MARCELLO DELANO BRONSTEIN
Projetos de Pesquisa
Unidades Organizacionais
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
19 resultados
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- Switching patients with acromegaly from octreotide to pasireotide improves biochemical control: crossover extension to a randomized, double-blind, Phase III study(2016) BRONSTEIN, Marcello D.; FLESERIU, Maria; NEGGERS, Sebastian; COLAO, Annamaria; SHEPPARD, Michael; GU, Feng; SHEN, Chiung-Chyi; GADELHA, Monica; FARRALL, Andrew J.; RESENDIZ, Karina Hermosillo; RUFFIN, Matthieu; CHEN, YinMiao; FREDA, PamelaBackground: Many patients with acromegaly do not achieve biochemical control with first-generation somatostatin analogues. A large, multicenter, randomized, Phase III core study demonstrated that pasireotide LAR had significantly superior efficacy over octreotide LAR. This analysis explores the efficacy and safety of switching therapeutic arms in inadequately controlled patients during a 12-month crossover extension. Methods: Patients with inadequate biochemical control (GH >= 2.5 mu g/L and/or IGF 1 > ULN) at end of core study (month 12) were eligible to switch to pasireotide LAR 40 mg/28 days (n = 81) or octreotide LAR 20 mg/28 days (n = 38). One dose escalation to pasireotide LAR 60 mg/28 days or octreotide LAR 30 mg/28 days was permitted, but not mandatory, at month 17 or 20. Results: Twelve months after crossover, 17.3 % of pasireotide LAR and 0 % of octreotide LAR patients achieved GH <2.5 mu g/L and normal IGF-1 (main outcome measure); 27.2 and 5.3 % of pasireotide LAR and octreotide LAR patients achieved normal IGF-1, respectively; 44.4 and 23.7 % of pasireotide LAR and octreotide LAR patients achieved GH < 2.5 mu g/L, respectively. Mean (+/- SD) tumor volume further decreased from the end of the core study by 25 % (+/- 25) and 18 % (+/- 28); 54.3 % of pasireotide LAR and 42.3 % of octreotide LAR patients achieved significant (>= 20 %) tumor volume reduction during the extension. The safety profile of pasireotide LAR was similar to that of octreotide LAR, with the exception of the frequency and degree of hyperglycemia-related adverse events. Conclusions: Pasireotide LAR is a promising treatment option for patients with acromegaly inadequately controlled with the first-generation somatostatin analogue octreotide LAR.
- A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update(2020) GIUSTINA, Andrea; BARKAN, Ariel; BECKERS, Albert; BIERMASZ, Nienke; BILLER, Beverly M. K.; BOGUSZEWSKI, Cesar; BOLANOWSKI, Marek; BONERT, Vivien; BRONSTEIN, Marcello D.; CASANUEVA, Felipe F.; CLEMMONS, David; COLAO, Annamaria; FERONE, Diego; FLESERIU, Maria; FRARA, Stefano; GADELHA, Monica R.; GHIGO, Ezio; GURNELL, Mark; HEANEY, Anthony P.; HO, Ken; IOACHIMESCU, Adriana; KATZNELSON, Laurence; KELESTIMUR, Fahrettin; KOPCHICK, John; KRSEK, Michal; LAMBERTS, Steven; LOSA, Marco; LUGER, Anton; MAFFEI, Pietro; MARAZUELA, Monica; MAZZIOTTI, Gherardo; MERCADO, Moises; MORTINI, Pietro; NEGGERS, Sebastian; PEREIRA, Alberto M.; PETERSENN, Stephan; PUIG-DOMINGO, Manel; SALVATORI, Roberto; SHIMON, Ilan; STRASBURGER, Christian; TSAGARAKIS, Stylianos; LELY, A. J. van der; WASS, John; ZATELLI, Maria Chiara; MELMED, ShlomoObjective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system. Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.
- Pituitary autoimmune disease: nuances in clinical presentation(2012) GLEZER, A.; BRONSTEIN, M. D.Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH.
- Challenges in the diagnosis and management of acromegaly: a focus on comorbidities(2016) ABREU, Alin; TOVAR, Alejandro Pinzon; CASTELLANOS, Rafael; VALENZUELA, Alex; GIRALDO, Claudia Milena Gomez; PINEDO, Alejandro Castellanos; GUERRERO, Doly Pantoja; BARRERA, Carlos Alfonso Builes; FRANCO, Humberto Ignacio; RIBEIRO-OLIVEIRA JR., Antonio; VILAR, Lucio; JALLAD, Raquel S.; DUARTE, Felipe Gaia; GADELHA, Monica; BOGUSZEWSKI, Cesar Luiz; ABUCHAM, Julio; NAVES, Luciana A.; MUSOLINO, Nina Rosa C.; FARIA, Maria Estela Justamante de; ROSSATO, Ciliana; BRONSTEIN, Marcello D.Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life. We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment. Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.
- Somatostatin receptor ligands in the treatment of acromegaly(2017) GADELHA, Monica R.; WILDEMBERG, Luiz Eduardo; BRONSTEIN, Marcello D.; GATTO, Federico; FERONE, DiegoFirst-generation somatostatin receptors ligands (SRL) are the mainstay in the medical treatment of acromegaly, however the percentage of patients controlled with these drugs significantly varies in the different studies. Many factors are involved in the resistance to SRL. In this review, we update the physiology of somatostatin and its receptors (sst), the use of SRL in the treatment of acromegaly and the factors involved in the response to these drugs. The SRL act through interaction with the sst, which up to now have been characterized as five subtypes. The first-generation SRL, octreotide and lanreotide, are considered sst2 specific and have biochemical response rates varying from 20 to 70%. Tumor volume reduction can be found in 36-75% of patients. Several factors may determine the response to these drugs, such as sst, AIP, E-cadherin, ZAC1, filamin A and beta-arrestin expression in the somatotropinomas. In patients resistant to first-generation SRL, alternative medical treatment options include: SRL high dose regimens, SRL in combination with cabergoline or pegvisomant, or the use of pasireotide. Pasireotide is a next-generation SRL with a broader pattern of interaction with sst. In the light of the recent increase of treatment options in acromegaly and the deeper knowledge of the determinants of response to the current first-line therapy, a shift from a trial-and-error treatment to a personalized one could be possible.
- Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study(2014) COLAO, A.; BRONSTEIN, M. D.; FREDA, P.; GU, F.; SHEN, C. -C.; GADELHA, M.; FLESERIU, M.; LELY, A. J. van der; FARRALL, A. J.; RESENDIZ, K. Hermosillo; RUFFIN, M.; CHEN, Y.; SHEPPARD, M.Context: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. Objective: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. Design and Setting: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. Patients: A total of 358 patients with medically naive acromegaly (GH > 5 mu g/L or GH nadir >= 1 mu g/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. Interventions: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH >= 2.5 mu g/L and/or IGF-1 was above the upper limit of normal. Main Outcome Measure: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 mu g/L and normal IGF-1) at month 12. Results: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 mu g/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). Conclusions: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
article 13 Citação(ões) na Scopus Pregnancy and pituitary adenomas(2016) GLEZER, Andrea; JALLAD, Raquel S.; MACHADO, Marcio C.; FRAGOSO, Maria Candida; BRONSTEIN, Marcello D.Infertility is frequent in patients harboring pituitary adenomas. The mechanisms involved include hypogonadism secondary to hormonal hypersecretion (prolactin, growth hormone and cortisol), stalk disconnection and pituitary damage. With the improvement of clinical and surgical treatment, pregnancy in women harboring pituitary adenomas turned into a reality. Pituitary hormonal hyper- and hyposecretion influences pregnancy outcomes, as well as pregnancy can interfere on pituitary tumors, especially in prolactinomas. We review literature about specific follow-up and management in pregnant women harboring prolactinomas, acromegaly, or Cushings disease and the impact of clinical and surgical treatment on each condition.- The interplay between prolactin and cardiovascular disease(2023) GLEZER, Andrea; SANTANA, Mariana Ramos; BRONSTEIN, Marcello D. D.; JR, Jose Donato; JALLAD, Raquel SoaresHyperprolactinemia can be caused by several conditions and its effects on the hypothalamic-pituitary-gonadal axis are understood in more detail. Nevertheless, in recent decades, other metabolic effects have been studied and data pointed to a potential increased cardiovascular disease (CVD) risk. A recent study showed a decrease in total and LDL- cholesterol only in men with prolactinoma treated with dopamine agonists (DA) supporting the previous results of a population study with increased CVD risk in men harboring prolactinoma. However, other population studies did not find a correlation between prolactin (PRL) levels and CVD risk or mortality. There is also data pointing to an increase in high-density lipoprotein levels, and decreases in triglycerides, carotid-intima-media thickness, C-reactive protein, and homocysteine levels in patients with prolactinoma on DA treatment. PRL was also implicated in endothelial dysfunction in pre and postmenopausal women. Withdrawal of DA resulted in negative changes in vascular parameters and an increase in plasma fibrinogen. It has been shown that PRL levels were positively correlated with blood pressure and inversely correlated with dilatation of the brachial artery and insulin sensitivity, increased homocysteine levels, and elevated D-dimer levels. Regarding possible mechanisms for the association between hyperprolactinemia and CVD risk, they include a possible direct effect of PRL, hypogonadism, and even effects of DA treatment, independently of changes in PRL levels. In conclusion, hyperprolactinemia seems to be associated with impaired endothelial function and DA treatment could improve CVD risk. More studies evaluating CVD risk in hyperprolactinemic patients are important to define a potential indication of treatment beyond hypogonadism.
- EXPERT CONSENSUS DOCUMENT A consensus on the medical treatment of acromegaly(2014) GIUSTINA, Andrea; CHANSON, Philippe; KLEINBERG, David; BRONSTEIN, Marcello D.; CLEMMONS, David R.; KLIBANSKI, Anne; LELY, Aart J. van der; STRASBURGER, Christian J.; LAMBERTS, Steven W.; HO, Ken K. Y.; CASANUEVA, Felipe F.; MELMED, ShlomoIn March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.
- Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial(2014) GADELHA, Monica R.; BRONSTEIN, Marcello D.; BRUE, Thierry; COCULESCU, Mihail; FLESERIU, Maria; GUITELMAN, Mirtha; PRONIN, Vyacheslav; RAVEROT, Gerald; SHIMON, Ilan; LIEVRE, Kayo Kodama; FLECK, Juergen; AOUT, Mounir; PEDRONCELLI, Alberto M.; COLAO, AnnamariaBackground 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 mu g/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 mu g/L and > 10 mu g/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 mu g/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.