Time filter

Source Type

Le Touquet – Paris-Plage, France

Boscaro M.,Marche Polytechnic University | Bertherat J.,French Institute of Health and Medical Research | Bertherat J.,Reference Center for Rare Adrenal Diseases | Bertherat J.,University of Paris Descartes | And 11 more authors.
Pituitary | Year: 2014

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease. © 2013 The Author(s). Source

Schopohl J.,Ludwig Maximilians University of Munich | Gu F.,Peking Union Medical College | Rubens R.,Ghent University | Van Gaal L.,University of Antwerp | And 9 more authors.
Pituitary | Year: 2015

Purpose: Report the efficacy and safety of pasireotide sc in patients with Cushing’s disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study. Methods: 162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300–1,200 μg bid). Dose titration was permitted according to efficacy or drug-related adverse events. Results: 40 patients completed 24 months’ treatment. Of the patients who entered the extension, 50.0 % (29/58) and 34.5 % (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3 % (95 % CI 40.7–73.9; n = 52) and 62.1 % (50.8–73.5; n = 33) after 12 and 24 months’ treatment, respectively. Improvements in clinical signs of Cushing’s disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6 %), nausea (48.1 %), hyperglycemia (38.9 %), and cholelithiasis (31.5 %). No new safety issues were identified during the extension. Conclusions: Reductions in mean UFC and improvements in clinical signs of Cushing’s disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing’s disease. © 2014, The Author(s). Source

Faillot S.,University of Paris Descartes | Faillot S.,CARPEM CAncer Research for PErsonalized Medicine | Assie G.,University of Paris Descartes | Assie G.,Reference Center for Rare Adrenal Diseases
European Journal of Endocrinology | Year: 2016

The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations in aldosterone-producing adenomas (APA), PRKACA mutations in cortisol-producing adenomas (CPA), ARMC5 mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and ZNRF3 mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches - including exome sequencing, transcriptome, miRNome, genome and methylome - converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such as ARMC5 mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine. © 2016 European Society of Endocrinology. Source

Berthon A.,University Blaise Pascal | Berthon A.,French National Center for Scientific Research | Sahut-Barnola I.,University Blaise Pascal | Sahut-Barnola I.,French National Center for Scientific Research | And 20 more authors.
Human Molecular Genetics | Year: 2010

Adrenocortical carcinoma is a rare but aggressive cancer with unknown aetiology. Constitutive activation of β-catenin is the most frequent alteration in benign and malignant adrenocortical tumours in patients. Here, we show that constitutive activation of β-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cells hyperplasia as well as dysplasia of the cortex and medulla. Over a 17 months time course, transgenic adrenals developed malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion. These oncogenic events were accompanied by ectopic differentiation of glomerulosa at the expense of fasciculata cells, which caused primary hyperaldosteronism. Altogether these observations demonstrate that constitutively active β-catenin is an adrenal oncogene which triggers benign aldosterone-secreting tumour development and promotes malignancy. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. Source

de Joussineau C.,University Blaise Pascal | de Joussineau C.,French Institute of Health and Medical Research | Sahut-Barnola I.,University Blaise Pascal | Sahut-Barnola I.,French Institute of Health and Medical Research | And 24 more authors.
Human molecular genetics | Year: 2014

Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signaling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signaling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. Source

Discover hidden collaborations