MARCELLO DELANO BRONSTEIN
Projetos de Pesquisa
Unidades Organizacionais
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
139 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 139
- 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.
- Cabergoline and prolactinomas: lack of association between DRD2 polymorphisms and response to treatment(2017) BUENO, C. B. F.; TRARBACH, E. B.; BRONSTEIN, M. D.; GLEZER, A.Background About 80% of prolactinomas respond to dopamine agonists (DA) with hormonal normalization and tumor shrinkage. Mechanisms of DA resistance include reduction of dopamine receptor subtype 2 (DRD2) expression, short and long isoform ratio and post-receptor mechanisms. It was suggested that polymorphisms in the gene encoding dopamine receptor subtype 2 gene (DRD2) could be associated with variable effectiveness of cabergoline (CAB). Objective To assess the influence of DRD2 polymorphisms in responsiveness of CAB treatment in patients with prolactinoma. Study design and patients Cross-sectional retrospective case-control study analyzing the frequency of five DRD2 polymorphisms in 148 patients with prolactinoma and 349 healthy subjects. The association of genetic variants and clinical characteristics with CAB responsiveness was performed in 118 patients (mean age at diagnosis 29 years; range 11-61 years) with hormonal evaluation. Patients with prolactin (PRL) normalization were considered as responders. Results No association in genotypes and allele proportions was found comparing patients and controls. On pharmacogenetic study, 118 patients on CAB were included and 20% were non-responders. No association was found between clinical characteristics (gender, age, PRL level and tumor size at diagnosis) and polymorphisms of DRD2 with CAB responsiveness. Otherwise, there was association between polymorphisms rs1076560 (allele A) and rs1800497 (allele T) and the presence of macroadenomas. Conclusion No correlation was found between DRD2 polymorphisms and CAB responsiveness in patients with prolactinoma. More data are necessary in order to assess the influence of DRD2 genotyping on DA treatment response.
- Prolactinomas in pregnancy: considerations before conception and during pregnancy(2020) GLEZER, Andrea; BRONSTEIN, Marcello D.Prolactinomas are the most common pituitary tumors and pathological hyperprolactinemia. Therefore, women harboring prolactinomas frequently present infertility due to the gonadal axis impairment. The gold-standard treatment is dopamine agonist (DA) which can reverse hyperprolactinemia and hypogonadism, and promote tumor shrinkage in the majority of cases. Therefore, reports of pregnancy in such cohort become more common. In this scenario, bromocriptine is still the DA of choice due to its shorter half-life and larger experience as compared to cabergoline. In DA resistant cases, transsphenoidal pituitary surgery is indicated. However, potential risks of DA-induced pregnancies include fetal exposition and symptomatic tumor growth. Dopamine agonist should be discontinued as soon as pregnancy is confirmed in microprolactinomas and intrasellar macroprolactinomas (MAC). Concerning expansive/invasive MAC, DA maintenance should be considered. Periodically clinical evaluation should be performed during pregnancy, being sellar imaging indicated if tumor symptomatic growth is suspected. In such cases, if DA treatment fails, neurosurgery is indicated.
- Acromegaly and pregnancy: a contemporary review(2017) ABUCHAM, Julio; BRONSTEIN, Marcello D.; DIAS, Monike L.Although fertility is frequently impaired in women with acromegaly, pregnancy is apparently becoming more common due to improvement in acromegaly treatment as well as in fertility therapy. As a result, several studies on pregnancy in patients with acromegaly have been published in recent years adding new and relevant information to the preexisting literature. Also, new GH assays with selective specificities and the knowledge of the expression of the various GH genes have allowed a better understanding of somatotrophic axis function during pregnancy. In this review, we show that pregnancy in women with acromegaly is generally safe, usually with tumoral and hormonal stability. Although the paucity of data limits evidence-based recommendations for preconception counseling and pregnancy surveillance, controlling tumor size and hormonal activity before pregnancy is highly recommended to ensure better outcomes, and surgical control should be attempted when feasible. Treatment interruption at pregnancy confirmation has also proven to be safe, as drugs are not formally allowed to be used during pregnancy. Drug exposure (somatostatin analogs) during early or whole pregnancy might increase the chance of a lower birth weight. Aggressive disease is uncommon and may urge individual decisions such as surgery or drug treatment during pregnancy or lactation.
- Influence of growth hormone receptor (GHR) exon 3 and-202A/C IGFBP-3 genetic polymorphisms on clinical and biochemical features and therapeutic outcome of patients with acromegaly(2015) JALLAD, Raquel S.; TRARBACH, Ericka B.; DUARTE, Felipe H.; JORGE, Alexander A. L.; BRONSTEIN, Marcello D.The association of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms with clinical presentation, biochemical measurements and response to therapies in acromegaly have been suggested. To evaluate the presence of these polymorphisms in acromegaly and their influence on clinical and laboratorial characteristics of patients at diagnosis and after treatment in a large cohort of acromegalic patients. This is a cross-sectional study developed in a single tertiary reference center. Clinical data were obtained from the medical records of 186 acromegalic patients (116 women, age range 21-88 years). GH and IGF1 levels and GHR-exon 3 and -202 A/C IGFBP3 polymorphisms were evaluated in the same hospital. At diagnosis, serum GH concentrations were lower in patients with GHR-d3 genotype than those with GHR-fl, whereas an association of lower IGFBP3 levels with d3 allele was observed only after neurosurgical or medical treatments. However, these associations were not confirmed in posterior statistical analysis. Our results suggest that GHR-exon 3 and -202 A/C IGFBP3 polymorphisms did not show any consistent association on clinical and laboratorial features of acromegalic patients even after treatment.
conferenceObject Phase III, Multicenter, Randomized Study (PAOLA) Demonstrating That Pasireotide LAR Has Superior Efficacy over Octreotide LAR and Lanreotide ATG in Patients with Inadequately Controlled Acromegaly(2014) COLAO, Annamaria; BRONSTEIN, Marcello D.; BRUE, Thierry; COCULESCU, Mihail Gr; FLESERIU, Maria; GUITELMAN, Mirtha; PRONIN, Vyacheslav; RAVEROT, Gerald; SHIMON, Ilan; LIEVRE, Kayo Kodama; FLECK, Juergen; AOUT, Mounir; PEDRONCELLI, Alberto M.; GADELHA, MA'nica- Pregnancy in Patients with Cushing's Syndrome(2018) MACHADO, Marcio Carlos; FRAGOSO, Maria Candida Barisson Vilares; BRONSTEIN, Marcello DelanoProgress in diagnosis and treatment of endocrine diseases has made pregnancy possible for women with endocrinopathies, including Cushing's syndrome (CS). The risk of maternal-fetal complications in patients who are not biochemically controlled, however, is substantial. Therefore, the surgical and/or medical control of hypercortisolism is mandatory before conceiving. A diagnosis of de novo CS during gestation is difficult because of changes in the hypothalamic-pituitary-adrenal axis during pregnancy, which may lead to some clinical features suggestive of CS along with abnormal laboratory test results. This article presents the diagnosis and management of CS during pregnancy.
- Women with prolactinomas presented at the postmenopausal period(2014) SHIMON, Ilan; BRONSTEIN, Marcello D.; SHAPIRO, Jonathan; TSVETOV, Gloria; BENBASSAT, Carlos; BARKAN, ArielIn women, prolactinomas (mainly microprolactinomas) are commonly diagnosed between 20-40-year old. In postmenopausal women, prolactinomas are rarely encountered and usually do not present with hyperprolactinemia-related symptoms as these are dependent on intact ovarian function. Therefore, the true incidence of prolactin (PRL)-secreting adenomas in postmenopausal woman is unknown. Our study objective was to characterize these rare and unique pituitary tumors. A retrospective study including a consecutive group of postmenopausal women followed and treated at 3 Endocrine academic clinics. Baseline clinical characteristics (PRL and gonadotropins levels, other pituitary hormones, adenoma size and invasiveness, visual fields) and response to treatment are reported. The cohort included 14 postmenopausal women with prolactinomas (mean age at diagnosis, 63.6 +/- A 7.1 years; range, 54-75 years). Mean adenoma size at presentation was 25.6 +/- A 12.4 mm (range, 8-50 mm). Six out of the 14 women had significant visual fields damage. Mean baseline PRL level was 1,783 ng/ml, and median PRL was 827 ng/ml (range, 85-6,732 ng/ml). Medical treatment with cabergoline was given to twelve of the patients. Cabergoline normalized/near-normalized PRL in eleven women; one woman was dopamine agonist-resistant. Five of the six subjects with visual disturbances normalized or improved their vision, and a pre-treatment diplopia in another patient disappeared. Two large pituitary tumors disappeared on MRI following long-term dopamine agonist therapy. All other treated prolactinomas, except the resistant adenoma, shrank following medical treatment. Prolactinomas are rarely diagnosed in postmenopausal women. These women usually harbor large and invasive macroadenomas, secreting high PRL levels, and usually respond to dopamine agonist treatment.
- PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation(2013) ARAUJO, Ricardo V.; CHANG, Claudia V.; CESCATO, Valter A. S.; FRAGOSO, Maria Candida B. V.; BRONSTEIN, Marcello D.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; CARVALHO, Luciani R. S.OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.
- Penetrance of Functioning and Nonfunctioning Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 in the Second Decade of Life(2014) GONCALVES, Tatiana D.; TOLEDO, Rodrigo A.; SEKIYA, Tomoko; MATUGUMA, Sergio E.; MALUF FILHO, Fauze; ROCHA, Manoel S.; SIQUEIRA, Sheila A. C.; GLEZER, Andrea; BRONSTEIN, Marcelo D.; PEREIRA, Maria A. A.; JUREIDINI, Ricardo; BACCHELLA, Telesforo; MACHADO, Marcel C. C.; TOLEDO, Sergio P. A.; LOURENCO JR., Delmar M.Context: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. Apotential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs. Objective: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers. Design: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center. Patients: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas. Methods: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS. Results: The overall penetrance of PETs during the second decade of life was42%(8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67 < 2%). Conclusions: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.