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Stine Linding Andersen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Niels Henrik Bruun Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark

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Peter Astrup Christensen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Simon Lykkeboe Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Aase Handberg Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Annebirthe Bo Hansen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Maja Hjelm Lundgaard Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Louise Knøsgaard Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Nanna Maria Uldall Torp Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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

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Jesper Karmisholt Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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

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Peter Vestergaard Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Steno Diabetes Center North Jutland, Aalborg University Hospital, Aalborg, Denmark

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Stig Andersen Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Geriatrics, Aalborg University Hospital, Aalborg, Denmark

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Objective

Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted.

Methods

Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated.

Results

The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up.

Conclusions

This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

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Henry B Burch National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
Endocrinology Division, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA

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Petros Perros Department of Endocrinology, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

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Tomasz Bednarczuk Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland

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David S Cooper Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Peter J Dolman Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

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Angela M Leung Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UCLA David Geffen School of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA

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Ilse Mombaerts Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium

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Mario Salvi Department of Clinical and Community Services, Graves’ Orbitopathy Center, Endocrinology, Fondazione IRCCS Cà Granda, Milan, Italy

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Marius N Stan Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, Minnesota, USA

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Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this Consensus Statement.

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Andrew J Bauer Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Department of Pediatrics, The University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Jonathan D Wasserman Division of Endocrinology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

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Steven G Waguespack Department of Endocrine Neoplasia and Hormonal Disorders and Department of Pediatrics-Patient Care, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Heleen I Jansen Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands

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Antonius E van Herwaarden Radboud University Medical Center, Department of Laboratory Medicine, Nijmegen, The Netherlands

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Henk J Huijgen Department of Clinical Chemistry, Red Cross Hospital, Beverwijk, The Netherlands

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Rebecca C Painter Department of Obstetrics and Gynaecology, Amsterdam UMC Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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Jacquelien J Hillebrand Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands

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Anita Boelen Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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Annemieke C Heijboer Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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Objective

Thyroid hormone measurements are often performed in pregnant women, as hypo- and hyperthyroidism during pregnancy can severely affect the fetus. Serum free thyroxine (fT4) measurements are well known for their analytical challenges, due to low serum concentrations and the subtle equilibrium between free and bound T4 (to thyroid-binding globulin (TBG), transthyretin and albumin). Pregnant women have high TBG concentrations due to an increase in human chorionic gonadotropin (hCG) and estrogen and lower albumin concentrations which change the equilibrium and may affect the validity of fT4 measurements in their samples. As accurate serum fT4 measurements in pregnant women are important for the long-term health of the fetus, we aimed to evaluate the accuracy of several fT4 immunoassays in the serum of pregnant women.

Methods

FT4 was measured in healthy controls and pregnant women using a candidate-reference method (LC-MS/MS) and five commercially available automated immunoassays (Alinity (Abbott), Atellica (Siemens), Cobas (Roche), Lumipulse (Fujirebio) and UniCel DXI (Beckman Coulter)). Method comparisons (Bland Altman plots and Passing and Bablok analyses) were performed.

Results

Serum samples from both healthy controls (n  = 30) and pregnant women (n  = 30; mean gestational age, 24.8 weeks) were collected. The fT4 immunoassays deviated +7 to +29% more from the LC-MS/MS in serum samples of pregnant women than healthy controls (falsely high).

Conclusions

Our results indicate that immunoassays overestimate fT4 in pregnant women, which might lead to an overestimation of thyroid status. Physicians and laboratory specialists should be aware of this phenomenon to avoid drawing false conclusions about thyroid function in pregnant women.

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Marine Sitbon Pharmacy Department, Hospital Saint-Louis APHP, Paris, France

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Porhuoy Chou Endocrine Oncology Department, Saint-Louis Hospital (AP-HP), Université Paris Cité, Paris, France

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Seydou Bengaly Endocrine Oncology Department, Saint-Louis Hospital (AP-HP), Université Paris Cité, Paris, France

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Brigitte Poirot Department of Molecular Oncology, Saint-Louis Hospital (AP-HP), Université Paris Cité INSERM U 944, CNRS UMR 7212, Paris, France

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Marie Laloi-Michelin Department of Internal Medicine, Hospital Lariboisière APHP, Paris, France

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Laure Deville Pharmacy Department, Hospital Saint-Louis APHP, Paris, France

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Atanas Pachev Radiology Department, Saint-Louis Hospital (AP-HP), Université Paris Cité, Paris, France

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Ahouefa Kowo-Bille Endocrine Oncology Department, Saint-Louis Hospital (AP-HP), Université Paris Cité, Paris, France

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Clement Dumont Medical Oncology Department, Saint-Louis Hospital (AP-HP), Université Paris Cité, Paris, France

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Cécile N Chougnet Endocrine Oncology Department, Saint-Louis Hospital (AP-HP), Université Paris Cité, Paris, France

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The endocrine secretions of carcinomas can be life-threatening. Medullary thyroid carcinoma (MTC) is a rare cancer that is often associated with cortisol secretion, leading to paraneoplastic Cushing’s syndrome. Mutations of the proto-oncogene RET are driver molecular events in 70% of MTC cases. Here, we report a case of a woman, born in 1956, who was diagnosed with sporadic MTC in 2005, with subsequent relapses treated with focal treatments. In April 2019, she presented with severe and rapidly progressive paraneoplastic Cushing’s syndrome associated with lymph node, lung, liver and bone metastases. A supraclavicular lymph node biopsy revealed a somatic p.M918T (c.2753T>C) mutation in exon 16 of the RET proto-oncogene. The patient began treatment with selpercatinib in September 2019. Clinical efficacy was immediate. Chronic diarrhea disappeared within a few days. Clinical hypercorticism quickly disappeared, with quick improvements in muscle and skin conditions and fatigue. Two months after treatment initiation, urinary free cortisol normalized to 42 µg/24 h. Levels of the tumor markers carcinoembryonic antigen (CEA) and calcitonin also greatly decreased from baseline. After 34 months of treatment, selpercatinib elicits sustained clinical, biological and morphological responses. In summary, this case report illustrates the rapid and long-lasting antisecretory effect of selpercatinib associated with tumor control. As Cushing’s syndrome associated with medullary thyroid cancer is associated with poor prognosis, this case report is very encouraging. In addition, this suggests the potential benefit of molecular testing in all cases of medullary thyroid cancer.

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Stamatina Ioakim CEDM, Centre of Endocrinology, Diabetes & Metabolism, Limassol, Cyprus
Medical School, University of Milan, Milan, Italy

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Akheel A Syed Department of Diabetes, Endocrinology & Obesity Medicine, Salford Royal NHS Foundation & University Teaching Trust, Salford, UK
Division of Diabetes, Endocrinology & Gastroenterology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

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George Zavros CEDM, Centre of Endocrinology, Diabetes & Metabolism, Limassol, Cyprus

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Michalis Picolos Alithias Endocrinology Centre, Nicosia, Cyprus

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Luca Persani Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Angelos Kyriacou CEDM, Centre of Endocrinology, Diabetes & Metabolism, Limassol, Cyprus
Department of Diabetes, Endocrinology & Obesity Medicine, Salford Royal NHS Foundation & University Teaching Trust, Salford, UK
Medical School, European University of Cyprus, Nicosia, Cyprus

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Background

The 2015 American Thyroid Association (ATA) Guidelines recommend the following size cut-offs based on sonographic appearances for subjecting nodules to fine-needle aspiration (FNA) biopsy: low risk: 15 mm and intermediate risk and high risk: 10 mm.

Objective

We conducted a ‘real-world’ study evaluating the diagnostic performance of the ATA cut-offs against increased thresholds, in the interest of safely limiting FNAs.

Methods

We performed a retrospective analysis of prospectively collected data on 604 nodules which were sonographically risk-stratified as per the ATA Guidelines and subsequently subjected to ultrasound-guided FNA. Nodules were cytologically stratified into ‘benign’ (Bethesda class 2) and ‘non-benign’ (Bethesda classes 3–6). We obtained the negative predictive value (NPV), accuracy, FNAs that could be spared, missed ‘non-benign’ cytologies and missed carcinomas on histology, according to the ATA cut-offs compared to higher cut-offs.

Results

In low-risk nodules, the high performance of NPV (≈91%) is unaffected by increasing the cut-off to 25 mm, and accuracy improves by 39.4%; 46.8% of FNAs could be spared at the expense of few missed B3–B6 cytologies (7.9%) and no missed carcinomas. In intermediate-risk nodules, a 15 mm cut-off increases the NPV by 11.3% and accuracy by 40.7%. The spared FNAs approach 50%, while B3–B6 cytologies are minimal, with no missed carcinomas. In high-risk nodules, low NPV (<35%) and accuracy (<46%) were obtained regardless of cut-off. Moreover, the spared FNAs achieved at higher cut-offs involved numerous missed ‘non-benign’ cytologies and carcinomas.

Conclusion

It would be clinically safe to increase the ATA cut-offs for FNA in low-risk nodules to 25 mm and in intermediate-risk nodules to 15 mm.

Open access
Luigi Bartalena University of Insubria, Varese, Italy

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Jeppe Lerche la Cour Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Line Tang Møllehave Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Capital Region, Denmark

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Bjarke Røssner Medici Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Christian Zinck Jensen Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Anne Ahrendt Bjerregaard Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Capital Region, Denmark

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Birte Nygaard Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Introduction

High compared with low educational level increases the odds of starting levothyroxine (L-T4) with a normal thyroid-stimulating hormone – the mechanism is most likely patient request. The use of liothyronine (L-T3) and desiccated thyroid extract (DTE) is also speculated to be initiated at patients’ request. Therefore, the primary aim of this study was to evaluate if educational level influences treatment with L-T3 and DTE.

Material and methods

In this register-based cross-sectional study, we included all Danish citizens ≥30 years with redeemed prescription of L-T4, L-T3, or DTE during 2017–2020. We defined educational levels as short, medium, and long (<10 years, 10–12 years, and above 12 years, respectively). The association between educational level and treatment with LT3 or DTE vs only LT4 was analyzed in logistic regression models adjusted for age and sex.

Results

We included 154,360 individuals using thyroid medication of whom 3829 were treated with L-T3 (2.48%) and 430 with DTE (0.28%). The usage was highest among women (3.15%) and the age group 40–49 (5.6%). Longer education compared with short increased the odds of being treated with DTE or L-T3 (medium education odds ratio (OR) 1.61 (95% CI 1.50–1.8) and long education OR 1.95 (95% CI 1.79–2.13)). Test for trend: OR: 1.37 (95% CI 1.31–1.42). Adjustment for other covariates did not affect the results substantially.

Conclusion

Persons with a longer compared to a shorter education are more often treated with either DTE or L-T3, and the usage of these drugs is limited to less than 3% of thyroid hormone users.

Open access
Rémy Louvel Head and Neck Surgical Oncology Department, Institut Curie, PSL University, Paris, France

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Nathalie Badois Head and Neck Surgical Oncology Department, Institut Curie, PSL University, Paris, France

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Jerzy Klijanienko Pathology Department, Institut Curie, PSL University, Paris, France

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Ségolène Hescot Medical Oncology Department, Institut Curie, PSL University, Paris, France

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Caroline Hoffmann Head and Neck Surgical Oncology Department, Institut Curie, PSL University, Paris, France

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Luciana Puleo Endocrine Unit, Department of Clinical and Experimental Medicine

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Laura Agate Endocrine Unit, Department of Clinical and Experimental Medicine

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Irene Bargellini Department of Vascular and Interventional Radiology

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Giuseppe Boni Regional Center of Nuclear Medicine

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Paolo Piaggi Endocrine Unit, Department of Clinical and Experimental Medicine

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Claudio Traino Regional Center of Nuclear Medicine

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Tommaso Depalo Regional Center of Nuclear Medicine

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Giulia Lorenzoni Department of Vascular and Interventional Radiology

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Francesca Bianchi Regional Center of Nuclear Medicine

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Duccio Volterrani Regional Center of Nuclear Medicine

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Sandra Brogioni Endocrine Unit, Department of Clinical and Experimental Medicine

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Valeria Bottici Endocrine Unit, Department of Clinical and Experimental Medicine

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Maurizia Rossana Brunetto Hepatology Unit, University of Pisa, Pisa, Italy

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Barbara Coco Hepatology Unit, University of Pisa, Pisa, Italy

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Eleonora Molinaro Endocrine Unit, Department of Clinical and Experimental Medicine

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Rossella Elisei Endocrine Unit, Department of Clinical and Experimental Medicine

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Objectives

Liver metastases occur in 45% of patients with advanced metastatic medullary thyroid cancer (MTC). Transarterial radioembolization (TARE) has been proposed to treat liver metastases (LM), especially in neuroendocrine tumors. The aim of this study was to investigate the biochemical (calcitonin and carcino-embryonic antigen) and objective response of liver metastases from MTC to TARE.

Methods

TARE is an internal radiotherapy in which microspheres loaded with β-emitting yttrium-90 (90Y) are delivered into the hepatic arteries that supply blood to LM. Eight patients with progressive multiple LM underwent TARE and were followed prospectively. They were clinically, biochemically and radiologically evaluated at 1, 4, 12 and 18 months after TARE.

Results

Two patients were excluded from the analysis due to severe liver injury and death due to extrahepatic disease progression, respectively. One month after TARE, a statistically significant (P = 0.02) reduction of calcitonin was observed in all patients and remained clinically relevant during follow-up; reduction of CEA, although not significant, was found in all patients. Significant reduction of liver tumor mass was observed 1, 4 and 12 months after TARE (P = 0.007, P = 0.004, P = 0.002, respectively). After 1 month, three of six patients showed partial response (PR) and three of six stable disease (SD) according to RECIST 1.1, while five of six patients had a PR and one of six a SD according to mRECIST. The clinical response remained relevant 18 months after TARE. Excluding one patient, all others showed only a slight and transient increase in liver enzymes.

Conclusions

TARE is effective in LM treatment of MTC. The absence of severe complications and the good tolerability make TARE a valid therapeutic strategy when liver LM are multiple and progressive.

Open access