Minaldi in
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Objective
The aim of this study was to assess the clinical impact of hand–foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features.
Methods
We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analyses were performed to verify which features could be correlated with HFS development.
Results
HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups.
Conclusion
HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.
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Graphical abstract
Abstract
Background
Thyroid carcinoma (TC) incidence increased over the past 50 years. The explanation for this is not consensual.
Objective
Compare incidental vs non-incidental TC (ITC vs NITC) regarding demographic, clinical, histological data and 5-year clinical outcomes.
Design
Retrospective analysis of 225 papillary TC (PTC) cases that completed a 5-year follow-up.
Methods
Created 2 groups: ITC (including the incidentalomas) and NITC (cases of palpable or visible nodules or with thyroid compressive complaints).
Results
Included 225 PTC (122 were ITC). There were 95 women in ITC and 78 in NITC. ITC patients were significantly older (53.3 ± 14.8 vs 47.2 ± 17.7, P = 0.006). Groups had no differences in family history of TC. ITC mean tumour size was smaller (19.1 ± 9.2 vs 28.6 ± 16.2, P < 0.01). Tumours > 20 mm comprised 36.1% of ITC and 58.2% of NITC. We found no differences in tumour multifocality, histological thyroiditis, aggressive PTC subtypes, capsule or lymph-vascular invasion and gross extrathyroidal extension. There were no differences regarding the number of patients submitted to RAI or in RAI activity. pTMN staging showed higher prevalence of T3a and T4 cases (P < 0.01), and M1 status (P = 0.025) in NITC. There were no differences in the rates of persistence of disease. Logistic regression showed that the diagnostic modality had no impact on the 5-year clinical outcome.
Conclusion
ITC patients were older and had smaller tumours. NITC showed no worst histological features or 5-year clinical outcome. Approximately, one third of ITC had diameters > 20 mm. As even large tumours can be ITC, overdiagnosis is the most likely cause of increasing incidence of TC.
