Center Hospitalier University Larrey

Saint-Pierre-du-Chemin, France

Center Hospitalier University Larrey

Saint-Pierre-du-Chemin, France
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Raverot G.,University of Lyon | Raverot G.,Groupement Hospitalier Est | Sturm N.,Joseph Fourier University | De Fraipont F.,Joseph Fourier University | And 20 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.

Debillon E.,Joseph Fourier University | Velayoudom-Cephise F.-L.,University of Bordeaux 1 | Caron P.,Center Hospitalier University Larrey | Chaffanjon P.,Joseph Fourier University | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Bilateral adrenalectomy is the reference treatment for Cushing's syndrome (CS) related to primary bilateral macronodular adrenal hyperplasia (PBMAH). It is, however, responsible for definitive adrenal insufficiency. Objective: The objective of the study was to evaluate the clinical interest of unilateral adrenalectomy (UA) of the larger gland for the treatment of CS related to PBMAH. Design, Setting, Patients, and Intervention: This was a retrospective study in four tertiary French centers including all 15 patients with PBMAH and CS who underwent UA of the larger gland between 2001 and 2015. Main Outcome Measures: Urinary free cortisol, plasma cortisol, ACTH, body mass index, blood pressure, plasma glucose, and lipids were registered pre- and postoperatively and on follow-up. Median follow-up was 60 months (interquartile range 39-105), including 8 of 15 patients followed up for at least 5 years. Results: A normal or low urinary free cortisol was obtained in 15 of 15 patients (100%) postoperatively. Six patients (40%) became adrenal insufficient, of whom three of six recovered a quantitatively normal cortisol secretion on follow-up. Decrease of both body mass index and blood pressure were observed at 1 year, and decrease of blood pressure was persistent 5 years postoperatively. Diabetes was cured in four of six patients. Two patients experienced a recurrence of hypercortisolism, and one was treated with mitotane, whereas the other underwent a second adrenal surgery 9 years after initial UA. Conclusion: UA induced remission of hypercortisolism in all patients, with sustained significant clinical improvement. The rates of both definitive adrenal insufficiency and 5-year recurrence were low. UA appears an interesting alternative to bilateral adrenalectomy as a first-line treatment in PBMAH responsible for overt CS. Copyright © 2015 by the Endocrine Society.

Caron P.,Center Hospitalier University Larrey | Simonds W.F.,U.S. National Institutes of Health | Maiza J.-C.,Center Hospitalier University Larrey | Rubin M.,Columbia University | And 5 more authors.
Clinical Endocrinology | Year: 2011

Objective Some patients with parathyroid carcinoma present with an over-production of nontruncated amino-terminal (NT-N) parathyroid hormone (PTH), a post-transcriptionally modified form of PTH(1-84). This is usually picked up on an elevated whole (W) PTH (third-generation)/total (T) (second-generation) PTH assay ratio (N > 0·8). Patients and design Two parathyroid cancer patients with several episodes of hypercalcaemia and multiple surgeries are described. In both patients, W-PTH, T-PTH and circulating PTH molecular forms separated by high-pressure liquid chromatography (HPLC) were measured with the same assays. qPCR was used to study HRPT2 gene mutation. Results The first patient had total calcium of 3·8 and 3·22 mmol/l before the fourth and fifth surgeries, and third/second-generation PTH ratios of 2·95 and 3·6, respectively. After the fourth surgery, the ratio remained normal for 1 year and increased progressively to 3·6 over 15 months. This preceded hypercalcaemia by 6 months. The ratio became normal after the fifth surgery. HPLC analysis disclosed an over-expression of NT-N PTH to 82·2% (N < 10%) relative to hPTH(1-84) before the fifth surgery. A deletion of all the tested exons of the HRPT2 gene was identified. In the second patient, W-PTH/T-PTH ratio was 0·89 when serum calcium was 3·3 mmol/l. NT-N PTH was also over-expressed at 51·9%. An inactivating mutation of the HRPT2 gene was also identified. Conclusions This may suggest that a progressive rise in third/second-generation ratio may have possible clinical utility to monitor parathyroid cancer recurrence. A possible association between NT-N PTH overproduction and HRPT2 gene inactivation is also suggested. © 2011 Blackwell Publishing Ltd.

Caron P.,Center Hospitalier University Larrey | Broussaud S.,Center Hospitalier University Larrey | Bertherat J.,University of Paris Descartes | Borson-Chazot F.,Federation dEndocrinologie et des Maladies de la Nutrition | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Few data are available on pregnancy outcomes in women with acromegaly. Study Design: This was a retrospective multicenter study. Patients: The study included 46 women with GH-secreting pituitary microadenomas (n = 7) or macroadenomas (n = 39). Their mean age was 31.7 yr (±4.5 yr). Incomplete transsphenoidal surgical resection (n = 39) and pituitary radiation (n = 14) had been performed, respectively, 2.9 ± 2.6 and 7.3 ± 4.2 yr before pregnancy. The patients were receiving dopamine agonists (n = 25) and/or somatostatin analogs (n = 14), and GH/IGF-I hypersecretion was controlled and uncontrolled in, respectively, 23 and 34 cases. Five pregnancies followed the fertility treatment. Results: Fifty-nine pregnancies resulted in 64 healthy babies. Gestational diabetes and gravid hypertension occurred in four (6.8%) and eight (13.6%) pregnancies, respectively, and both were more frequent when GH/IGF-I hypersecretion was not controlled before pregnancy. Visual field defects were diagnosed during pregnancy in four women, three of whom were diagnosed with acromegaly during the pregnancy. Seven women had isolated headache. Magnetic resonance imaging performed 3.9 ± 0.3 months after delivery showed that the size of the adenoma had increased in three cases, decreased in two cases, and remained stable in 22 cases. Seventeen women breast-fed with no complications. Four women gave birth to a small-for-gestational-age infant; all had received somatostatin analogs, alone or in combination with dopamine agonists, during pregnancy. The mean IGF-I level fell significantly during the first trimester in 12 cases (before conception 588 ± 207 ng/ml, first trimester 319 ± 126 ng/ml, P = 0.002), whereas the GH concentration did not change significantly. Conclusion: The following conclusions were reached: 1) pregnancy in women with active or uncontrolled acromegaly may be associated with an increased risk of gestational diabetes and gravid hypertension; 2) pregnancy is occasionally associated with symptomatic enlargement of GH-secreting pituitary macroadenomas; 3) changes in serum GH and IGF-I concentrations are variable during pregnancy, indicating that routine monitoring is not mandatory if the pregnancy is uneventful; and 4) GH-suppressive treatment can be safely withdrawn after conception in most acromegalic women. Copyright © 2010 by The Endocrine Society.

Caron P.J.,Center Hospitalier University Larrey | Bevan J.S.,Royal Infirmary | Petersenn S.,Center for Endocrine Tumors | Flanagan D.,Derriford Hospital | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Methodological shortcomings often compromise investigations into the effects of primary somatostatin-analog treatment on tumor size in acromegaly. There are also limited data for the long-acting lanreotide formulation. Objective: The aim of the study was to better characterize the effects of primary lanreotide Autogel treatment on tumor size in patients with GH-secreting macroadenomas. Design: PRIMARYS was a 48-week, multicenter, open-label, single-arm study. Setting: The study was conducted at specialist endocrine centers. Patients: Treatment-nave acromegalic patients with GH-secretingmacroadenomas participated in the study. Intervention: Lanreotide Autogel 120 mg was administered sc every 28 days (without dose titration). Outcome Measures: The primary endpoint was the proportion of patients with clinically significant (20%) tumor volume reduction (TVR) at week 48/last post-baseline value available using central assessments from three readers. The null hypothesis (H0 ) for the primary endpoint was that the proportion with TVRwas-55%. Secondary endpointsincluded: TVR at other time points, GH andIGF-1, acromegalic symptoms, quality of life (QoL), and safety. Results: Sixty-four of 90 (71.1%) patients completed the study. Clinically significant TVR at 48 weeks/last post-baseline value available was achieved by 62.9% (95% confidence interval, 52.0, 72.9) of 89 patients in the primary analysis (intention-to-treat population; H0 not rejected) and 71.9 -75.3% in sensitivity (n89) and secondary analyses (n63) (H0 rejected). At 12 weeks, 54.1% had clinically significant TVR. Early and sustained improvements also occurred in GH and IGF-1, acromegalic symptoms, and QoL. No patients withdrew due to gastrointestinal intolerance. Conclusions: Primary treatment with lanreotide Autogel, administered at 120 mg (highest available dose) without dose titration, in patients with GH-secreting macroadenomas provides early and sustained reductions in tumor volume, GH and IGF-1, and acromegalic symptoms, and improves QoL. Copyright © 2014 by the Endocrine Society.

PubMed | Ipsen, Center Hospitalier University Larrey, Royal Infirmary, Center for Endocrine Tumors and Autonomous University of Barcelona
Type: Clinical Trial | Journal: Pituitary | Year: 2016

To evaluate the effects of lanreotide Autogel on patient-reported outcomes and association with biochemical control, using PRIMARYS data.PRIMARYS was a 1-year, open-label study of lanreotide Autogel (Depot in USA) 120 mg every 4 weeks in 90 treatment-nave patients with acromegaly. Symptoms were assessed using Patient-assessed Acromegaly Symptom Questionnaire (PASQ) and health-related quality of life (HRQoL) using the AcroQoL questionnaire. Correlations between PASQ and AcroQoL scores, and between PASQ/AcroQoL and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) levels were also evaluated (post hoc).Acromegaly symptoms and HRQoL significantly improved from week 12 to week 48, with modest correlations at week 48 between PASQ total score (R = -0.55, p < 0.0001) and AcroQoL global and physical scores (R = -0.67, p < 0.0001). Approximately 60% of patients achieved a minimal important difference (MID; improvement >50% of baseline standard deviation) in PASQ total score and >40% achieved a MID in AcroQoL global score (post hoc). Changes in PASQ scores were similar in biochemically controlled (GH levels 2.5 g/L and normal IGF-1 levels) and uncontrolled groups, while changes in global and psychological AcroQoL scores were greater in the controlled group. There was no correlation between changes in PASQ or AcroQoL scores and changes in GH or IGF-1 levels.Primary treatment with lanreotide Autogel over 1 year was associated with rapid and sustained improvements in clinical signs and symptoms and HRQoL in patients with acromegaly. Improvements in HRQoL, but not symptoms, were greater in those achieving biochemical control ( NCT00690898; EudraCT: 2007-000155-34).

Sans N.,Center Hospitalier University Purpan | Faruch M.,Center Hospitalier University Purpan | Chiavassa-Gandois H.,Center Hospitalier University Purpan | Ribes C.L.C.D.,Center Hospitalier University Purpan | And 2 more authors.
European Journal of Radiology | Year: 2011

Purpose: To validate quantitative and qualitative criteria of normal healthy skin using high-resolution MR imaging. Materials and methods: FIESTA and spin echo sequences of the skin of the heel, back and calf were obtained in 31 healthy volunteers. A dedicated 3-in. coil for study of the skin was used to optimize reception sensitivity. Quantitative analysis was performed to measure skin thickness in these three sites and qualititative analysis aimed to differentiate the various skin layers. Results: With both sequences, the stratum corneum appeared as a hyperintense layer. The epidermis was visualized appeared as a fine, homogeneous, hyperintense line. The dermoepidermal junction was clearer particularly in the calf. The dermis was also identified in each sequence and in each anatomic site. The signal was hypointense in both sequences, homogeneous with spin echo and more heterogeneous with FIESTA. Moreover the interface between the papillary and the reticular dermis could be distinguished. The hypodermis was visualized in both sequences and in all sites and hypodermal inclusions in the dermis were seen particularly in the back and calf. Lastly, the pilosebaceous follicles and the deep vascular network of the reticular dermis were more clearly seen with FIESTA sequence. Measures of overall skin thickness and for each layer according to site, sex and MRI sequence were performed. Statistical analysis was then performed to seek significant differences between the results according to these parameters. Conclusion: MR imaging provides global analysis with high resolution of the various skin layers down to the hypodermis and the muscular fascia. © 2010 Elsevier Ireland Ltd.

Petersenn S.,Center for Endocrine Tumors | Farrall A.J.,University of Edinburgh | Block C.,University of Antwerp | Melmed S.,Cedars Sinai Medical Center | And 10 more authors.
Pituitary | Year: 2014

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 μg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20 %) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume. © 2013 The Author(s).

PubMed | Center hospitalier University Larrey and Institut Universitaire de France
Type: Journal Article | Journal: Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique | Year: 2016

To assess the outcome of locally advanced medullary thyroid carcinoma treated with surgery and adjuvant external beam radiotherapy.Twenty-nine consecutive patients with non-metastatic medullary thyroid carcinoma treated in our institution between January 1995and December 2012were retrospectively evaluated. All underwent curative-intended optimal surgery, followed by external beam radiotherapy because of high risk of locoregional relapse. Twelve patients were stage III, 16IVa and 1IVb. Positive surgical margins were present in 11cases (10R1and 1R2). Median and average preradiotherapy serum calcitonin were 141pg/mL and 699pg/mL, respectively. Fourteen patients received 3D-conformal radiotherapy and 15received intensity-modulated radiotherapy. Median prescribed dose was 63Gy to the high-risk volumes and 54Gy to the low-risk volumes. Treatment was delivered in 30fractions. The median gap between surgery and radiotherapy was 1.9months. Median follow-up was 76.4months.Kaplan-Meier estimates of 5-year locoregional relapse-free survival and overall survival were 79and 96%, respectively. Among the five locoregional relapses, two were related to a macroscopic metastatic cervical lymph node that was unfortunately not removed during the lymphadenectomy. Eight of ten patients with microscopic positive margins (R1) were controlled regarding the thyroidectomy bed. Eight patients had normal serum calcitonin after external beam radiotherapy, of whom only one developed a locoregional relapse during follow-up. Regarding the 21patients with persistent positive serum calcitonin after treatment, only ten developed a macroscopic locoregional or distant relapse. One grade III and no grade IV acute morbidity were reported. Fifteen patients reported grade II chronic morbidity and no grade III/IV.Maximal surgery followed by adjuvant external beam radiotherapy as a treatment for locally advanced medullary thyroid carcinoma provides a high rate of long-term locoregional control and overall survival with limited toxicity. Postoperative external beam radiotherapy should be considered when patients present features indicating a high risk of locoregional relapse.

Bousquet C.,Institute National Of La Sante | Lasfargues C.,Institute National Of La Sante | Chalabi M.,Institute National Of La Sante | Billah S.M.,Institute National Of La Sante | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR). Evidence Acquisition: The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy. Evidence Synthesis: The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy. Conclusions: The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors. Copyright © 2012 by The Endocrine Society.

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