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Kenneth Ka Hei Lai Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Fatema Mohamed Ali Abdulla Aljufairi Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Department of Ophthalmology, Salmaniya Medical Complex, Government Hospitals, Bahrain

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Jake Uy Sebastian Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Department of Ophthalmology, Vicente Sotto Memorial Medical Center, Cebu City, Philippines

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Yingying Wei Department of Statistics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Ruofan Jia Department of Statistics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Karen Kar Wun Chan Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

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Elaine Yuen Ling Au Division of Clinical Immunology, Department of Pathology, Queen Mary Hospital, Hong Kong Special Administrative Region, China

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Alan Chun Hong Lee Division of Endocrinology and Metabolism, Department of Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region, China

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Chiu Ming Ng Department of Medicine, Queen Elizabeth Hospital, Hong Kong Special Administrative Region, China

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Hunter Kwok Lai Yuen 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

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Wilson Wai Kuen Yip Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

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Alvin Lerrmann Young Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

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George Pak Man Cheng Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Clement Chee Yung Tham Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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

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Chi Pui Pang Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Kelvin Kam Lung Chong Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
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

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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.

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Chae Won Chung Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea
Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea

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Kyungsik Kim Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

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Sue K Park Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Korea

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Dal Lae Ju Department of Food Service and Nutrition Care, Seoul National University Hospital, Seoul, Korea

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Young Joo Park Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea

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Choong Ho Shin Department of Pediatrics, Seoul National University Children’s Hospital and Seoul National University College of Medicine, Seoul, Korea

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Jong Kwan Jun Department of Obstetrics and Gynecology, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea

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June-Key Chung Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea

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Yoon Ju Song Department of Food Science and Nutrition, The Catholic University of Korea, Bucheon, Korea

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Young Ah Lee Department of Pediatrics, Seoul National University Children’s Hospital and Seoul National University College of Medicine, Seoul, Korea

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Gi Jeong Cheon Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea

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Sun Wook Cho Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea

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Objective

This study aimed to assess selenium status in South Korean pregnant women and its impact on maternal thyroid function and pregnancy outcomes.

Methods

‘Ideal Breast Milk (IBM) Cohort Study’ included 367 pregnant women out of 442 participants and categorized into three groups based on plasma selenium levels: deficient (< 70 μg/L), suboptimal (70–99 μg/L), and optimal (≥ 100 μg/L). During the second or third trimester, various blood parameters, including selenium, thyroid-stimulating hormone, free T4, free T3, and anti-thyroid peroxidase antibody levels, were measured. Thyroid parenchymal echogenicity was assessed as another surrogate marker for thyroid autoimmunity using ultrasonography.

Results

The median plasma selenium was 98.8 (range: 46.7–206.4) μg/L, and 30 individuals (8%) were categorized as deficient, while 164 (45%) were classified in the suboptimal group. Selenium deficiency was associated with markers of autoimmune thyroiditis, including positive anti-thyroid peroxidase antibody results (13.3 (deficient) vs 4.6 (optimal) %, P = 0.031) and thyroid parenchymal heterogeneity on ultrasound (33.3 (deficient) vs 14.6 (suboptimal) vs 17.3 (optimal) %, P = 0.042), independently of gestational age. The incidence of severe preeclampsia was higher in the group not taking selenium supplements, particularly among those with twin pregnancies, compared to the group taking selenium supplements (0 (selenium supplement) vs 9.0 (no supplement) %, P = 0.015).

Conclusion

Pregnant women experience mild selenium deficiency, which can lead to significant health issues including maternal thyroid autoimmunity and obstetrical complications during pregnancy. Guidelines for appropriate selenium intake according to the stage of pregnancy and the number of fetuses are needed.

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Luca Persani L Persani, Medical Biotechnologies and Translational Medicine, University of Milan, Milano, 20149, Italy

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Patrice Rodien P Rodien, EDN, Centre Hospitalier Universitaire d'Angers, Angers, 49933, France

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Carla Moran C Moran, Diabetes & Endocrinology Section, Beacon Hospital, Sandyford, Ireland

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W. Edward Visser W Visser, Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands

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Stefan Groeneweg S Groeneweg, Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands

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Robin P. Peeters R Peeters, Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands

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Samuel Refetoff S Refetoff, Departments of Medicine and Pediatrics, The University of Chicago, Chicago, 60637-1476, United States

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Mark Gurnell M Gurnell, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland

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Paolo Beck-Peccoz P Beck-Peccoz, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy

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Krishna Chatterjee K Chatterjee, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom of Great Britain and Northern Ireland

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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 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 summarising 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.

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Elisa Minaldi E Minaldi, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Virginia Cappagli V Cappagli, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Loredana Lorusso L Lorusso, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Laura Valerio L Valerio, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Carlotta Giani C Giani, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Matilde Viglione M Viglione, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Laura Agate L Agate, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Eleonora Molinaro E Molinaro, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Antonio Matrone A Matrone, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Rossella Elisei R Elisei, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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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 analysis was 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.

Conclusions:

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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Inês Cosme I Cosme, Endocrinology, Unidade Local de Saúde Santa Maria, Lisbon, Portugal

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Ana Figueiredo A Figueiredo, Endocrinology, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal

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Sara Pinheiro S Pinheiro, Endocrinology, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal

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Valeriano Leite V Leite, Endocrinology, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal

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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 >20mm 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.

Conclusions: 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 >20mm. As even large tumours can be ITC, overdiagnosis can be the most likely cause for the TC increasing incidence.

Open access
Julia Baran J Baran, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Mya Bojarsky M Bojarsky, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Stephen Halada S Halada, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Julio C. Ricarte-Filho J Ricarte-Filho, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Amber Isaza A Isaza, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Aime T. Franco A Franco, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Lea F. Surrey L Surrey, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, United States

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Tricia Bhatti T Bhatti, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, United States

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Zubair W. Baloch Z Baloch, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States

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N. Scott Adzick N Adzick, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, United States

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Sogol Mostoufi-Moab S Mostoufi-Moab, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Ken Kazahaya K Kazahaya, Division of Pediatric Otolaryngology, The Children's Hospital of Philadelphia, Philadelphia, United States

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Andrew Bauer A Bauer, Division of Endocrinology and Diabetes, The Thyroid Center, The Children's Hospital of Philadelphia, Philadelphia, United States

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Objective: The American Thyroid Association (ATA) Pediatric Guidelines recommend selective, prophylactic central neck dissection (pCND) for patients with papillary thyroid carcinoma (PTC) based upon tumor focality, tumor size, and the surgeon’s experience. With the expansion of pre-surgical somatic oncogene testing, and continued controversy over the benefit of pCND, oncogenic alteration data may provide an opportunity to stratify pCND. This study compared lymph node (LN) involvement in pediatric patients with PTC between tumors with low- and high-invasive-associated alterations to explore the potential utility of preoperative oncogenic alterations in stratification of pCND.

Methods: Retrospective cohort study of pediatric patients who underwent somatic oncogene testing post-thyroidectomy for PTC between July 2003-July 2022.

Results: Of 192 eligible PTC patients with postoperative somatic oncogene data, 19 tumors harbored somatic alterations associated with low-invasive disease (19/192, 10%), and 128 tumors harbored a BRAFV600E alteration (45/192, 23%) or an oncogenic fusion (83/192, 43%). Tumors with low-invasive alterations were less likely to present malignant preoperative cytology (2/18, 11%) than those with high-invasive alterations (97/124, 78%; p<0.001). Twelve patients with low-invasive alterations had LNs dissected from the central neck (12/19, 63%) compared to 127 patients (127/128, 99%) with high-invasive alterations. LN metastasis was identified in two patients with low-invasive alterations (2/19, 11%) compared to 107 patients with high-invasive alterations (107/128, 84%; p<0.001).

Conclusions: Pediatric patients with low-invasive somatic oncogenic alterations are at low-risk for metastasis to central neck LNs. Our findings suggest that preoperative knowledge of somatic oncogene alterations provides objective data to stratify pediatric patients who may not benefit from pCND.

Open access
Andrea Leoncini A Leoncini, EOC, Bellinzona, Switzerland

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Chiara Camponovo C Camponovo, EOC, Bellinzona, Switzerland

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Gaetano Paone G Paone, EOC, Bellinzona, Switzerland

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Elena Gamarra E Gamarra, Endocrinologia-Diabetologia, Repubblica e Cantone Ticino Ente Ospedaliero Cantonale, Lugano, Switzerland

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Giorgio Treglia G Treglia, EOC, Bellinzona, Switzerland

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Pierpaolo Trimboli P Trimboli, EOC, Bellinzona, Switzerland

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Objective.

Thyroid nodule (TN) is usually managed according to Thyroid Imaging And Reporting Data Systems (TIRADS) with the major aim to reduce as much as possible unnecessary fine-needle aspiration cytologies (UN-FNACs). Since the assessment of autonomously functioning thyroid nodule (AFTN) according to TIRADS is heterogeneous, that virtually benign entity may increase the rate of UN-FNAC. This study retrospectively analyzed the appropriateness of TIRADS-based FNAC indication in AFTNs, also looking at the impact of TSH and nodule size.

Methods.

Cases diagnosed with AFTN on scintigraphy were searched. Patients who had undergone AFTN treatment, were on medications or supplementation that could affect thyroid function, or had multiple AFTNs were excluded. The AFTNs were assessed according to ACR-TIRADS.

Results.

Forty-eight AFTNs were included and a 37.5% of cases had FNAC indication according to TIRADS. The FNAC indication rate of patients with TSH lower than 0.4 mIU/L was significantly higher than the remaining ones (p = 0.0078). The most accurate cut-off of TSH and AFTN size associated with UN-FNAC was ≤0.41 mIU/L and >22 mm, respectively. The multivariate analysis showed that both TSH and nodule size were independent predictors of UN-FNAC with OR 6.65 and 6.46, respectively. According to these data, the rate of FNAC indication dropped up to 4.16%.

Conclusion.

Inappropriate FNACs in AFTNs are primarily observed in patients with low TSH and large AFTN. Since these cases typically undergo scintigraphy, the risk of TIRADS-based UN-FNAC is clinically negligible. There is no need for integrating other imaging procedures into the TIRADS model.

Open access
Jingyue Chen Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Chenyan Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Weiping Teng Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Zhongyan Shan Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Jun Jin Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Yining Wei Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Jing Sun Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Yushu Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Huifang Zhou Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Objective

The management of thyroid eye disease (TED) has undergone significant changes for decades. The study sought to investigate current clinical practice on the management of TED in China.

Methods

An online questionnaire survey was conducted from April to May 2023. The questionnaire involved diagnostic criteria for TED, multidisciplinary treatment (MDT) collaboration, and treatment preference for mild, moderate, and severe TED.

Results

A total of 289 questionnaires were collected, with 165 from endocrinologists and 124 from ophthalmologists. Only 36.7% of participants claimed there was an MDT clinical pattern for TED in their institutions. The coverage of biological agents was around 10% or lower. These were distinctly lower than in Western countries. About 62.6% of participants believed the incidence of TED has increased in recent years. Imaging techniques were used widely to assist in the diagnosis of TED. However, there was still controversy regarding the definition of proptosis in the Chinese population. Most doctors managed risk factors and provided orbital supportive treatments of artificial tears and glasses. For mild active TED, endocrinologists (39.4%) were inclined to recommend therapy for hyperthyroidism alone, while ophthalmologists (43.6%) preferred orbital corticosteroid injections. Currently, the most widely used treatment for moderate to severe active TED was high-dose intravenous corticosteroid (94.8%), while orbital radiotherapy combined with immunosuppressive agents was the most recognized second-line therapy (43.6%).

Conclusion

The study documented the consistency and differences between current clinical practices in the management of TED in China and the recently updated guidelines. There was a remarkable difference between ophthalmology and endocrinology departments, warranting management optimization.

Open access
Line Tang Møllehave Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Nils Knudsen Department of Endocrinology, Bispebjerg University Hospital, University of Copenhagen, Denmark

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Allan Linneberg Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Inge Bülow Pedersen Department of Endocrinology and Medicine, Aalborg University Hospital, Aalborg, Denmark

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Gitte Ravn-Haren Research Group for Risk Benefit, National Food Institute, Technical University of Denmark, Lyngby, Denmark

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Anja Lykke Madsen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Allan Carlé Department of Endocrinology and Medicine, Aalborg University Hospital, Aalborg, Denmark

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Charlotte Cerqueira The Danish Clinical Quality Program – National Clinical Registries (RKKP), Denmark

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Anne Krejbjerg Department of Oncology, Aalborg University Hospital, Aalborg, Denmark

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Lone Banke Rasmussen Independent researcher, Klemensker, Denmark

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Lars Ovesen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Hans Perrild Department of Endocrinology, Bispebjerg University Hospital, University of Copenhagen, Denmark

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Lena Bjergved Sigurd Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Internal Medicine, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark

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Betina Heinsbæk Thuesen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Pernille Vejbjerg Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Torben Jørgensen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild–moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program – as IF – is initiated.

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Ana Isabel Álvarez-Mancha Department of Medicine, University of Malaga, Malaga, Spain
Department of Pathology, General University Hospital of Ciudad Real, Ciudad Real, Spain

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Isabel Mancha-Doblas Department of Medicine, University of Malaga, Malaga, Spain
Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain

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María Molina-Vega Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain
The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA-BIONAND Platform), University of Malaga, Malaga, Spain

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Diego Fernández-García Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain

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Ana María Gómez-Pérez Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain
The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA-BIONAND Platform), University of Malaga, Malaga, Spain

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Elena Gallego-Domínguez Department of Medicine, University of Malaga, Malaga, Spain
Department of Pathology, Virgen de la Victoria University Hospital, Málaga, Spain

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María Victoria Ortega-Jiménez Department of Medicine, University of Malaga, Malaga, Spain
Department of Pathology, Virgen de la Victoria University Hospital, Málaga, Spain

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Isabel Hierro-Martín Department of Pathology, Virgen de la Victoria University Hospital, Málaga, Spain

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Francisco J Tinahones Department of Medicine, University of Malaga, Malaga, Spain
Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain
The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA-BIONAND Platform), University of Malaga, Malaga, Spain

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Graphical abstract

Abstract

Objective

The objective of this study was to analyze the evolution in the diagnosis and management of indeterminate thyroid nodules over three time periods.

Methods

In total, 3020 patients with thyroid nodules underwent cytological evaluation during three periods (2006–2008, 2012–2014, 2017–2019). The distribution of diagnostic cytology, risk of malignancy, diagnostic performance indices of fine needle aspiration (FNA), and cytologic–histologic correlation in indeterminate cytology were analyzed.

Results

Only 2.2% of cytology tests were insufficient for a diagnosis. About 86.9% cytology was benign, 1.7% malignant, and 11.4% indeterminate. Indeterminate cytology rates were 15.9% (2006–2008), 10.1% (2012–2014), and 10% (2017–2019). Surgery was performed in 13% of benign cytology, resulting in malignant histology in 2.7%. All malignant and suspicious cytology underwent surgery, with malignancy confirmed in 98% and 77% of cases, respectively.

All ‘indeterminate with atypia’ cytology (2006–2008) and Bethesda IV (2012–2014; 2017–2019) underwent surgery, with malignancy confirmed in 19.6%, 43.8%, and 25.7%, respectively. In the ‘indeterminate without atypia’ category (2006–2008) and Bethesda III (2012–2014; 2017–2019), diagnostic surgery was performed in 57.7%, 78.6%, and 59.4%, respectively, with malignancy confirmed in 3.3%, 20.5%, and 31.6%. The FNA sensitivity was 91.6%, with a negative predictive value greater than 96% in all periods. The specificity exceeded 75% in the last two periods.

Conclusion

The Bethesda system reduces indeterminate cytology and improves the accuracy of FNA diagnosis. We reported a higher proportion of malignancy than expected in Bethesda III, underscoring the importance of having institution-specific data to guide decision-making. However, there is a need for risk stratification tools that allow for conservative management in low-risk cases.

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