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Carole Guerin, Pauline Romanet, David Taieb, Thierry Brue, André Lacroix, Frederic Sebag, Anne Barlier and Frederic Castinetti

Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET. Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia.

Free access

Carole Guerin, David Taieb, Giorgio Treglia, Thierry Brue, André Lacroix, Frederic Sebag and Frederic Castinetti

Therapeutic options available for the treatment of Cushing's syndrome (CS) have expanded over the last 5 years. For instance, the efficient management of severe hypercortisolism using a combination of fast-acting steroidogenesis inhibitors has been reported. Recent publications on the long-term efficacy of drugs or radiation techniques have also demonstrated low toxicity. These data should encourage endocrinologists to reconsider the place of bilateral adrenalectomy in patients with ACTH-dependent aetiologies of CS; similarly, the indication of bilateral adrenalectomy is reassessed in primary bilateral macronodular adrenal hyperplasia. The objective of this review is to compare the efficacy and side effects of the various therapeutic options of hypercortisolism with those of bilateral adrenalectomy, in order to better define its indications in the 21st century.

Free access

Arthur Varoquaux, Electron Kebebew, Fréderic Sebag, Katherine Wolf, Jean-François Henry, Karel Pacak and David Taïeb

The vagus nerve (cranial nerve X) is the main nerve of the parasympathetic division of the autonomic nervous system. Vagal paragangliomas (VPGLs) are a prime example of an endocrine tumor associated with the vagus nerve. This rare, neural crest tumor constitutes the second most common site of hereditary head and neck paragangliomas (HNPGLs), most often in relation to mutations in the succinate dehydrogenase complex subunit D (SDHD) gene. The treatment paradigm for VPGL has progressively shifted from surgery to abstention or therapeutic radiation with curative-like outcomes. Parathyroid tissue and parathyroid adenoma can also be found in close association with the vagus nerve in intra or paravagal situations. Vagal parathyroid adenoma can be identified with preoperative imaging or suspected intraoperatively by experienced surgeons. Vagal parathyroid adenomas located in the neck or superior mediastinum can be removed via initial cervicotomy, while those located in the aortopulmonary window require a thoracic approach. This review particularly emphasizes the embryology, molecular genetics, and modern imaging of these tumors.

Free access

Alexandru Saveanu, Mihaela Muresan, Catherine De Micco, David Taieb, Anne-Laure Germanetti, Frederic Sebag, Jean-François Henry, Laurent Brunaud, Alain Enjalbert, Georges Weryha and Anne Barlier

While somatostatin receptors (sst), through somatostatin-radiolabeled analogs, are used, mainly in second line, in the diagnosis and treatment of pheochromocytomas (PCC) and paragangliomas (PGL), the clinical significance of dopamine receptor subtype 2 (D2) in PCC/PGL is unknown. Indeed, radiolabeled dopamine (DA) analogs such as fluorine 18 (18F)-DA, used for positron emission tomography in PCC localization, are mainly correlated to the presence of noradrenaline transporter (NAT) and vesicular monoamine transporters (VMAT) but not to D2. The aim of this study was to quantitate D2 and sst expression in 52 PCC/PGL and to compare it with that of 35 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Quantitative RT-PCR of sst 1–3 and sst 5, D2, NAT, VMAT1/2 was performed in all tumors, while immunohistochemistry analysis of sst2 and D2 was performed in seven tumors. D2 mRNA was expressed in all PCC/PGL. Mean expression was significantly higher in PCC/PGL than in GEP-NETs (4.8 vs 0.5 copy/copy β-glucuronidase (Gus)). sst2 and sst1 were expressed in most PCC/PGL, with sst2-dominant expression (mean mRNA: 1.6 vs 0.4 copy/copy β-Gus). sst2 expression level was similar to that of GEP-NETs, whereas sst5 expression level was significantly lower (0.12 vs 0.78 copy/copy β-Gus). Our study evidenced strong D2 mRNA expression in PCC and for the first time in PGL. PCC/PGL express sst 2 mRNA at levels similar to those of GEP-NETs. New drugs can target ssts and D2 more efficiently than current somatostatin analogs. Moreover, transporters like NAT and VMAT1/2, could be co-targeted with sst, as a basis of new radionuclide compounds in the imaging and treatment of these tumors.

Open access

Helene Myrtue Nielsen, Alexandre How-Kit, Carole Guerin, Frederic Castinetti, Hans Kristian Moen Vollan, Catherine De Micco, Antoine Daunay, David Taieb, Peter Van Loo, Celine Besse, Vessela N Kristensen, Lise Lotte Hansen, Anne Barlier, Frederic Sebag and Jörg Tost

Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas. Previous studies investigating the IGF2/H19 locus have mainly focused on a single molecular level such as genomic alterations or altered DNA methylation levels and the causal changes underlying IGF2 overexpression are still not fully established. In the current study, we analyzed 62 tumors of the adrenal gland from patients with Conn's adenoma (CA, n=12), pheochromocytomas (PCC, n=10), adrenocortical benign tumors (ACBT, n=20), and adrenocortical carcinomas (ACC, n=20). Gene expression, somatic copy number variation of chr11p15.5, and DNA methylation status of three differential methylated regions of the IGF2/H19 locus including the H19 imprinting control region were integratively analyzed. IGF2 overexpression was found in 85% of the ACCs and 100% of the PCCs compared to 23% observed in CAs and ACBTs. Copy number aberrations of chr11p15.5 were abundant in both PCCs and ACCs but while PCCs retained a diploid state, ACCs were frequently tetraploid (7/19). Loss of either a single allele or loss of two alleles of the same parental origin in tetraploid samples resulted in a uniparental disomy-like genotype. These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles. Our data provide conclusive evidence that loss of the maternal allele correlates with IGF2 overexpression in adrenal tumors and that hypermethylation of the H19 ICR is a consequence thereof.

Free access

Frederic Castinetti, Ana Luiza Maia, Mariola Peczkowska, Marta Barontini, Kornelia Hasse-Lazar, Thera P Links, Rodrigo A Toledo, Sarka Dvorakova, Caterina Mian, Maria Joao Bugalho, Stefania Zovato, Maria Alevizaki, Andrei Kvachenyuk, Birke Bausch, Paola Loli, Simona R Bergmann, Attila Patocs, Marija Pfeifer, Josefina Biarnes Costa, Ernst von Dobschuetz, Claudio Letizia, Gerlof Valk, Marcin Barczynski, Malgorzata Czetwertynska, John T M Plukker, Paola Sartorato, Tomas Zelinka, Petr Vlcek, Svetlana Yaremchuk, Georges Weryha, Letizia Canu, Nelson Wohllk, Frederic Sebag, Martin K Walz, Charis Eng and Hartmut P H Neumann