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Silvia Vandeva, Adrian F Daly, Patrick Petrossians, Sabina Zacharieva and Albert Beckers

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

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Patrick Petrossians, Liliane Borges-Martins, Consuelo Espinoza, Adrian Daly, Daniela Betea, Hernan Valdes-Socin, Achille Stevenaert, Philippe Chanson and Albert Beckers

Introduction: Invasive GH-secreting pituitary adenomas are rarely cured by surgery and although long-term therapy with somatostatin analogs (SSAs) may be employed, hormonal control is achieved in only 60% of cases. The impact of tumor debulking on subsequent control of acromegaly with SSAs has not been studied previously.

Methods: We studied retrospectively the response to SSA therapy in acromegalic patients before and after incomplete surgical tumor excision. A case review identified 24 acromegalic patients who had received SSA therapy for ≥1 month before and after gross total resection or debulking of adenomas. No patient received radiotherapy or combination treatment with SSAs and dopamine agonists during the study. GH and IGF-I responses to SSAs were recorded pre- and postoperatively. Postoperative SSA therapy was begun after a washout period of 1–3 months to assess the hormonal effects of the surgery alone.

Results: Before preoperative SSA treatment, 24/24 (100%) patients had elevated GH levels and IGF-I levels were elevated in 19/21 (90.5%) patients with recorded values. During preoperative SSA treatment, GH and IGF-I levels were normalized in 7/24 (29.2%) and 11/24 (45.8%) patients respectively. Following postoperative washout, GH was controlled in only 3/24 (12.5%) patients, while IGF-I was controlled in 8/19 (42.1%) patients with available data. During the second SSA treatment period, normal GH levels were seen in 13/24 (54.2%) patients, while IGF-I control was noted in 18/23 (78.3%).

Conclusion: Gross total tumor resection or debulking increases the likelihood of achieving biochemical disease control with SSAs in acromegalic patients with adenomas that were not amenable to complete surgical resection and in whom primary SSA therapy was unable to achieve good biochemical control.

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Thierry Brue, Frederic Castinetti, Frida Lundgren, Maria Koltowska-Häggström, Patrick Petrossians and on behalf of all ACROSTUDY investigators

Context

Pegvisomant (Somavert, Pfizer Inc.) is the first and only available GH receptor antagonist. ACROSTUDY is an international surveillance study that offers inclusion in a web-based registry to all patients with acromegaly treated with pegvisomant; it aims at monitoring long-term safety and efficacy of this compound.

Patients and methods

This report summarizes the main baseline characteristics of this particular population of patients. In February 2009, over 300 centres in 10 countries had contributed 792 patients. A gradual increase in cumulative patient recruitment was observed since the launching of ACROSTUDY in 2004: from 116 patients in 2005, it steeply increased to 792 at the latest data freeze in February 2009. At the time of enrolment, 91.8% of patients were already treated with pegvisomant but baseline was considered at the time of pegvisomant start. IGF1 concentrations were measured at local laboratories.

Results

Of all patients, 80% were reported to have had surgery and 33% to have received radiation therapy. Of the 792 patients, 14% had received no prior medical treatment before pegvisomant start, 65.9% had received somatostatin analogues and 18.6% dopamine agonists. Interestingly, 66.7% had received only pegvisomant at study start, while it was taken in association with dopamine agonists in 5.7%, with somatostatin analogues in 23.4% and with both types of agents in 3.8%. Mean IGF1 at baseline was 522 ng/ml.

Conclusion

Analysis of the baseline features of these patients treated with pegvisomant and reported in the ACROSTUDY database underscores the severity of the disease in this subset of the population of patients with acromegaly previously unresponsive to several medical, surgical or radiation treatment approaches.

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Sandrine Fieffe, Isabelle Morange, Patrick Petrossians, Philippe Chanson, Vincent Rohmer, Christine Cortet, Françoise Borson-Chazot, Thierry Brue, Brigitte Delemer and The French Acromegaly Registry

Objectives

The French Acromegaly Registry records data of acromegalic patients' since 1992 in French, Belgian (Liège), and Swiss (Lausanne) centers. We studied the prevalence of diabetes in this population looking for risk factors. Patients from one of the centers (Reims) were then analyzed more thoroughly.

Methods

This study has been conducted on all the patients recorded from 1999 until 2004 (519 patients). Evolution of cohorts' was reassessed in 2009. Of the different variables recorded in the registry: age, sex, body mass index (BMI), duration of acromegaly, GH, IGF1 and prolactin levels, pituitary tumor size, hormonal deficiencies, presence, duration and treatment of diabetes, hypertension, and rheumatological disease were analyzed.

Results

The prevalence of diabetes in the registry was 22.3%. Diabetic patients were older and had a higher BMI. Compared with the data of the French Social Security, acromegalic patients showed a more precocious apparition of diabetes and prevalence was higher in each age group.

Compared with non-diabetic acromegalic subjects, diabetic patients had a more prolonged evolution of acromegaly before diagnosis. The levels of GH and IGF1 were not significantly different between the two groups. Only hypertension was significantly more frequent in diabetic patients.

Conclusions

In our population, the prevalence of diabetes was estimated to be 22.3%. The GH and IGF1 levels did not appear as predictive factors for the presence of diabetes. On the contrary, age, BMI, and hypertension were significant risk factors as in the general population of type 2 diabetics.

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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.

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Laurent Vroonen, Marie-Lise Jaffrain-Rea, Patrick Petrossians, Gianluca Tamagno, Philippe Chanson, Lucio Vilar, Françoise Borson-Chazot, Luciana A Naves, Thierry Brue, Blandine Gatta, Brigitte Delemer, Enrica Ciccarelli, Paolo Beck-Peccoz, Philippe Caron, Adrian F Daly and Albert Beckers

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Laurent Vroonen, Marie-Lise Jaffrain-Rea, Patrick Petrossians, Gianluca Tamagno, Philippe Chanson, Lucio Vilar, Françoise Borson-Chazot, Luciana A Naves, Thierry Brue, Blandine Gatta, Brigitte Delemer, Enrica Ciccarelli, Paolo Beck-Peccoz, Philippe Caron, Adrian F Daly and Albert Beckers

Background

Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood.

Design and methods

A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly.

Results

Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CABmax/w) was 3.5 mg (2.0–10.5). Despite a higher CABmax/w in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CABmax/w (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CABmax/w or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%).

Conclusion

CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

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Maria A Tichomirowa, Anne Barlier, Adrian F Daly, Marie-Lise Jaffrain-Rea, Cristina Ronchi, Maria Yaneva, Jonathan D Urban, Patrick Petrossians, Atanaska Elenkova, Antoine Tabarin, Rachel Desailloud, Dominique Maiter, Thomas Schürmeyer, Renato Cozzi, Marily Theodoropoulou, Caroline Sievers, Ignacio Bernabeu, Luciana A Naves, Olivier Chabre, Carmen Fajardo Montañana, Vaclav Hana, Georges Halaby, Brigitte Delemer, José Ignacio Labarta Aizpún, Emmanuel Sonnet, Ángel Ferrandez Longás, Marie-Thérèse Hagelstein, Philippe Caron, Günter K Stalla, Vincent Bours, Sabina Zacharieva, Anna Spada, Thierry Brue and Albert Beckers

Background

Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.

Methods

We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.

Results

Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.

Conclusion

Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.