Altérations de la voie de l'AMPc dans la tumorigénèse cortico-surrénalienne (étude des phosphodiestérases PDE11A et PDE8B)

La voie de l AMPc est une voie impliquée dans la physiopathologie de nombreuses tumeurs endocrines. Les phosphodiestérases sont des enzymes clés de la voie de l AMPc dans la mesure où elles permettent de réguler finement les niveaux intra-cellulaires d AMPc en hydrolysant l AMPc en son catabolite inactif, le 5 AMP. L hyperplasie macronodulaire bilatérale des surrénales est une étiologie rare de syndrome de Cushing ACTH-indépendant responsable d un syndrome de Cushing souvent modéré contrastant avec la taille des nodules surrénaliens. Sa physiopathologie est mal connue.Nous avons tout d abord pu montrer dans ce travail que les variants faux sens de la phosphodiestérase 11A pouvaient participer au développement des tumeurs corticosurrénales bilatérales sécrétrices de cortisol. Ces variants sont, en effet, non seulement retrouvés de façon plus fréquente chez les patients porteurs d une hyperplasie nodulaire comparés à des sujets contrôles, mais ils ont également des conséquences fonctionnelles in vitro.Nous avons, dans une seconde partie, montré grâce à une étude de transcriptome ayant porté sur un groupe d adénomes cortisoliques comparés à un groupe d adénomes non-sécrétant que plusieurs gènes codant pour la voie de l AMPc étaient impliqués dans la sécrétion cortisolique et que la phosphodiestérase 8 B semblait avoir un rôle prépondérant. Ces résultats ont ensuite été confirmés au niveau protéique.Pas de résumé en anglaisPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Alterations of the cAMP pathway in adrenocortical tumorigenesis : study of phosphodiesterase 11A and 8B

La voie de l’AMPc est une voie impliquée dans la physiopathologie de nombreuses tumeurs endocrines. Les phosphodiestérases sont des enzymes clés de la voie de l’AMPc dans la mesure où elles permettent de réguler finement les niveaux intra-cellulaires d’AMPc en hydrolysant l’AMPc en son catabolite inactif, le 5’AMP. L’hyperplasie macronodulaire bilatérale des surrénales est une étiologie rare de syndrome de Cushing ACTH-indépendant responsable d’un syndrome de Cushing souvent modéré contrastant avec la taille des nodules surrénaliens. Sa physiopathologie est mal connue.Nous avons tout d’abord pu montrer dans ce travail que les variants faux sens de la phosphodiestérase 11A pouvaient participer au développement des tumeurs corticosurrénales bilatérales sécrétrices de cortisol. Ces variants sont, en effet, non seulement retrouvés de façon plus fréquente chez les patients porteurs d’une hyperplasie nodulaire comparés à des sujets contrôles, mais ils ont également des conséquences fonctionnelles in vitro.Nous avons, dans une seconde partie, montré grâce à une étude de transcriptome ayant porté sur un groupe d’adénomes cortisoliques comparés à un groupe d’adénomes non-sécrétant que plusieurs gènes codant pour la voie de l’AMPc étaient impliqués dans la sécrétion cortisolique et que la phosphodiestérase 8 B semblait avoir un rôle prépondérant. Ces résultats ont ensuite été confirmés au niveau protéique.Pas de résumé en anglai

Familial SDHC mutation associated with prolactin/gh-secreting pituitary adenoma and paraganglioma

Introduction: SDH genes mutations are associated with hereditary phaeochromocytoma and paraganglioma syndromes. We describe the case of a patient with SDHC related familial paraganglioma and pituitary adenoma. Case: A 65-year old man consulted for an incidentally discovered 7 cm abdominal mass on CT-scan, lateral to the right kidney, invading inferior vena cava, associated to a retroperitoneal adenomegaly and a lesion on the body of L2 vertebra with spinal MRI aspect of metastasis. All these lesions showed hypermetabolism on 18F-FDG PET. Continuous blood pressure monitoring, plasma catecholamines and their methoxylated metabolites were normal. Chromogranine A was four times normal (Normal range<100 μg/l). Total right adrenalectomy, lumbo-aortic lymphadenectomy and nephrectomy were performed. Vertebral metastasis was treated by radiofrequency. Histopathology of the primary tumor confirmed the diagnosis of paraganglioma with 2% mitotic index. During follow-up, erectile dysfunction developed. Endocrine evaluation revealed partial hypogonadotropic hypogonadism (testosterone 214 ng/dl Normal: (280–820), LH 2.2 mUI/ml, FSH 2.5 mUI/ml) with hyperprolactinaemia (470 ng/ml, normal value <19 ng/ml) and elevated IGF1 level (214 ng/ml, normal: 41–196 ng/ml). OGTT confirmed GH hypersecretion. MRI showed a T2 hyperintense pituitary adenoma of 15×17 mm with left cavernous sinus extension without optic compression. We retained the diagnosis of PRL/GH-secreting pituitary adenoma and started dopamine agonist plus somatostatin analogue treatment. Genetic analysis revealed an new mutation on SDHC gene on exon 4 c239-242dupGTGC. The same mutation was found in his siblings (son, daughter and the grandson). His son had a non-secreting pituitary microadenoma, without pituitary abnormalities in the daughter. Work-up for paraganglioma was negative in siblings. Conclusion: This case suggests that SDHC gene mutations could be related to pituitary adenomas occurrence in association with paraganglioma syndromes, but more studies should be conducted to define the pathogenic pathways of this relationship

Adrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series

International audienceBackground: Cancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent. Cases presentation: We describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor. Conclusions: CR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients' evolution, the persistence of TMA may reflect an uncontrolled malignancy

Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study

Item does not contain fulltex

Pre-term birth in women exposed to Cushing’s disease: the baby-cush study

International audienceDesign Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing’s disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy. Methods It was a retrospective multicentric study focusing on mothers with a history of Cushing’s disease or diagnosed during pregnancy, followed in French tertiary referral centers. We compared the outcomes of pregnancies depending on the cortisolic status at the time of pregnancy. Results A total of 60 patients (78 pregnancies including 21 with hypercortisolism, 32 with hypocortisolism and 25 in eucortisolism in 25) were evaluated. The overall rate of preterm birth was 24.3%, with a peak in women diagnosed during pregnancy (62.5%), a high risk in hypercortisolic (33%) and hypocortisolic (19.3%), and a low risk (8%) in eucortisolic women Gestational diabetes and hypertension were observed in 21% and 10.4% of the whole cohort, with a higher risk in hypercortisolic women. Cesarean delivery was performed in 33.7% of the cohort. Conclusions Being non-eucortisolic at the time of pregnancy increases the risk of prematurity and comorbidities compared to the general population. Women with a history of Cushing’s disease should thus be carefully monitored during pregnancy. The high rate of cesarean delivery emphasizes the fact that these pregnancies should always be considered at risk

The French COMETE-Cancer network for adrenal cancer: 10 years of activity as part of a national plan for clinical care of rare cancers

International audienceP826The French COMETE-Cancer network for adrenal cancer: 10 years of activity as part of a national plan for clinical care of rare cancersIntroductionThe French National Institute of Cancer (INCa) launched supported by the Ministry of Health in 2008 a program for the recognition of national networks for the management of rare cancers. Among the 23 selected networks COMETECancer was recognized by INCa in 2009 for Adrenocortical carcinoma (ACC) and malignant pheochromocytoma/paraganglioma (MPP). At that time 60–120 new ACC/year and 30 new MPP/year were expected at the national level.AimTo describe the general activities of COMETE-cancer after 10-years of activity.Materials and methodsINCa list 7 tasks for the national rare cancer networks: 1) Expertise: double reading of tumor samples, Referral National Multisciplinary Staff (RNMS); 2) Care practice: national best practice guidelines release; 3) Referral: patient access to highly specialized/innovative treatments (clinical trial); 4) Observation: exhaustive recording of national cases in registries; 5) Clinical and translationalresearch; 6) Healthcare professional training; 7) Role of patient associations. TheFrench COMETE-K network is coordinated by two-sites Centers (Cochin andGustave Roussy). Ten Regional Experts Centers have been recognized for anational geographical coverage.ResultsA double reading is done in about 200 cases of ACC/MPP tumor samples/year. A RNMS is organized twice a month (web based system): about 170 ACC and MPP patients/year are discussed. The coverage rate of ‘new’ patients reviewed in RNMS/‘estimated’ total number cases was 68%. The consistency between treatment proposed in RNMS and treatment administered was of 84%. Since2010, 958 ACC and 384 MPP have been entered in the ENSAT database. Two National best practice guidelines for ACC/MPP were released. About 70 ACC/MPP have been referred to the COMETE-Cancer centers for highly specialized and innovative treatment (phase II-III trial, radiofrequency/cryotherapy, liver chimioembolisation). COMETE-Cancer participated in two international trials (ADIUVO in ACC and FIRSTMAPP in MPP) and more than 20 translational studies. Every year more than 500 healthcare professional (student, endocrinologists, surgeons, pathologist, oncologists) are trained. Moreover, it strongly collaborates with the patients ‘Association Surre´nale’ by writing specific documents on the clinical ACC/MPP management.ConclusionsCOMETE-cancer has led to a homogenous national organization for clinical care of ACC and MPP. The RNMS proved to be very efficient for that. Links with the ENSAT, ENDO-ERN and EURACAN networks will allow further progress at the European level.DOI: 10.1530/endoabs.63.P82

Image-Guided Precision Medicine in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

In this comprehensive review, we aimed to discuss the current state-of-the-art medical imaging for pheochromocytomas and paragangliomas (PPGLs) diagnosis and treatment. Despite major medical improvements, PPGLs, as with other neuroendocrine tumors (NETs), leave clinicians facing several challenges; their inherent particularities and their diagnosis and treatment pose several challenges for clinicians due to their inherent complexity, and they require management by multidisciplinary teams. The conventional concepts of medical imaging are currently undergoing a paradigm shift, thanks to developments in radiomic and metabolic imaging. However, despite active research, clinical relevance of these new parameters remains unclear, and further multicentric studies are needed in order to validate and increase widespread use and integration in clinical routine. Use of AI in PPGLs may detect changes in tumor phenotype that precede classical medical imaging biomarkers, such as shape, texture, and size. Since PPGLs are rare, slow-growing, and heterogeneous, multicentric collaboration will be necessary to have enough data in order to develop new PPGL biomarkers. In this nonsystematic review, our aim is to present an exhaustive pedagogical tool based on real-world cases, dedicated to physicians dealing with PPGLs, augmented by perspectives of artificial intelligence and big data