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Sainte-Foy-lès-Lyon, France

Raverot G.,University of Lyon | Sturm N.,Joseph Fourier University | De Fraipont F.,Joseph Fourier University | Muller M.,Joseph Fourier University | And 17 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: To date only 18 patients with aggressive pituitary tumors or carcinomas treated with temozolomide have been reported. Increased expression of O6-methylguanine-DNA-methyltranferase (MGMT) has been suggested to predict resistance to temozolomide. Objectives: The objective of the study was to describe the antitumoral efficacy and toxicity of temozolomide in patients with aggressive pituitary tumors or carcinomas and evaluate the possible prognostic value of MGMT promoter methylation and protein expression. Patients: Eight patients, five with pituitary carcinomas (three prolactin (PRL) and two ACTH) and three with aggressive pituitary tumors (one PRL and two ACTH), all treated with temozolomide administered orally for four to 24 cycles, were included in our French multicenter study. Design: MGMT expression was assessed by immunohistochemistry and MGMT promoter methylation by pyrosequencing. Results: Three of the eight patients (two ACTH adenomas and one PRL carcinoma) responded to temozolomide as demonstrated by significant tumor shrinkage and reduced hormone secretion. Three cycles of temozolomide were sufficient to identify treatment-responsive patients. Additional cycles did not improve treatment efficacy in those not responding, even when associated with carboplatin and vepeside. MGMT expression did not predict tumoral response to temozolomide because it was positive in one responder and negative in two nonresponders. Similarly, MGMT promoter methylation (three of seven tumors) did not predict clinical response. Toxicity remained mild in all patients. Conclusion: Temozolomide treatment may be an effective option for some aggressive pituitary tumors or carcinomas. Response to a trial of three cycles of treatment seems sufficient to identify responders and more reliable than patient MGMT status. Copyright © 2010 by The Endocrine Society. Source

Jouanneau E.,French Institute of Health and Medical Research | Jouanneau E.,University of Lyon | Wierinckx A.,French Institute of Health and Medical Research | Wierinckx A.,University of Lyon | And 11 more authors.
Pituitary | Year: 2012

To evaluate the antitumoral efficacy of everolimus in pituitary carcinoma resistant to temozolomide, the correlation with mammalian target of rapamycin (mTOR) signaling in the tumor and to present recent advances and future treatments of pituitary carcinomas. Pituitary carcinomas are rare and largely unresponsive to current treatment options. Recent reports on the antitumoral efficacy of temozolomide in some such patients are encouraging, yet most patients appear to show resistance to its actions. As a potential alternative, the mTOR inhibitor, everolimus, has been shown to potently inhibit pituitary cell proliferation highlighting mTOR inhibition as a promising therapeutic approach for pituitary carcinomas. We described the tumoral effects of a combination therapy with everolimus (5 mg/day) and octreotide (30 mg/month) and the mTOR signalling expression in a patient with pituitary ACTH carcinoma, compared to 17 other ACTH adenomas. Clinical and biochemical evaluation were performed every month, and imaging after 3 month of treatment. mTOR signaling was assessed by microarray expression analysis of each of the 18 adenoma tissues. Combined therapy failed to control pituitary tumor growth and ACTH secretion. Slight activation of mTOR signaling was found in all ACTH tumors alongside important variations between tumors. Low antitumor efficacy shown by everolimus might be explained by the weak activation of mTOR pathway in ACTH tumors. Everolimus treatment was inefficient at controlling secretion and tumor growth of one ACTH pituitary carcinoma. More clinical cases, with mTOR signalling expression analysis of the tumor, must be published before any conclusions can be drawn. © 2011 Springer Science+Business Media, LLC. Source

Gadelha M.R.,Federal University of Rio de Janeiro | Bronstein M.D.,University of Sao Paulo | Brue T.,Aix - Marseille University | Coculescu M.,Carol Davila University of Medicine and Pharmacy | And 10 more authors.
The Lancet Diabetes and Endocrinology | Year: 2014

Background: Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. Methods: In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2˙5 μg/L and insulin-like growth factor 1 [IGF-1] concentration >1˙3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2˙5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2˙5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. Findings: Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15˙4%, 95% CI 7˙6-26˙5, p=0˙0006 for pasireotide 40 mg group, 20˙0%, 11˙1-31˙8, p<0˙0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. Interpretation: Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. Funding: Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. © 2014 Elsevier Ltd. Source

Background: The iodine status of the French population has been improved since 1952. As iodine requirements increase during pregnancy, the World Health Organization recommended in 2005 systematic iodine supplementation for pregnant women. Our work tried to assess the benefits and risks of iodine supplementation during pregnancy. Methods: We reviewed the international literature from 1991 to 2011 and consulted the main references databases. Keywords were combined with boolean operators AND and OR. Selected studies were assessed with Consort grid. Results: Among 226 papers, 99 were original articles. After analysis, 13 studies were included in this review. A favorable trend toward iodine supplementation from pregnancy desire to the end of pregnancy was observed. Iodine supplementation may prevent psychomotor and neuro-intellectual disorders. Conclusion: Iodine status of pregnant women could be improved before pregnancy by more widespread use of iodized salt and iodine-enriched bread in French households. A randomized controlled trial is recommended to confirm the benefit of iodine supplementation. © 2013 Elsevier Masson SAS. Source

D'Herbomez M.,Lille 2 University of Health and Law | Do Cao C.,Center Hospitalier Of Lille | Vezzosi D.,Service dendocrinologie | Borzon-Chasot F.,Federation dEndocrinologie | Baudin E.,Institute Gustave Roussy
Annales d'Endocrinologie | Year: 2010

Chromogranins belong to the family of secretory chromogranin and secretogranin proteins. They are found in secretory vesicles throughout the neuroendocrine system. Chromogranin A (CgA) is the main component. CgA acts as a prohormone submitted to processes of degradation through which active peptides are generated. CgA has auto, para and endocrine functions. It is widely used as an immunohistochemical marker. Despite the lack of international standardization, and the lack of an accurate definition of the diagnostic cut-off levels, some CgA assays are reliable. Numerous studies have suggested that CgA determination may be of interest for the diagnosis and the follow-up of various endocrine tumors. Plasma levels of this general marker are proportional to tumor mass. The localization of the primitive tumor, the presence of associated hormonal secretions and possible renal failure and/or hypergastrinemia must be taken into consideration for proper interpretation of CgA levels. New clinical indications are emerging for the evaluation of stress in intensive care units and the assessment of cardiovascular risk. New assays estimating the concentration of active peptides are under development. © 2010 Elsevier Masson SAS. Source

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