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Andreas Machens Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

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Kerstin Lorenz Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

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Frank Weber Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Tim Brandenburg Department of Endocrinology, Diabetology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Dagmar Führer-Sakel Department of Endocrinology, Diabetology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Henning Dralle Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5–50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

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Marcia S. Brose M Brose, Department of Medical Oncology,, Thomas Jefferson University Sidney Kimmel Medical College, Philadelphia, United States

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Jaume Capdevilla J Capdevilla, Medical Oncology Department, Gastrointestinal and Endocrine Tumor Unit, Vall d´Hebron Institut d´Oncologia, Barcelona, Spain

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

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Lars Bastholt L Bastholt, Department of Clinical Oncology, Odense Universitetshospital, Odense, Denmark

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Dagmar Führer-Sakel D Führer-Sakel, Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, University Hospital Essen, Essen, Germany

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Sophie Leboulleux S Leboulleux, Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Villejuif, France

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Iwao Sugitani I Sugitani, Surgery, Nihon Ika Daigaku, Bunkyo-ku, Japan

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Matthew H. Taylor M Taylor, Providence Cancer Institute, Earle A Chiles Research Institute, Portland, United States

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Zhuoying Wang Z Wang , Department of Head Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

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Lori J. Wirth L Wirth, Department of Medicine, Massachusetts General Hospital, Boston, United States

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Francis P. Worden F Worden, Rogel Cancer Center, University of Michigan, Ann Arbor, United States

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John Bernard J Bernard, Clinical Development, Sanofi, Cambridge, United States

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Paolo Caferra P Caferra, Clinical Development, Sanofi, Amsterdam, Netherlands

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Raffaella M. Colzani R Colzani, Medical Affairs, Sanofi, Cambridge, United States

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Shiguang Liu S Liu, Clinical Development, Sanofi, Cambridge, United States

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Martin Schlumberger M Schlumberger, Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Villejuif, France

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VERIFY study is a randomized, double-blind, multicenter phase III clinical trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic differentiated thyroid cancer (DTC), refractory to radioiodine (RAI) therapy with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib and 118 patients received placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.55–1.03; p = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events [CTCAE] adverse events of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo though the difference in OS was not statistically significant.

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