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Michel Polak, Jerome Bertherat, Jacques Y. Li, Michelle Kujas, Michelle Le Dafniet, Hussein Weizani, Remy Van Effenterre, Jacques Epelbaum, and Gerard Turpin

Abstract.

An invasive TSH-secreting adenoma inducing mild hyperthyroidism was diagnosed in a 16-year-old male. Initial surgical treatment led to a temporary clinical and biological improvement. Recurrence of the thyrotoxicosis was treated with the somatostatin analogue, SMS 201-995 (octreotide) with normalization of the serum thyroid hormone levels with a dose of 200 μg per day. With immunoelectron microscopy, the tumour cells appeared poorly granulated with small secretory granules located at the periphery of the cells; only part of those were immunoreactive with an anti-TSHβ monoclonal antibody. No specific TRH binding site was found in a tumour membrane preparation. By quantitative autoradiography, somatostatin specific binding sites were as numerous in the TSH-secreting tumour as in control GH-secreting tumours. Binding kinetics and guanosine triphosphate dependency of the binding were equivalent in the TSH and GH tumours tested. Although all of the tumour cells displayed the same ultrastructural features, some were non-immunoreactive, suggesting that they could secrete an altered form of TSH. The absence of TRH receptors in the tumour cells is in accordance with previous reports on this type of tumour. We confirm the efficiency of octreotide treatment in this case of neoplastic TSH inappropriate secretion. The therapeutic effect of octreotide goes along with the presence of a high density of guanine nucleotide-dependent somatostatin binding sites in the tumour cells.

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Rossella Libé, Joël Coste, Laurence Guignat, Frédérique Tissier, Hervé Lefebvre, Gaëlle Barrande, Christiane Ajzenberg, Igor Tauveron, Eric Clauser, Bertrand Dousset, Xavier Bertagna, Jérôme Bertherat, and Lionel Groussin

Context

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors.

Objective

A large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status.

Design and patients

Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS).

Methods

A baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed.

Results

At least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS.

Conclusions

Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.

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Camille Baudry, Joël Coste, Roula Bou Khalil, Stéphane Silvera, Laurence Guignat, Jean Guibourdenche, Halim Abbas, Paul Legmann, Xavier Bertagna, and Jérôme Bertherat

Context

Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD.

Objective

Evaluation of the efficacy and tolerance of mitotane in CD patients.

Design and setting

Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center.

Main outcome measure

Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC).

Results

Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2–8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5±8.9 mg/l, with a mean daily dose of 2.6±1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0–67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32–1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery.

Conclusion

Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.

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Gwenaëlle Abiven-Lepage, Joël Coste, Frédérique Tissier, Lionel Groussin, Line Billaud, Bertrand Dousset, François Goffinet, Xavier Bertagna, Jérôme Bertherat, and Marie-Laure Raffin-Sanson

Objective

Adrenocortical carcinoma (ACC) is a rare, severe disease. Pregnancy-associated ACC has rarely been reported. We wished to evaluate the characteristics and prognosis of ACC diagnosed in patients during pregnancy or in the postpartum period, comparing them with those for ACC diagnosed in nonpregnant women.

Design

Clinical presentation, hormonal secretion, staging, survival, and obstetric data are reported. Patients were included between 1963 and 2007. Mean follow-up was 48 months.

Patients and methods

This is a retrospective cohort study carried out at a referral center. All female patients aged 16–49 years diagnosed with ACC during the observation period were included (n=110). Twelve of these women were pregnant or in the first 6 months after delivery. Hormonal secretion, staging, obstetric data, and survival were analyzed. For the survival analysis, pregnant patients were compared with a subgroup of nonpregnant women matched for age, stage, and year of diagnosis (1 pregnant patient/2 controls).

Results

Adrenocortical tumors diagnosed during pregnancy or in the postpartum period tend to be more often cortisol-secreting tumors (P=0.06) and to be discovered at a more advanced stage than those in nonpregnant women, although the differences were not significant. Fetal outcome was poor. Overall survival of the mother was worse than that of matched controls (hazard ratio of death: 3.98, confidence interval=1.34–11.85, P=0.013).

Conclusion

ACC diagnosed during pregnancy or in the postpartum period is associated with a poor fetal outcome and a poorer prognosis than ACC diagnosed in nonpregnant women.

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Ricardo Correa, Mihail Zilbermint, Annabel Berthon, Stephanie Espiard, Maria Batsis, Georgios Z Papadakis, Paraskevi Xekouki, Maya B Lodish, Jerome Bertherat, Fabio R Faucz, and Constantine A Stratakis

Objective

Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing's syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes.

Design

All of the nodules were obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocol and the ARMC5 sequence was determined by the Sanger method.

Results

Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: six were frame shift, four were missense, three were nonsense, and one was a splice site variation. Allelic losses were confirmed in two of the nodules.

Conclusion

This is the most genetic variance of the AR MC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, ‘private,’ and – in most cases – completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery.

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Alfredo Berruti, Rossella Libè, Marta Laganà, Hester Ettaieb, Mohamad Anas Sukkari, Jérôme Bertherat, Richard A Feelders, Salvatore Grisanti, Jérôme Cartry, Gherardo Mazziotti, Sandra Sigala, Eric Baudin, Harm Haak, Mouhammed Amir Habra, and Massimo Terzolo

Introduction

Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent.

Objective

The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis.

Methods

This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States.

Results

Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19–4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range.

Conclusion

Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.

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Claire Chambre, Emily McMurray, Camille Baudry, Marine Lataud, Laurence Guignat, Sébastien Gaujoux, Najiba Lahlou, Jean Guibourdenche, Frédérique Tissier, Mathilde Sibony, Bertrand Dousset, Xavier Bertagna, Jérôme Bertherat, Paul Legmann, and Lionel Groussin

Context

Computed tomography (CT) unenhanced attenuation value of <10 Hounsfield units (HU) has an excellent specificity (98%) to diagnose lipid-rich adrenocortical adenomas (ACAs) with a weaker sensitivity (71%).

Objective

To determine from a routine clinical perspective if unenhanced attenuation value is influenced by cortisol secretion in ACAs.

Design

This was a retrospective study of cases collected between 2009 and 2012.

Setting

This study was conducted in a tertiary-care university hospital.

Patients

Seventy-two patients operated on for an ACA (Weiss score ≤2) were analysed. Thirty-four patients had an ACA oversecreting cortisol (Cush-ACA). Thirty-eight patients had an ACA without cortisol oversecretion (Non Hyper-ACA).

Main outcome measure

CT unenhanced attenuation value was correlated with the functional status. The Weiss score items were analysed.

Results

Among the 34 patients with a Cush-ACA a minority (n=7) had an unenhanced attenuation value under 10 HU. Among the high precontrast density (>10 HU) Cush-ACAs, washout analysis after contrast administration was consistent with the benign nature of the tumor in ∼60% of the cases. Less than 25% clear cells (lipid-rich cells), a Weiss score item, was present in 50% of the Cush-ACAs in favour of a lipid-poor content.

Conclusions

Unenhanced attenuation value has a poor sensitivity to diagnose an ACA in case of cortisol oversecretion due to poor lipid content. Nevertheless, the accuracy of washout analysis was preserved in the group of Cush-ACAs.

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Bruno Ragazzon, Rossella Libé, Guillaume Assié, Frédérique Tissier, Olivia Barreau, Claude Houdayer, Karine Perlemoine, Anne Audebourg, Eric Clauser, Fernande René-Corail, Xavier Bertagna, Bertrand Dousset, Jérôme Bertherat, and Lionel Groussin

Context

Adrenocortical carcinoma (ACC) is a rare disease with a poor overall outcome. Transcriptome analysis identified two groups of ACCs with different prognosis. In aggressive ACCs, somatic mutations of the tumor suppressor gene TP53 and the proto-oncogene β-catenin are detected in 50% of cases. For the remaining aggressive ACCs and for the group with a better prognosis, molecular alterations are unknown.

Objective

To identify new molecular actors driving adrenal tumorigenesis.

Experimental design

Analysis by mass array of 374 mutations among 32 common oncogenes or tumor suppressor genes was performed on the tumoral DNA of 26 ACCs, using Sequenom OncoCarta Panels.

Results

Four mutations were identified, two previously known β-catenin mutations and one alteration in two other genes: JAK3 and retinoblastoma gene (RB1). The JAK3 alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The full RB1 tumor suppressor gene was subsequently sequenced in a cohort of 49 ACCs (26 ACCs from the ‘OncoCarta cohort’ and 23 other ACCs): three somatic mutations were identified, all in the poor-outcome ACC group. By immunohistochemistry, a loss of the retinoblastoma protein (pRb) was found exclusively in aggressive ACCs in 27% of cases (seven out of 26), three of them with an inactivating RB1 mutation. Among the seven pRb-negative ACCs, five had an allele loss at the RB1 locus.

Conclusions

Parallel analysis of somatic mutations among known cancer genes allowed us to identify RB1 as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs.

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Laure Cazabat, Rossella Libè, Karine Perlemoine, Fernande René-Corail, Nelly Burnichon, Anne-Paule Gimenez-Roqueplo, Laurence Dupasquier-Fediaevsky, Xavier Bertagna, Eric Clauser, Philippe Chanson, Jérôme Bertherat, and Marie-Laure Raffin-Sanson

Objective: Germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have recently been described in three families with GH or prolactin-secreting tumors, as well as in a few patients with apparently sporadic somatotropinomas. The aim of the study was to determine the prevalence of AIP mutations in a large cohort of patients with apparently sporadic GH-secreting tumors.

Design: One hundred and fifty-four patients were included in a prospective cohort designed to study the genetic predisposition to GH-secreting tumors together with 270 controls.

Methods: In all these subjects, the entire coding sequence of the AIP gene was screened for germline mutations.

Results: AIP mutations were detected in 5 out of 154 patients (3%): nonsense mutations in exon 4 (p.Lys201X; n = 2) and in exon 6 (p.Arg304X), one deletion in exon 3 (c.404delA; pHis135LeufsX21), and one mutation affecting the splice acceptor site of exon 4 (c.469-2 A > G). The five patients with an AIP mutation were significantly younger (mean age ± S.D.: 25 ± 10 vs 43 ± 14 years, P = 0.005) and three of them presented with gigantism. One missense mutation (p.Arg304Gln) was found in a single patient that was absent in all controls.

Conclusions: Germline mutations of the AIP gene were found in a small proportion of patients with sporadic pituitary somatotropinomas. This study shows that age and gigantism are simple clinical features which can help to select patients for mutation screening. It also supports the role of AIP in pituitary tumorigenesis.

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Luigi Maione, Thierry Brue, Albert Beckers, Brigitte Delemer, Patrick Petrossians, Françoise Borson-Chazot, Olivier Chabre, Patrick François, Jérôme Bertherat, Christine Cortet-Rudelli, Philippe Chanson, and for the French Acromegaly Registry Group

Context

Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries.

Design

The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012.

Results

Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94–1.87) in men and 1.24 (0.77–1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70–1.42). Most deaths were due to cancer.

Conclusions

The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.