MARIA CANDIDA BARISSON VILLARES FRAGOSO
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Pregnancy in Women Previously Treated for an Adrenocortical Carcinoma(2015) CORBIERE, Pauline de; RITZEL, Katrin; CAZABAT, Laure; ROPERS, Jacques; SCHOTT, Matthias; LIBE, Rosella; KOSCHKER, Ann-Cathrin; LEBOULLEUX, Sophie; DEUTSCHBEIN, Timo; CAO, Christine Do; HAHNER, Stefanie; DRUI, Delphine; MIEHLE, Konstanze; CARON, Philippe; WALDMANN, Jens; CHABRE, Olivier; QUINKLER, Marcus; TOURAINE, Philippe; FRAGOSO, Maria C. Villares; BERTHERAT, Jerome; BERTAGNA, Xavier; FASSNACHT, Martin; RAFFIN-SANSON, Marie-LaureContext: Adrenocortical carcinomas (ACCs) are rare, aggressive tumors, of which some express receptors for estradiol, progesterone, and/or human chorionic gonadotoropin. Because this disease is encountered frequently in young women, pregnancy is a relevant issue. Objective: to evaluate the impact of pregnancy on outcome of patients previously treated for ACC. Design/Setting: retrospective observational multicenter study of the European Network for the Study of Adrenal Tumors. Patients: Seventeen ACC patients (21 pregnancies), becoming pregnant at least 3 months after the initial treatment, were compared with 247 nonpregnant ACC patients less than 47 years old. A control group of 34 patients matched for age, sex, and tumor stage was used for survival analysis. Main Outcome Measure(s): Overall survival, tumors characteristics at diagnosis, pregnancy outcome. Results: All 17 patients with pregnancies had localized ACC. The median time between surgery and conception was 4 years (0.3-12 y). Two pregnancies were terminated at 8 weeks. Sixteen women gave birth to 19 live infants. With exception of 1 (presumably unrelated) cardiac malformation, no severe fetal or maternal complication was observed. After a median follow-up time of 8.36 years and 5.26 years after the first conception, 1 of the 17 patients had died and 5 had experienced a recurrence, among whom 3 occurred before conception. Overall survival was not significantly different between the ""pregnancy group"" and the matched controls. Conclusion: Pregnancy in patients previously treated forACCseems to not be associated with worse clinical outcome, although a ""healthy mother effect"" cannot be excluded.
- Radiographic Characteristics of Adrenal Masses Preceding the Diagnosis of Adrenocortical Cancer(2015) NOGUEIRA, T. M.; LIROV, R.; CAOILI, E. M.; LERARIO, A. M.; MILLER, B. S.; FRAGOSO, M. C. B. V.; DUNNICK, N. R.; HAMMER, G. D.; ELSE, T.Incidentally discovered adrenal masses are common and the clinical evaluation and surveillance aims to diagnose hormone excess and malignancy. Adrenocortical cancer (ACC) is a very rare malignancy. This study aims to define the imaging characteristics of adrenal tumors preceding the diagnosis of ACC. Patients with prior (> 5 months) adrenal tumors (< 6 cm) subsequently diagnosed with ACC were identified in a large registry at a tertiary referral center. Retrospective chart and image review for patient characteristics and initial, interval, and diagnostic imaging characteristics (size, homogeneity, borders, density, growth rate, etc.) was conducted. Twenty patients with a diagnosis of ACC and a prior adrenal tumor were identified among 422 patients with ACC. Of these, 17 patients were initially imaged with CT and 3 with MR. Only 2 of the 20 patients had initial imaging characteristics suggestive of a benign lesion. Of initial tumors, 25 % were < 2 cm in size. Surveillance led to the diagnosis of ACC within 24 months in 50 % of patients. The growth pattern was variable with some lesions showing long-term stability (up to 8 years) in size. In conclusion, antecedent lesions in patients with a diagnosis of ACC are often indeterminate by imaging criteria and can be small. Surveillance over 2 years detected only 50 % of ACCs. Current practice and guidelines are insufficient in diagnosing ACCs. Given the rarity of ACC, the increased risk and health care costs of additional evaluation may not be warranted.
- DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis(2015) SOUSA, G. R. V. de; SOARES, I. C.; FARIA, A. M.; DOMINGUES, V. B.; WAKAMATSU, A.; LERARIO, A. M.; ALVES, V. A. F.; ZERBINI, M. C. N.; MENDONCA, B. B.; FRAGOSO, M. C. B. V.; LATRONICO, A. C.; ALMEIDA, M. Q.DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively ((2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis.
- Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer(2015) FARIA, Andre M.; SBIERA, Silviu; RIBEIRO, Tamaya C.; SOARES, Ibere C.; MARIANI, Beatriz M. P.; FREIRE, Daniel S.; SOUSA, Gabriela R. V. de; LERARIO, Antonio M.; RONCHI, Cristina L.; DEUTSCHBEIN, Timo; WAKAMATSU, Alda; ALVES, Venancio A. F.; ZERBINI, Maria Claudia N.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.; LATRONICO, Ana Claudia; FASSNACHT, Martin; ALMEIDA, Madson Q.ObjectiveLIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs). Patients and methodsLIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. ResultsLIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (P=001), but for overall survival only a trend was detectable (P=0117). In the multivariate analysis, only Ki67 index 10% (HR 46, P=0000) and weak LIN28 protein expression (HR 20, P=003) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 1334 (from 24 to 5193); P=0011] and was highly associated with reduced overall (P=001) and disease-free survival (P=001). However, mir-9 prognostic role should be further evaluated in a larger cohort. ConclusionWeak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.
- MANAGEMENT OF ENDOCRINE DISEASE Management of pregnant patients with Cushing's syndrome(2015) BRONSTEIN, M. D.; MACHADO, M. C.; FRAGOSO, M. C. B. V.Progress in the diagnosis and treatment of endocrine diseases has turned pregnancy into a possibility for women with such medical disorders, including Cushing's syndrome (CS). Nevertheless, despite its rarity, pregnancy in patients with CS can be troublesome because of the risk of maternal-fetal complications. Therefore, hypercortisolism, if present, should be surgically or medically controlled in most cases. Moreover, changes in the hypothalamic-pituitary-adrenal axis during normal pregnancy may mislead the diagnosis of CS during this period, because many laboratory assessments suggestive of CS may be present in normal pregnancy, with clinical features mimicking those seen in patients with CS. The aim of the present review is to update the diagnostic approach to this medical condition, mainly for pregnant women without previous diagnosis of CS, and to describe the therapeutic strategies for CS during pregnancy in order to minimize complications for both mother and fetus.
- Prognostic value of DICER1 expression in adrenocortical cancer patients(2015) SOUSA, Gabriela Resende V. de; RIBEIRO, Tamaya C.; FARIA, Andre M.; MARIANI, Beatriz M. P.; LERARIO, Antonio M.; SOARES, Ibere C.; ZERBINI, Maria Claudia N.; WAKAMATSU, Alda; ALVES, Venancio A. F.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.; LATRONICO, Ana Claudia; ALMEIDA, Madson
- POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells(2015) FRANCA, Monica Malheiros; FERRAZ-DE-SOUZA, Bruno; LERARIO, Antonio Marcondes; FRAGOSO, Maria Candida Barisson Villares; LOTFI, Claudimara Ferini PaciccoPOD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMyc Pod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers.
article 36 Citação(ões) na Scopus Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors(2015) PINHEIRO, Celine; GRANJA, Sara; LONGATTO-FILHO, Adhemar; FARIA, Andre M.; FRAGOSO, Maria C. B. V.; LOVISOLO, Silvana M.; LERARIO, Antonio M.; ALMEIDA, Madson Q.; BALTAZAR, Fatima; ZERBINI, Maria C. N.Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.article 17 Citação(ões) na Scopus Low DICER1 expression is associated with poor clinical outcome in adrenocortical carcinoma(2015) SOUSA, Gabriela Resende Vieira de; RIBEIRO, Tamaya C.; FARIA, Andre M.; MARIANI, Beatriz M. P.; LERARIO, Antonio M.; ZERBINI, Maria Claudia N.; SOARES, Ibere C.; WAKAMATSU, Alda; ALVES, Venancio A. F.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.; LATRONICO, Ana Claudia; ALMEIDA, Madson Q.Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.- Genetics of primary macronodular adrenal hyperplasia(2015) FRAGOSO, Maria Candida Barisson Villares; ALENCAR, Guilherme Asmar; LERARIO, Antonio Marcondes; BOURDEAU, Isabelle; ALMEIDA, Madson Queiroz; MENDONCA, Berenice Bilharinho; LACROIX, AndreACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term ` ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression.