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Laura Fugazzola Department of Clinical Sciences and Community Health, University of Milan and Endocrine Unit, Fondazione IRCCS Ca' Granda, Milan, Italy

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Medullary thyroid cancer can be highly aggressive, especially if the diagnosis is done in advanced stages. Early diagnosis is based on RET genetic testing, for familial forms, and on the routine measurement of calcitonin (Ct). Nevertheless, since false-positive results can be obtained with the basal measurement of Ct, a provocative test to evaluate stimulated Ct is often needed. Pentagastrin which has been widely used to stimulate basal Ct, especially in European countries, is now hardly available. Thus, the stimulation with calcium (Ca), used in the 1970s-1980s and then abandoned for around 30 years, has recently elicited more interest. In the past 3 years, studies in patients and normal controls have demonstrated that the stimulation with Ca (2.3-2.5 mg/kg of elemental Ca, corresponding to 25 mg/kg of Ca gluconate) is highly potent and accurate. Novel gender-related cut-offs have been proposed for the Ca test, though the analysis of additional large series is predicted to modify these preliminary data. Finally, Ca seems to be the test of choice to stimulate Ct for the diagnosis and follow-up of medullary thyroid cancer, also because it is widely available, has a low cost and it is associated with a low number and intensity of side effects. In the present review the different methods to stimulate Ct and the cut-offs for the identification of the hyperplastic/neoplastic transformation of the C cells will be reported and discussed.

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Kris Poppe Endocrine Unit, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Peter Bisschop Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Laura Fugazzola Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Gesthimani Minziori Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

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David Unuane Department of Internal Medicine, Endocrine Unit, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium

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Andrea Weghofer Department of Gynecological Endocrinology & Reproductive Medicine, Medical University of Vienna, Vienna, Austria

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Severe thyroid dysfunction may lead to menstrual disorders and subfertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be a solution. Prior to an ART treatment, ovarian stimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating levothyroxine (LT4) supplements before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic subfertility have a higher prevalence of TAI. Women with hypothyroidism treated with LT4 prior to ART should have a serum TSH level <2.5 mIU/L. Subfertile women with hyperthyroidism planning an ART procedure should be informed of the increased risk of maternal and foetal complications, and euthyroidism should be restored and maintained for several months prior to an ART treatment. Fertilisation rates and embryo quality may be impaired in women with TSH >4.0 mIU/L and improved with LT4 therapy. In meta-analyses that mainly included women with TSH levels >4.0 mIU/L, LT4 treatment increased live birth rates, but that was not the case in 2 recent interventional studies in euthyroid women with TAI. The importance of the increased use of intracytoplasmic sperm injection as a type of ART on pregnancy outcomes in women with TAI deserves more investigation. For all of the above reasons, women of subfertile couples should be screened routinely for the presence of thyroid disorders.

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Marta Di Stefano Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Carla Colombo Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Simone De Leo Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Michela Perrino Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Mauro Viganò Division of Hepatology, San Giuseppe Hospital Multimedica IRCCS, Milan, Italy

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Luca Persani Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Clinical Sciences and Community Health, Milan, Italy

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Laura Fugazzola Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Introduction: Lenvatinib (LEN) is a multitarget tyrosine kinase inhibitor currently used for advanced, radioiodine refractory differentiated thyroid cancer (RAI-R DTC). Among adverse events (AEs), nausea, vomiting, and decreased appetite have been frequently described. We aimed to evaluate the prevalence, the clinical presentation, and the effectiveness of conservative treatment of gallbladder disorders in a consecutive series of patient treated with LEN. Methods: Patients with RAI-R DTC experiencing clinical symptoms suggestive for gallbladder disorders during LEN treatment were evaluated with laboratory investigations and contrast-enhanced abdominal computed tomography (CT) and ultrasound scan (US). Results: After a median time of 2 months from the start of treatment, 5/13 patients (38.4%) complained of gastrointestinal symptoms, with increased biliary enzymes levels, especially γGT, and CT/US suggestive of acute cholecystitis (AC). The onset of symptoms and the peak of γGT levels frequently corresponded to the highest reduction in body weight during the first months of treatment. All patients were treated with supportive care and, when appropriate, with ursodeoxycholic acid; in 4 patients, LEN dose reduction or short interruption was needed, too. Conclusions: In patients with RAI-R DTC treated with LEN, a high prevalence of AC in the first months of treatment was documented. Mainly due to the low specificity of symptoms such as anorexia, nausea, and vomiting, this AE is likely to be frequently misdiagnosed. The onset of the disease was associated to the weight loss observed during the first months of treatment and contributes to further decrease in body weight. Therefore, particularly during the first months of treatment, or at any time of huge reduction of body weight, monitoring of γGT and US is crucial for prompt diagnosis and treatment. Conservative medical treatment and LEN dosage titration, together with dietary and rehabilitative supports, can limit or avoid the need for drug withdrawal and cholecystectomy.

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Carla Colombo C Colombo, Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Milano, Italy

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Daniele Ceruti D Ceruti, Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy

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Massimiliano Succi M Succi, Department of Biotechnology and Translational Medicine, University of Milan, Milano, Italy

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Simone De Leo S De Leo, Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Istituto Auxologico Italiano, Milan, Italy

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Matteo Trevisan M Trevisan, Department of Biotechnology and Translational Medicine, University of Milan, 20100, Milan, Italy., University of Milan, Milano, Italy

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Claudia Moneta C Moneta, Department of Biotechnology and Translational Medicine, University of Milan, 20100, Milan, Italy. , University of Milan, Milan, Italy

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Laura Fugazzola L Fugazzola, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy

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Background: Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI).

Aim: To assess the entire adrenal function in patients on systemic treatments.

Methods: ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, 6 on vandetanib, and 5 on selpercatinib). ACTH stimulation test was performed in 26 cases.

Results: After a median treatment period of 7 months, we observed an increase in ACTH values in 80-100% of patients, and an impaired cortisol response to ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-Androstenedione and 17-OH progesterone levels were below the median of normal values (n.v.) in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of n.v. in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the n.v. in most cases, while renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI.

Conclusions: Our data confirm that systemic treatments for advanced thyroid cancer can lead to an impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been firstly reported and should be considered in the more appropriate management of these fragile patients.

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Laura Fugazzola Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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

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Dagmar Fuhrer Department of Endocrinology, Diabetes and Metabolism, Endocrine Tumour Center at West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany

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Barbara Jarzab Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute, Oncology Center, Gliwice Branch, Gliwice, Poland

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Sophie Leboulleux Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France

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Kate Newbold Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom

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Jan Smit Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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The vast majority of thyroid cancers of follicular origin (TC) have a very favourable outcome, but 5–10% of cases will develop metastatic disease. Around 60–70% of this subset, hence less than 5% of all patients with TC, will become radioiodine refractory (RAI-R), with a significant negative impact on prognosis and a mean life expectancy of 3–5 years. Since no European expert consensus or guidance for this challenging condition is currently available, a task force of TC experts was nominated by the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. The task force started to work in September 2018 and after several revision rounds, prepared a list of recommendations to support the treatment and follow-up of patients with advanced TC. Criteria for advanced RAI-R TC were proposed, and the most appropriate diagnostic tools and the local, systemic and palliative treatments are described. Systemic therapy with multikinase inhibitors is fully discussed, including recommendations on how to start it and at which dosage, on the duration of treatment, and on the management of side effects. The appropriate relationship between the specialist and the patient/family as well as ethical issues are covered. Based on the available studies and on personal experience, the experts provided 39 recommendations aimed to improve the management of advanced RAI-R TCs. Above all of them is the indication to treat and follow these patients in a specialized setting which allows the interaction between several specialists in a multidisciplinary team.

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Simone De Leo Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Carla Colombo Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

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Marta Di Stefano Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy

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Antonella Dubini Division of Laboratory Medicine, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Silvia Cozzi Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

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Luca Persani Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy

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Laura Fugazzola Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

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Weight loss is one of the most frequent adverse events during treatment with multikinase inhibitors, but scanty data are available on its extent and characteristics. This is the first assessment of the body composition by bioelectrical impedance analysis and of circulating leptin and ghrelin levels, in patients with advanced thyroid cancer before and at regular intervals during treatment with the tyrosine kinase inhibitor lenvatinib. Body mass index (BMI) decreased in all patients, with an average ∆ reduction of –6.4, –9.8, and –15.3% at 3, 6, and 12 months of treatment, respectively. Interestingly, in most patients, after the first year of treatment, BMI remained stable. In all patients, fat mass (FM) reduced more than fat-free mass, the highest decrement being of –60 and –16%, respectively. A decrease in the body cell mass, a parameter mainly due to muscle tissue, was observed only in patients with a vast baseline muscular mass. Total body water decreased in parallel to BMI. During treatment, leptin tightly paralleled the decrease of BMI values, consistent with the decrease in FM, whereas ghrelin levels increased upon BMI decrease. The loss of the FM accounts for the largest portion of BMI reduction during lenvatinib treatment. The increase in ghrelin could account for the BMI stabilization observed after 1 year of treatment. Nevertheless, oral nutritional supplements should be given as early as possible and athletic patients should be encouraged to maintain physical activity. In some circumstances, parenteral nutrition is required for the rehabilitation of these patients.

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Giovanni Mauri Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
Division of Interventional Radiology, European Institute of Oncology, IRCCS, Milan, Italy

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Laszlo Hegedüs Department of Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark

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Steven Bandula Interventional Oncology Service, University College Hospital, London, United Kingdom

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Roberto Luigi Cazzato Department of Interventional Radiology, University Hospital of Strasbourg, Strasbourg, France

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Agnieszka Czarniecka The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

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Oliver Dudeck Center for Microtherapy, Klinik Hirslanden, Zurich, Switzerland

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Laura Fugazzola Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Romana Netea-Maier Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Gilles Russ Thyroid and Endocrine Tumors Unit, La Pitie-Salpetriere Hospital, Sorbonne University, Paris, France

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Göran Wallin Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

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Enrico Papini Department of Endocrinology & Metabolism, Ospedale Regina Apostolorum, Albano, Italy

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The growing detection of papillary thyroid microcarcinomas (PTMCs) is paralleled by an increase in surgical procedures. Due to the frequent indolent nature, cost, and risk of surgery, active surveillance (AS) and ultrasound-guided minimally invasive treatments (MITs) are in suitable cases of incidental PTMC proposed as alternatives to thyroidectomy. Surgery and radioiodine are the established treatments for relapsing cervical differentiated thyroid carcinoma (DTC) metastases. But radioiodine refractoriness, risk of surgical complications, adverse influence on quality of life, or declining repeat surgery have led to AS and MIT being considered as alternatives for slow-growing DTC nodal metastases. Also, for distant radioiodine-refractory metastases not amenable to surgery, MIT is proposed as part of a multimodality therapeutic approach. The European Thyroid Association and the Cardiovascular and Interventional Radiological Society of Europe commissioned these guidelines for the appropriate use of MIT. Based on a systematic PubMed search, an evidence-based approach was applied, and both knowledge and practical experience of the panelists were incorporated to develop the manuscript and the specific recommendations. We recommend that when weighing between surgery, radioiodine, AS, or MIT for DTC, a multidisciplinary team including members with expertise in interventional radiology assess the demographic, clinical, histological, and imaging characteristics for appropriate selection of patients eligible for MIT. Consider TA in low-risk PTMC patients who are at surgical risk, have short life expectancy, relevant comorbidities, or are unwilling to undergo surgery or AS. As laser ablation, radiofrequency ablation, and microwave ablation are similarly safe and effective thermal ablation (TA) techniques, the choice should be based on the specific competences and resources of the centers. Use of ethanol ablation and high-intensity focused ultrasound is not recommended for PTMC treatment. Consider MIT as an alternative to surgical neck dissection in patients with radioiodine refractory cervical recurrences who are at surgical risk or decline further surgery. Factors that favor MIT are previous neck dissection, presence of surgical complications, small size metastases, and <4 involved latero-cervical lymph nodes. Consider TA among treatment options in patients with unresectable oligometastatic or oligoprogressive distant metastases to achieve local tumor control or pain palliation. Consider TA, in combination with bone consolidation and external beam radiation therapy, as a treatment option for painful bone metastases not amenable to other established treatments.

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Irene Campi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Maura Agostini Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Federica Marelli Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Tiziana de Filippis Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Beatriz Romartinez-Alonso Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom

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Odelia Rajanayagam Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Giuditta Rurale Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Ilaria Gentile Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Federica Spagnolo Unit of Endocrinology, University Hospital “G. Martino”, Messina, Italy

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Massimiliano Andreasi Laboratorio Analisi Cliniche, Centro di Ricerche e Tecnologie Biomediche, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Italy

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Francesco Ferraù Unit of Endocrinology, University Hospital “G. Martino”, Messina, Italy
Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

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Salvatore Cannavò Unit of Endocrinology, University Hospital “G. Martino”, Messina, Italy
Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

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Laura Fugazzola Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Krishna V. Chatterjee Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Luca Persani Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Introduction: Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. Case Presentation: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. Conclusion: Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.

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Carla Colombo Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Daniele Ceruti Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Simone De Leo Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Grzegorz Bilo Department of Cardiology, San Luca Hospital, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy

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Matteo Trevisan Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Noemi Giancola Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Claudia Moneta Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Gianfranco Parati Department of Cardiology, San Luca Hospital, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy

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

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Laura Fugazzola Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Background

Hypertension (HTN) is the most frequent adverse event during treatment with lenvatinib (LEN), but data on its best management are limited.

Aim

The objective of this study was to assess incidence, features and best management of LEN-related HTN in a consecutive single tertiary-care centre cohort.

Methods

Twenty-nine patients were followed up for a mean time of 29.8 months (6–77 months).

Results

After a mean follow-up of 6.8 months, HTN was recorded in 76% of cases, as a de novo occurrence in half of them. HTN significantly correlated with LEN dose and was of grade 1, grade 2 and grade 3 in 5%, 50% and 45% of patients, respectively. The majority (77%) of patients with HTN developed proteinuria. There was no correlation between HTN and proteinuria or clinical features or best morphological response or any other adverse event (AE), with the exception of diarrhoea. Patients with or without pre-existing HTN or any other cardiovascular disease had a similar incidence of HTN during LEN, thus excluding the impact of this potential predisposing factor. After evaluation by a dedicated cardiologist, medical treatment was introduced in 21/22 patients (polytherapy in 20 of them). The most frequently used drugs were calcium channel blockers (CCBs) due to their effect on vasodilation. In case of poor control, CCBs were associated with one or more anti-hypertensive drug.

Conclusion

HTN is a frequent and early AE in patients on LEN treatment. We suggest a diagnostic and therapeutic algorithm to be applied in clinical practice to allow efficient HTN control and improve patient compliance, reducing LEN discontinuation.

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