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Y de Keyzer, D Vieau, A Picon, and X Bertagna

Cushing's syndrome refers to the manifestations induced by chronic exposure to glucocorticoid excess and may result from various causes that are all associated with tumors. The most frequent one, that which was first recognized by Harvey Cushing (Cushing 1932) – and therefore called Cushing's disease – is due to adrenocorticotropin (ACTH) hypersecretion by a pituitary corticotrope adenoma; the ectopic ACTH syndrome is another, much rarer (∼5-10%) one, caused by a variety of so-called ACTH-secreting non-pituitary tumors; finally, approximately 30% of Cushing's syndromes are ACTH-non-dependent, caused by primary adrenocortical tumors, most often unilateral and either benign or malignant. The first case of ectopic ACTH syndrome was probably reported by Brown (1928) who described the case of a bearded woman with diabetes. At that time the author had no idea that ACTH existed. The discovery of ACTH, the development of an ACTH bioassay, and the pioneering work of Liddle's group eventually led
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O Chabre, R Libé, G Assie, O Barreau, J Bertherat, X Bertagna, J-J Feige, and N Cherradi

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Local and distant recurrences occur in a subset of tumors classified as ‘aggressive’ ACC (aACC), as opposed to ‘non-aggressive’ ACC (naACC). In this study, we investigated whether tissue and serum microRNAs (miRNAs) are predictive of ACC prognosis. Tissue miRNA expression profiles were determined using microarrays in a test series of six adrenocortical adenomas (ACAs), six naACCs, and six aACCs. Eight miRNAs were selected for further validation by quantitative RT-PCR (ten ACAs, nine naACCs, nine aACCs, and three normal adrenals). Serum levels of five miRNAs were measured in samples from 56 subjects (19 healthy controls (HC), 14 ACA, nine naACC, and 14 aACC patients). MiR-195 and miR-335 levels were significantly decreased in both tumor and serum samples of ACC patients relative to ACA patients or HC. MiR-139-5p and miR-376a levels were significantly increased in aACC compared with naACC patients in tumor samples only. Tissue miR-483-5p was markedly upregulated in a majority of ACC compared with ACA patients or HC, but most importantly, serum miR-483-5p was detected only in aACC patients. High circulating levels of miR-483-5p or low circulating levels of miR-195 were associated with both shorter recurrence-free survival (P=0.0004 and P=0.0014 respectively) and shorter overall survival (P=0.0005 and P=0.0086 respectively). In conclusion, this study reports for the first time that circulating miR-483-5p and miR-195 are promising noninvasive biomarkers with a highly specific prognostic value for the clinical outcome of ACC patients.