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Genfeng Yu Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Siyang Liu Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Cheng Song Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Qintao Ma Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Xingying Chen Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Yuqi Jiang Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Hualin Duan Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Yajun He Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Dongmei Wang Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Heng Wan Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Jie Shen Department of Endocrinology and Metabolism, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Guangdong, China

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Background

This study aimed to examine the associations of thyroid hormone sensitivity indices, including free triiodothyronine-to-free thyroxine (FT3/FT4) ratio, thyroid feedback quantile-based index by FT4 (TFQIFT4), thyroid-stimulating hormone index (TSHI), and thyrotrophic thyroxine resistance index (TT4RI) with all-cause mortality in euthyroid adults.

Methods

The study included 6243 euthyroid adults from the National Health and Nutrition Examination Survey (NHANES) 2007–2012. FT3/FT4 ratio, TFQIFT4, TSHI, and TT4RI were calculated. The multivariable Cox proportional hazard regression, restricted cubic spline (RCS), and subgroup analysis were conducted.

Results

Individuals in fourth quartile (Q4) had lower all-cause mortality than those in first quartile (Q1) of FT3/FT4 ratio (hazard ratio (HR): 0.70, 95% CI: 0.51, 0.94). Regarding TFQIFT4, individuals in Q4 of TFQIFT4 had a 43% higher all-cause mortality than those in Q1 (HR: 1.43, 95% CI: 1.05, 1.96) (P < 0.05, all). Compared with participants in Q1, no associations of TSHI and TT4RI with mortality were found. TFQIFT4 was linearly and positively associated with mortality. However, the FT3/FT4 ratio showed a U-shaped association with mortality.

Conclusions

Increased risk for all-cause mortality was positively associated with TFQIFT4, suggesting that increased risk for all-cause mortality was associated with decreased central sensitivity to thyroid hormones. Furthermore, the FT3/FT4 ratio showed a U-shaped association with mortality, with an inflection point at 0.5. However, more cohort studies are needed to validate the conclusions.

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Janice Ser Huey Tan Division of Radiation Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Timothy Kwang Yong Tay Department of Pathology, Singapore General Hospital, Singapore

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Enya Hui Wen Ong Division of Radiation Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Michael Fehlings ImmunoScape, 1 Scotts Road #24-10, Singapore

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Daniel Shao-Weng Tan Division of Medical Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Nadiah Binte Sukma Department of Pathology, Singapore General Hospital, Singapore

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Eileen Xueqin Chen Department of Pathology, Singapore General Hospital, Singapore

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Jen-Hwei Sng Department of Pathology, Singapore General Hospital, Singapore

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Connie Siew Poh Yip Division of Radiation Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Kok Hing Lim Department of Pathology, Singapore General Hospital, Singapore

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Darren Wan-Teck Lim Division of Medical Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Narayanan Gopalakrishna Iyer Division of Surgical Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Jacqueline Siok Gek Hwang Department of Pathology, Singapore General Hospital, Singapore

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Melvin Lee Kiang Chua Division of Radiation Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Mei-Kim Ang Division of Medical Oncology, National Cancer Centre Singapore, Hospital Boulevard, Singapore

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Objective

Anaplastic thyroid cancer (ATC) is an aggressive disease associated with poor outcomes and resistance to therapies. Our study aim was to evaluate the activity of a combinatorial regimen of sandwich sequencing of pembrolizumab immunotherapy and hypofractionated radiotherapy (RT).

Methods

In this case series, patients with ATC received hypofractionated RT (QUAD-shot) and intravenous pembrolizumab 200 mg every 3–4 weeks. Pembrolizumab was continued until disease progression or up till 24 months. Concurrent lenvatinib treatment was allowed. Primary endpoint was best overall response (BOR) and progression-free survival (PFS). Additionally, we performed immune profiling of circulating T cells in a responder to investigate the immune response to our combinatorial treatment.

Results

At median follow-up of 32.6 months (IQR: 26.4–38.8), of a cohort of five patients, BOR was 80%; with two complete responses (CR) and two partial responses (PR). Patients who achieved CR remained disease-free at last follow-up. Median PFS was 7.6 months (IQR: 6.2–NR), and 1-year PFS and overall survival rate was 40% (95% CI: 13.7–100) for both. Treatment was well-tolerated, with mostly grade 1–2 adverse events. Immune profiling of one partial responder revealed an increase in activated CD4 and CD8 T cells post-QUAD-shot RT, which was further enhanced during the maintenance phase of pembrolizumab.

Conclusion

Herein, we report a case series of five patients with ATC, with two long-term survivors who were treated with surgical debulking followed by QUAD-shot RT and pembrolizumab, possibly due to synergy of local and systemic treatments in activating anti-tumour immunogenic cytotoxicity. This regimen warrants further investigation in a larger cohort of patients.

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Rachelle P Mendoza Department of Pathology, University of Rochester Medical Center, Rochester, New York, USA

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Richard Cody Simon Department of Pathology, University of Chicago, Chicago, Illinois, USA

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Nicole A Cipriani Department of Pathology, University of Chicago, Chicago, Illinois, USA

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Tatjana Antic Department of Pathology, University of Chicago, Chicago, Illinois, USA

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Objective

This study aims to analyze the diagnostic utility of multiple repeat FNA on thyroid nodules with initially benign diagnosis.

Methods

In a 5-year period, 1658 thyroid nodules with initially benign FNAs were retrospectively reviewed and followed for subsequent resection and repeat biopsy.

Results

Out of 2150 thyroid nodules, 1658 (77.1%) were diagnosed as benign on FNAs. The average age at diagnosis was 57.4 years (range: 11–93 years), and most were females (83.8%). Repeat FNA was performed on 183 benign nodules, of which 141 (8.5%) were sampled a second time and 42 (2.5%) had two or more repeat samplings. For the benign nodules without repeat FNAs, 124 had benign resection. Of cases with one-time repeat FNA, most (n = 101) remained benign on repeat FNAs, 13 of which were benign on resection. Eleven had atypical repeat FNAs, five were resected, four of which were benign and one was atypical follicular neoplasm with HRAS and TERT promoter mutations. Of cases with multiple repeat FNA, most (n = 35) were still benign on repeat FNAs, one had benign resection. Two had atypical repeat biopsies, one was PTC on resection with CCD6::RET fusion. The positive predictive value significantly decreased from 41.1% on single FNA to 8.3% on one-time repeat (P < 0.001) and 16.7% on multiple repeat (P = 0.002). The total cost for the work-up of previously benign nodules was $285,454.

Conclusions

Repeat FNA biopsies did not provide an additional diagnostic value in the evaluation of benign thyroid nodules, and often led to unwarranted follow-up procedures and significantly increased health-care cost.

Open access
Shaodong Hou Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China
Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China

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Yiceng Sun Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Zeyu Yang Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Mi Tang Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Tingjie Yin Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Cong Shao Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Cunye Yan Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Linlong Mo Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Yuquan Yuan Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Supeng Yin Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China

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Fan Zhang Department of Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing, China
Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China

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Objective

It is crucial to diagnose lymph node (LN) metastases (LNM) before or during thyroid carcinoma surgery. Measurement of thyroglobulin (Tg) in the fine needle aspirate washout (FNA-Tg) is useful to assist in the diagnosis of LNM for papillary thyroid carcinoma (PTC). This study aimed to assess the diagnostic performance of a new technique based on a colloidal gold-based immunochromatographic assay (GICA) for intraoperative FNA-Tg in diagnosing LNM.

Clinical trial information

This study is registered with chictr.org.cn, ID: ChiCTR2200063561 (registered 11 September, 2022).

Methods

This prospective study enrolled 51 PTC patients who underwent cervical LN dissection. A total of 150 LNs dissected from the central and lateral compartments were evaluated by FNA-Tg-GICA at three different time points and compared with frozen sections and the conventional Tg measurement method electrochemiluminescence immunoassay (ECLIA). Receiver operating characteristic curve (ROC) and area under the curve (AUC), cutoff value to discriminate benign and malignant LNs, sensitivity, specificity, and accuracy were provided.

Results

The cutoff value of FNA-Tg to predict LNM was 110.83 ng/mL for ECLIA and 13.19 ng/mL, 38.69 ng/mL, and 77.17 ng/mL for GICA at 3, 10, and 15 min, respectively. There was no significant difference between the AUCs of GICA at different time points compared to using ECLIA and frozen sections. Besides, the diagnostic performance of GICA and ECLIA showed no significant difference in evaluating LNM from central and lateral compartments or between the TgAb-positive subgroup and TgAb-negative subgroup.

Conclusion

GICA is a promising method for intraoperative FNA-Tg measurement and has high value in predicting LNM. It may be a novel alternative or supplementary method to frozen section or ECLIA.

Open access
Georgios Kostopoulos G Kostopoulos, Endocrinology and Metabolism, General Hospital of Thessaloniki Ippokratio, Thessaloniki, Greece

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Grigoris Effraimidis G Effraimidis, Faculty of Medicine, University of Thessaly School of Health Sciences, Larissa, Greece

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Atrial fibrillation (AF) is a common condition with a global estimated prevalence of 60 million cases, and the most common cardiac complication of hyperthyroidism, occurring in 5-15% of overtly hyperthyroid patients. Additionally, subclinical hyperthyroidism and high-normal free T4 have been associated with an increased risk in the development of AF. Hyperthyroidism-related AF is a reversible cause of AF and the majority of patients spontaneously revert to sinus rhythm in 4-6 months during or after restoration of euthyroidism. Therefore, restoring thyroid function is an indispensable element in hyperthyroidism-related AF management. Rate control with beta-blockers consists another first-line therapy, reserving rhythm control in cases of persistent hyperthyroidism-related AF. It is still controversial whether hyperthyroidism is an independent risk factor of stroke in nonvalvular AF. As a result, initiating anticoagulation should be guided by the clinical thrombo-embolic risk score CHA2DS2-VASc score in the same way it is applied in patients with non- hyperthyroidism related AF. Treatment with the novel direct oral anticoagulants appears to be as beneficial and maybe safer than warfarin in patients with hyperthyroidism-related AF. In this review, we address the epidemiology, natural history and diagnosis of hyperthyroidism-related AF and we discuss the management strategies and controversies in patients with hyperthyroidism-related AF.

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Rodrigo Moreno-Reyes R Moreno-Reyes, Department of Nuclear Medicine, Université Libre de Bruxelles, Bruxelles, 1050, Belgium

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Ulla Feldt-Rasmussen U Feldt-Rasmussen, Department of Endocrinology and Metabolism, University of Copenhagen, Kobenhavn, 1165, Denmark

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Agnieszka Piekiełko-Witkowska A Piekiełko-Witkowska, Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, 01-813, Poland

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Adriana Gaspar da Rocha A Gaspar da Rocha, Public Health Unit, University of Porto Institute of Molecular Pathology and Immunology, Porto, 4200-465, Portugal

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Corin Badiu C Badiu, National Institute of Endocrinology "C Davila" University of Medicine and Pharmacy, Bucharest, Romania

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Josef Koehrle J Koehrle, Institut für Experimentelle Endokrinologie, Berlin, Germany

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Leonidas Duntas L Duntas, Metabolism and Diabetes National Kapodistrian University of Athens, Athens, Greece

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Abstract

In 2022, the European Chemicals Agency (ECHA) made a statement concluding that iodine is an endocrine disruptor (ED). "We stress the fact that the ECHA opinion ECHA/BPC/357/2022 is based on their misguidedly zooming in on exclusively the biocidal products (e.g., hand disinfectants, disinfection of animals’ teats/udder, embalming fluids before cremation, etc.) that contain molecular iodine (I2), entirely neglecting [see the 2013 ECHA Regulation (EU) n°528/2012 describing iodine as being of “great importance for human health”. Clearly, the current sweeping and erroneous classification of “iodine” as an endocrine disruptor is ill-advised. We moreover call upon the scientific and medical community at large to use the accurate scientific nomenclature, i.e., iodide or iodate instead of “iodine” when referring to iodized salts and food prepared there with. Drugs, diagnostic agents, and synthetic chemicals containing the element iodine in the form of covalent bonds must be correctly labelled ‘’iodinated’’, if possible, using each time their distinctive and accurate chemical or pharmacological name.

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Rodrigo Moreno-Reyes Department of Nuclear Medicine, Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium

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Ulla Feldt-Rasmussen Department of Endocrinology and Metabolism, University Hospital Rigshospitalet, and Faculty of Ηealth and Clinical Sciences, University of Copenhagen, Copenhagen, Denmark

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Agnieszka Piekiełko-Witkowska Centre of Postgraduate Medical Education, Centre of Translational Research, Department of Biochemistry and Molecular Biology, Warsaw, Poland: Basic Lead of the European Society of Endocrinology Focus Area on Thyroid

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Adriana Gaspar da Rocha Public Health Unit, ULS Baixo Mondego, Figueira da Foz, Portugal Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal

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Corin Badiu National Institute of Endocrinology "C. Davila" University of Medicine and Pharmacy, Bucharest, Romania

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Josef Köhrle Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, Berlin, Germany: Co-Lead of the European Society of Endocrinology Focus Area on Environmental Endocrinology

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Leonidas Duntas Evgenideion Hospital, Unit of Endocrinology, Metabolism and Diabetes, National Kapodistrian University of Athens, Athens, Greece

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Graphical abstract

Abstract

In 2022, the European Chemicals Agency (ECHA) made a statement concluding that iodine is an endocrine disruptor (ED). We stress the fact that the ECHA opinion ECHA/BPC/357/2022 is based on their misguidedly zooming in on exclusively the biocidal products (e.g. hand disinfectants, disinfection of animals’ teats/udder, embalming fluids before cremation) that contain molecular iodine (I2), entirely neglecting the 2013 ECHA Regulation (EU) no. 528/2012 describing iodine as being of ‘great importance for human health’. Clearly, the current sweeping and erroneous classification of ‘iodine’ as an endocrine disruptor is ill-advised. We moreover call upon the scientific and medical community at large to use the accurate scientific nomenclature, i.e. iodide or iodate instead of ‘iodine’ when referring to iodized salts and food prepared there with. Drugs, diagnostic agents, and synthetic chemicals containing the element iodine in the form of covalent bonds must be correctly labeled ‘iodinated’, if possible, using each time their distinctive and accurate chemical or pharmacological name.

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Tommaso Piticchio T Piticchio, Department of Clinical and Experimental Medicine, University of Catania, Catania, 95131, Italy

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Gilles Russ G Russ, Centre de Pathologie et d'Imagerie, 75014 - PARIS 14, France

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Maija Radzina M Radzina, Radiology research laboratory, Riga, Latvia

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Francesco Frasca F Frasca, Endocrinology, Garibaldi-NesimaMedical Center, Catania, Italy

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Cosimo Durante C Durante, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy

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Pierpaolo Trimboli P Trimboli, Clinic for Endocrinology and Diabetology, Lugano Regional Hospital, Ente Ospedaliero Cantonale, Lugano, Switzerland, Lugano, Switzerland

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Context

Ultrasound-based risk stratification systems (TIRADSs) of thyroid nodules (TNs) have been implemented in clinical practice worldwide, based on their high performance. However, it remains unexplored whether different TIRADSs perform uniformly across a range of TNs in routine practice. This issue is highly relevant today, given the ongoing international effort to establish a unified TIRADS (i.e. I-TIRADS), supported by the leading societies specializing in TNs. The study aim was to conduct a direct comparison among ACR-, EU-, and K-TIRADS in the distribution of TNs: 1) across the TIRADS categories, and 2) based on their estimated cancer risk.

Methods

A search was conducted on Pubmed and Embase until June 2023. Original studies that sequentially assessed TNs using TIRADSs, regardless of FNAC indication, were selected. General study characteristics and data of distribution of TNs across TIRADSs were extracted.

Results

Seven studies, reporting a total of 41,332 TNs, were included in the analysis. The prevalence of ACR-TIRADS 1-2 was significantly higher than that of EU-TIRADS 2 and K-TIRADS 2, with no significant difference observed among intermediate- and high-risk categories of TIRADSs. According to malignancy risk estimation, K-TIRADS often classified TNs as having more severe risk, ACR-TIRADS as moderate risk, while EU-TIRADS classified TNs as lower risk.

Conclusions

ACR-, EU-, and K-TIRADS assess TNs similarly across their categories, with slight differences in low-risk classifications. Despite this, focusing on cancer risk estimation, the three TIRADSs assess TNs differently. These figures should be considered as prerequisite for developing the I-TIRADS

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Thea Riis T Riis, Department of Endocinology , Odense University Hospital, Odense , Denmark

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Steen Joop Bonnema S Bonnema, Odense University Hospital, Odense C, 5000, Denmark

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Thomas Heiberg Brix T Brix, Department of Endocrinology, Odense University Hospital, Odense, Denmark

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Lars Folkestad L Folkestad, Department of Endocrinology, Odense University Hospital, Odense, Denmark

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Objectives: Cancer is the second most common cause of death worldwide. It is currently debated whether thyroid dysfunction is a modifiable cancer risk factor. Our aim was to evaluate the risk of cancer in patients with hyperthyroidism.

Methods: This is a register-based nationwide cohort study of individuals with a diagnosis of hyperthyroidism. Each hyperthyroid case was matched with four reference individuals according to age and sex. Using Fine and Gray competing risk regression models, we studied the association of hyperthyroidism and subsequent all-cause cancer diagnoses, adjusted for preexisting morbidity. Sub-analyses were stratified for cause of hyperthyroidism (Graves’ disease and toxic nodular goiter, age when diagnosed with hyperthyroidism, sex, and cancer localization (lung-, prostate-, breast-, and colorectal).

Results: The cohort consisted of 95,469 patients with hyperthyroidism (followed for a median of 10.9 years (range: 5.2-17.2)), and 364,494 reference individuals (followed for a median of 11.2 years (range: 5.4-17.4)). Hyperthyroidism was associated with increased all-cause cancer risk (sub-distribution hazard ratio (SHR): 1.12; 95% confidence interval (CI): 1.10-1.14), as well as an increased risk of breast- (SHR: 1.07; 95% CI: 1.02-1.13), lung- (SHR: 1.20; 95% CI: 1.16-1.26), and prostate cancer (SHR: 1.10; 95% CI: 1.02-1.19), but not colorectal cancer (SHR: 1.04; 95% CI: 0.99-1.09). Sub-analyses stratified for age when diagnosed with hyperthyroidism and cause of hyperthyroidism yielded similar results.

Conclusion: In this register-based study, patients with hyperthyroidism had an increased risk of cancer, in particular lung, prostate, and breast cancer. Whether a causal link exists remains to be proven.

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