MADSON QUEIROZ DE ALMEIDA
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Differences in the molecular mechanisms of adrenocortical tumorigenesis between children and adults(2012) FARIA, Andre M.; ALMEIDA, Madson Q.Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. The incidence of pediatric adrenocortical tumors (ACT) is remarkably high in Southern Brazil, where it is estimated to be 15 times greater than the world occurrence, due to a high frequency of a germline mutation (p.R337H) of the TP53 gene. Differently from adults, pediatric adrenocortical neoplasms with apparently poor prognosis based on histopathological features have often a good clinical outcome. A high Weiss score is definitely not a good predictor of survival in children, but it is much more discriminative of a poor outcome in adult tumors. Besides important differences in prognosis, adrenocortical tumorigenesis has distinct patterns between children and adults. In this review, we summarize recent data from ours and other Institutions, showing that the prognostic importance of molecular markers is striking different between pediatric and adult ACT. Although the majority of pediatric ACT are associated with p.R337H germline mutation, it is not a predictor of poor outcome in children and adolescents with ACT. On the other side, TP53 somatic mutations define a subgroup of adult ACC with different tumorigenesis and unfavorable prognosis. IGF system has a central role in the malignant phenotype of ACT, but in adult tumors it is mediated by IGF2 over-expression and in pediatric tumors by IGF1R over-expression. Finally, SF1 over-expression is associated with decreased overall survival and recurrence-free survival in adult ACC, but not in the pediatric group. In conclusion, discriminating benign and malignant behavior is more challenging in pediatric ACT than in adult tumors.
- Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and beta-Catenin(2012) HEATON, Joanne H.; WOOD, Michelle A.; KIM, Alex C.; LIMA, Lorena O.; BARLASKAR, Ferdous M.; ALMEIDA, Madson Q.; FRAGOSO, Maria C. B. V.; KUICK, Rork; LERARIO, Antonio M.; SIMON, Derek P.; SOARES, Ibere C.; STARNES, Elisabeth; THOMAS, Dafydd G.; LATRONICO, Ana C.; GIORDANO, Thomas J.; HAMMER, Gary D.Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal beta-catenin staining and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal beta-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized beta-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized beta-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis. (Ant J Pathol 2012, 181:1017-1033; http://dx.doi.org/10.1016/j.ajpath.2012.05.026)
- Recent advances in the molecular pathogenesis and targeted therapies of medullary thyroid carcinoma(2012) ALMEIDA, Madson Q.; HOFF, Ana O.Purpose of review This review will focus on the recent advances in molecular pathogenesis and targeted therapies for medullary thyroid carcinoma (MTC). Unlike hereditary MTC in which rearranged during transfection (RET) mutations are the most important precipitating events, in sporadic MTC the genetic or molecular biomarkers are yet to be established. Recent findings Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC and are under investigation. In addition, the recent findings of H-RAS mutations in 56% of RET-negative sporadic MTC and the activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway in hereditary MTC suggests that additional or alternative genetic events are important for MTC pathogenesis. Summary Recently, vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR 3, RET, and epidermal growth factor receptor (EGFR), was approved for the treatment of adults with symptomatic or progressive MTC. Significant advantages for vandetanib over placebo were seen in terms of response rate, disease control rate, and biochemical response in a phase III study. Furthermore, cabozantinib (XL184), an inhibitor of VEGFR 1 and VEGFR 2, hepatocyte growth factor receptor (MET), and RET, was associated with partial response and stable disease in 29 and 41%, respectively.
- Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: validation in a Brazilian cohort of adult and pediatric patients(2012) FRAGOSO, Maria Candida B. V.; ALMEIDA, Madson Queiroz; MAZZUCO, Tania L.; MARIANI, Beatriz M. P.; BRITO, Luciana P.; GONCALVES, Talita Cardoso; ALENCAR, Guilherme A.; LIMA, Lorena de O.; FARIA, Andre M.; BOURDEAU, Isabelle; LUCON, Antonio M.; FREIRE, Daniel S.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; LACROIX, Andre; LERARIO, Antonio M.Background: A recent microarray study identified a set of genes whose combined expression patterns were predictive of poor outcome in a cohort of adult adrenocortical tumors (ACTs). The difference between the expression values measured by qRT-PCR of DLGAP5 and PINK1 genes was the best molecular predictor of recurrence and malignancy. Among the adrenocortical carcinomas, the combined expression of BUB1B and PINK1 genes was the most reliable predictor of overall survival. The prognostic and molecular heterogeneity of ACTs raises the need to study the applicability of these molecular markers in other cohorts. Objective: To validate the combined expression of BUB1B, DLGAP5, and PINK1 as outcome predictor in ACTs from a Brazilian cohort of adult and pediatric patients. Patients and methods: BUB1B, DLGAP5, and PINK1 expression was assessed by quantitative PCR in 53 ACTs from 52 patients - 24 pediatric and 28 adults (one pediatric patient presented a bilateral asynchronous ACT). Results: DLGAP5 PINK1 and BUB1B PINK1 were strong predictors of disease-free survival and overall survival, respectively, among adult patients with ACT. In the pediatric cohort, these molecular predictors were only marginally associated with disease-free survival but not with overall survival. Conclusion: This study confirms the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a Brazilian group of adult ACTs. Among pediatric ACTs, other molecular predictors of outcome are required.
- The role of fibroblast growth factor receptor 4 overexpression and gene amplification as prognostic markers in pediatric and adult adrenocortical tumors(2012) BRITO, Luciana Pinto; RIBEIRO, Tamaya Castro; ALMEIDA, Madson Q.; JORGE, Alexander Augusto de Lima; SOARES, Ibere Cauduro; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson Villares; LERARIO, Antonio Marcondes