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Andreas Machens Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Saale, 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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Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a ‘window of opportunity’, within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal ‘tissue-sparing’ adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

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Andreas Machens General, Pathology, Departments of

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Steffen Hauptmann General, Pathology, Departments of

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Henning Dralle General, Pathology, Departments of

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Rearranged during transfection (RET) germ-line mutations in exon 10 are peculiar because they produce both gain-of-function multiple endocrine neoplasia 2A and loss-of-function Hirschsprung's disease phenotypes. Drawing on 38 medullary thyroid cancer patients harboring germ-line mutations in codon 620 (n=8), 618 (n=19), 611 (n=10), and 609 (n=1), this study aimed to test the hypothesis that closer proximity of RET germ-line mutations in exon 10 to the cell membrane may translate into earlier or more advanced disease. The closer mutations in codon 620, 618, and 611 were located to the transmembrane domain (codons 657–636) of the RET receptor, the greater were mean primary tumor diameters (23.5, 18.7, and 7.5 mm, P=0.020), the frequency of lymph node metastasis (75, 68, and 30%, P=0.11) and pheochromocytoma (38, 16, and 0%, P=0.11). Periods of observation were broadly comparable for these groups (mean age 33.4–39.3 years; P=0.71). When mutations in adjoining codons were collapsed (codons 620/618 vs 611/609), the differences in mean primary tumor diameter (20.1 vs 7.4 mm, P=0.005) and lymph node metastasis (70 vs 36%; P=0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, n=78; codon 630, n=2), the 38 carriers of exon 10 mutations, which are rarer and confer a weaker transforming activity in vitro than exon 11 mutations, required significantly more time to develop fewer tumors. Although limited in numbers, these data suggested that membrane proximity is an important determinant of tumor development in carriers of RET mutations in exon 10.

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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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Andreas Machens Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Florian Hoffmann Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Carsten Sekulla Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Henning Dralle Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany

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Men and women differ in thyroidal C-cell mass and calcitonin secretion. This difference may have implications for the definition of calcitonin thresholds to distinguish sporadic C-cell hyperplasia from occult medullary thyroid cancer. This retrospective study examined the hypothesis that gender-specific calcitonin thresholds predict occult medullary thyroid cancer more accurately among patients with increased basal calcitonin levels than unisex thresholds. A total of 100 consecutive patients were evaluated with occult sporadic C-cell disease no larger than 10 mm who were referred for increased basal calcitonin levels and underwent pentagastrin stimulation preoperatively at this institution. Altogether, gender-specific calcitonin thresholds predicted medullary thyroid cancer better than unisex thresholds. At lower (≤50 pg/ml basally; ≤500 pg/ml after stimulation), but not higher, calcitonin serum levels, women revealed medullary thyroid cancer four to eight times more often than men. Most discriminatory between C-cell hyperplasia and medullary thyroid cancer was a basal calcitonin threshold of 15 pg/ml (corrected 20 pg/ml) for women and 80 pg/ml (corrected 100 pg/ml) for men, based on the greatest accuracy at the lowest possible calcitonin level. The respective gender-specific stimulated peak calcitonin thresholds were 80 pg/ml (corrected 100 pg/ml) and 500 pg/ml. Corresponding positive predictive values for medullary thyroid cancer at these calcitonin thresholds were 89 and 90% for women, as opposed to 100% for men. To increase the positive predictive value for women to 100%, the respective calcitonin thresholds would have to be raised to 40 pg/ml (corrected 50 pg/ml) and 250 pg/ml. These findings indicate that gender-specific calcitonin thresholds predict sporadic occult medullary thyroid cancer better than unisex thresholds.

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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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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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