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Frank Weber Department of General‐, Visceral‐ and Transplantations Surgery, Division of Endocrine Surgery, Medical Faculty, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45130 Essen, Germany

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Immune responses by innate and adaptive immune cells are crucial for the suppression of carcinogenesis and tumor spread. Effector T cells such as, cytotoxic CD8+ T (CTL), natural killer (NK), and NK T cells (NKT cells) prevent tumor growth by their ability to induce apoptosis in cancer cells. To circumvent anti-tumor immunity, tumors commonly attract regulatory T cells (Treg), which suppress the function of CTL and NKT cells in a contact- and cytokine-dependent manner. Recent findings in patients with thyroid cancer have suggested that an imbalance between immune suppressive and anti-tumor cells occurs during thyroid carcinogenesis. However, the composition and regulation of immune responses in thyroid cancer are still elusive and a comprehensive immune profile of thyroid cancer is missing. In this issue of Endocrine-Related Cancer, Imam et al. compare immune profiles between patients with papillary thyroid carcinoma and autoimmune thyroiditis. Their data suggest that an imbalance between immunosuppressive Treg cells and effector T cells occurs during papillary thyroid carcinogenesis. Their study identified double-negative T cells as a novel key factor involved in this process. Future research is required to recapitulate these findings, to elucidate the mechanisms by which the immune response is regulated and to evaluate if this process might be used for the therapeutical management of thyroid cancer.

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

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Lois M Mulligan Division of Cancer Biology and Genetics Cancer Research Institute, Queen’s University, Kingston, Canada

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Andreas Machens Medical Faculty, Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Kerstin Lorenz Medical Faculty, Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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

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Henning Dralle Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Serisha Moodley Division of Cancer Biology and Genetics, Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada

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

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Lois M Mulligan Division of Cancer Biology and Genetics, Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada

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Andreas Machens Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

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Kerstin Lorenz Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, 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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Henning Dralle Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

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Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1–40 mm (node metastasis and biochemical cure) and 10.1–40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27–41% (overall 24.0%) point difference, followed by biochemical cure with a −15–35% (overall −20.3%) point difference and extrathyroid extension with a 17–24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

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Vera Tiedje Department of Endocrinology, Diabetology and Metabolism, Endocrine Tumour Center at West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Martin Stuschke Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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

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Henning Dralle Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Laura Moss Velindre Cancer Centre, Cardiff, Wales, UK

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

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Anaplastic thyroid carcinoma (ATC) is an orphan disease and in most patients fatal. So far no established treatment is available that prolongs survival. Several large retrospective studies have identified negative prognostic markers, analyzed efficacy of multimodal approaches such as radiotherapy with and without concurrent chemotherapy and chemotherapy protocols. Recently, single case reports have suggested some effectiveness of newer therapies targeting single somatic alterations in ATC. Overall, the conclusions that can be drawn from published retrospective studies and the scarce prospective approaches is that new treatment protocols should be developed including surgery, radiotherapy, chemotherapy and targeted therapy approaches and combinational therapy with immunotherapies. These protocols then need to be evaluated prospectively to improve ATC patients’ outcome in routine care.

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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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