Silvia Regina Brandalise

University of São Paulo, São Paulo, Estado de Sao Paulo, Brazil

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Publications (38)167.66 Total impact

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    ABSTRACT: Background: The sonic hedgehog (SHH) pathway plays a key role in rodent adrenal cortex development and is involved in tumorigenesis in several human tissues, but data in human adrenal glands are limited. Objectives: To analyze the involvement of the SHH pathway in human adrenal development and tumorigenesis and the effects of SHH inhibition on an adrenocortical tumor (ACT) cell line. Patients & Methods: Expression of SHH pathway components was evaluated by immunohistochemistry (IHC) in 51 normal adrenals (33 fetal) and 34 ACTs (23 pediatric), and by qPCR in 81 ACTs (61 pediatric) and 19 controls (10 pediatric). The effects of SHH pathway inhibition on gene expression and cell viability in the NCI-H295A adrenocortical tumor cell line after cyclopamine treatment were analyzed. Results: SHH pathway proteins were present in fetal and postnatal normal adrenals and showed distinct patterns of spatiotemporal expression throughout development. Adult ACCs presented with higher expression of PTCH1, SMO, GLI3 and SUFU compared with normal adult adrenal cortices. Conversely, pediatric ACTs showed lower mRNA expression of SHH, PTCH1, SMO, GLI1 and GLI3 compared with normal pediatric adrenal cortices. In vitro treatment with cyclopamine resulted in decreased GLI3, SFRP1, CTNNB1 mRNA expression and beta-catenin staining, as well as decreased cell viability. Conclusions: The SHH pathway is active in human fetal and postnatal adrenals, up regulated in adult ACCs and down regulated in pediatric ACTs. SHH pathway antagonism impaired cell viability. The SHH pathway is deregulated in ACTs and might provide a new target therapy to be explored.
    The Journal of clinical endocrinology and metabolism 04/2014; · 6.50 Impact Factor
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    ABSTRACT: ContextThe role of planar cell polarity (Wnt/PCP) and calcium-dependent (Wnt/Ca) noncanonical Wnt pathways in adrenocortical tumours (ACTs) is unknown.Objectives To investigate gene expression of Wnt/PCP and Wnt/Ca pathways and its association with TP53 p.R337H and CTNNB1 mutations in paediatric and adult ACTs and to correlate these findings with clinical outcome.PatientsExpression of noncanonical Wnt-related genes was evaluated in 91 ACTs (66 children, 25 adults) by qPCR and beta-catenin, P53, and protein effectors of Wnt/Ca (NFAT) and Wnt/PCP (JNK) by immunohistochemistry. TP53 and CTNNB1 genes were sequenced.ResultsTP53 p.R337H mutation frequency was higher in children (86% vs 28%) while CTNNB1 mutation was higher in adults (32% vs 6%). Mortality was higher in adults harbouring TP53 p.R337H and in children with CTNNB1 mutations. Overexpression of WNT5A, Wnt/Ca ligand, was observed in children and adults. Overexpression of MAPK8 and underexpression of PRICKLE, Wnt/PCP mediators, were observed in paediatric, but not in adult cases. Cytoplasmic/nuclear beta-catenin and P53 accumulation were observed in the majority of pediatric and adult ACTs as well as NFAT and JNK. Overexpression of MAPK8 and underexpression of PRICKLE were associated with mortality in children while overexpression of WNT5A and underexpression of PRICKLE were associated with mortality in adults.Conclusions In our study, TP53 p.R337H and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. We demonstrate, for the first time, the activation of Wnt/PCP and Wnt/Ca noncanonical pathway genes, and their association with poor outcome in children and adults, suggesting their putative involvement in ACTs aggressiveness.This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 04/2014; · 3.40 Impact Factor
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    ABSTRACT: Abstract Cellular hypoxic condition is a key event in several human cancers but the knowledge about its role in childhood ALL is very limited. In the present study gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone marrow samples of 113 pediatric patients. HIF1A mRNA up-regulation was significantly associated with higher 5-years event-free survival rates in B-ALL patients as well as in the overall ALL population in both univariate and multivariate analysis (P = 0.023 and P = 0.041 respectively). In gene expression analysis, low oxygen levels promoted HIF1A activation in a time-dependent manner, in both ALL cell lines. In vitro cytotoxic assays suggested an initial trend to hypoxia-related resistance in the first 24 hours, but later time points (48 - 72 hours) evaluation clearly showed that there is no relevant difference in drug response when comparing hypoxic to normal oxygen level conditions. Modulation of mRNA expression of several hypoxia-related genes was also observed after hypoxic exposure in a cell specific manner, suggesting that HIF1A mRNA expression could play a different role in specific subtypes of leukemia. Despite the remaining questions regarding hypoxia-mediated mechanisms, these findings could be helpful to provide new insights in the role of hypoxia in childhood ALL.
    Leukemia & lymphoma 10/2013; · 2.40 Impact Factor
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    ABSTRACT: Pediatric adrenocortical tumors (ACT) are rare malignancies and treatment has a small impact on survival in advanced disease and the discovery of potential target genes could be important in new therapeutic approaches. The mRNA expression levels of spindle checkpoint genes AURKA, AURKB, BUB, and BUBR1 were analyzed in 60 children with ACT by quantitative real time PCR. The anticancer effect of ZM447439, an experimental AURK inhibitor, was analyzed in a primary childhood ACT culture carrying the TP53 p.R337H mutation. A significant association was observed between malignancy as defined by Weiss score ≥3 and higher AURKA (2.0-fold, P = 0.01), AURKB (7.0-fold, P = 0.007), and BUBR1 (5.8-fold, P = 0.007) gene expression, and between unfavorable event (death or relapse) and higher expression of AURKA (6.0-fold, P = 0.034) and AURKB (17-fold, P = 0.013). Overexpression of AURKA and AURKB was associated with lower event-free survival in uni- (P < 0.001 and P = 0.006, respectively) and multivariate (P = 0.002 and P = 0.03, respectively) analysis. Significant lower Event free survival (EFS) was also observed in patients with moderate/strong immunostaining to AURKA (P = 0.012) and AURKB (P = 0.045). ZM447439 was able to induce inhibition of proliferation and colony formation in a primary childhood ACT culture carrying the TP53 p.R337H mutation. Our results suggest that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease and the inhibition of these proteins could be an interesting approach for the treatment of these tumors. Pediatr Blood Cancer. © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 06/2013; · 2.35 Impact Factor
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    ABSTRACT: Advanced disease is a risk factor for eye loss in patients with retinoblastoma (RB). We still record critical rates of enucleation, especially for unilateral RB due to advanced stages of disease at diagnosis. This retrospective study of 223 RB patient records referred to treatment at Centro Infantil Boldrini, Brazil, between 1978 and 2008, showed that 176 patients (79%) presented intraocular tumors while 47 (21%) already had extraocular involvement. At the time of diagnosis, the age of patients was 26.2 months in the group that had enucleated eyes and 13.7 months in the group that preserved both eyes. Under a multiple logistic regression model, familial history (OR = 0.195; p = .01) and age at diagnosis in months (OR = 1.047; p = .04) were significantly correlated with enucleation. Strategies to early detect RB must be changed in order to offer better chances of ocular preservation with visual function. Authors propose a systematic referral of all children to the ophthalmologist for an indirect ophthalmoscopy once a year in the first two years of life, as a measure to be adopted by all pediatricians in daily routine to early detect the tumor.
    Pediatric Hematology and Oncology 03/2013; · 0.90 Impact Factor
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    ABSTRACT: Introduction T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from leukemic transformation of T-cell progenitors in the thymus. It accounts for approximately 15% of ALL cases in childhood and 20–25% in adults and is a leading cause of death in children. IL-7 and its receptor (IL-7R) play a critical role in normal T-cell development and homeostasis. Methods The IL-7R gene was sequenced in T-ALL from three cohorts. Results Mutations in IL-7R were identified in 9% of pediatric T-ALL patients. These mutations usually involved insertions of three amino acids including cysteine and proline in the extracellular juxtamembrane region. WT or mutant forms of the human IL-7R (hIL-7R) from patients were retrovirally transfected into an IL-7-dependent murine thymic cell line D1. Mutant hIL-7Rs induced ligand-independent activation of the Jak-Stat and PI3K pathways, cell survival and proliferation. Notably, mutant hIL-7R-expressing D1 cells induced subcutaneous tumors in Rag1-/- mice, with substantial infiltration into various organs that are normally affected in advanced stages of T-ALL, such as bone marrow, liver, lymph nodes and spleen. Further functional assays revealed that mutant hIL-7Rs constitutive signaling required homodimerization via cysteines in the inserted sequences and downstream Jak1 activation, and was IL-7, gc and Jak3-independent. Conclusion Our findings indicate that hIL-7R mutational activation drives T-ALL leukemogenesis and implicate IL-7R and Jak1 as therapeutic targets in T-ALL.
    Cytokine 09/2012; 59(3):507. · 2.52 Impact Factor
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    ABSTRACT: The present study evaluated the expression profile of 19 genes previously reported in microarray studies and associated with resistance or sensitivity to vincristine (RPLP2, CD44, TCFL5, KCNN1, TRIM24), prednisolone (F8A, CDK2AP1, BLVRB, CD69), daunorubicin (MAP3K12, SHOC2, PCDH9, EGR1, KCNN4) and l-asparaginase (GPR56, MAN1A1, CLEC11A, IGFBP7, GATA3). We studied 140 bone marrow samples at diagnosis from children with acute lymphoblastic leukemia (ALL) treated according to the Brazilian Childhood Leukemia Treatment Group (GBTLI) ALL-99 protocol. The expression profiles of the genes listed above were analyzed by real-time quantitative polymerase chain reaction (PCR) and then related to the clinical and biological prognostic factors. The results showed significant associations (p ≤ 0.05) between the expression levels of genes GPR56, BLVRB, IGFBP7 and white blood cell (WBC) count at diagnosis; GATA3, MAN1A1, CD44, MAP3K12, CLEC11A, SHOC2 and CD10 B-lineage ALL; TCFL5 and bone marrow status at day 14; MAP3K12 and TRIM24 and bone marrow status at day 28; and CD69, TCFL5 and TRIM24 genes and ETV6/RUNX1 positive ALL. The up-regulation of SHOC2 was also associated with better 5-year event-free survival (EFS) in univariate and multivariate analysis (p = 0.02 and p = 0.03, respectively). These findings highlight genes that could be associated with clinical and biological prognostic factors in childhood ALL, suggesting that these genes may characterize and play a role in the treatment outcome of some ALL subsets.
    Leukemia & lymphoma 08/2012; · 2.40 Impact Factor
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    ABSTRACT: Impaired apoptosis has been implicated in the development of childhood adrenocortical tumors (ACT), although the expression of apoptosis-related gene expression in such tumors has not been reported. The mRNA expression levels of the genes CASP3, CASP8, CASP9, FAS, TNF, NFKB, and BCL2 were analyzed by quantitative real-time PCR in consecutive tumor samples obtained at diagnosis from 60 children with a diagnosis of ACT and in 11 non-neoplastic adrenal samples. BCL2 and TNF protein expression was analyzed by immunohistochemistry. A significant association was observed between tumor size ≥100 g and lower expression levels of the BCL2 (P=0.03) and TNF (P=0.05) genes; between stage IV and lower expression levels of CASP3 (P=0.008), CASP9 (P=0.02), BCL2 (P=0.002), TNF (P=0.05), and NFKB (P=0.03); Weiss score ≥3 and lower expression of TNF (P=0.01); unfavorable event and higher expression values of CASP9 (P=0.01) and lower values of TNF (P=0.02); and death and lower expression of BCL2 (P=0.04). Underexpression of TNF was associated with lower event-free survival in uni- and multivariate analyses (P<0.01). Similar results were observed when patients with Weiss score <3 were excluded. This study supports the participation of apoptosis-related genes in the biology and prognosis of childhood ACT and suggests the complex role of these genes in the pathogenesis of this tumor.
    European Journal of Endocrinology 05/2012; 167(2):199-208. · 3.14 Impact Factor
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    ABSTRACT: The present study aimed to analyze the expression profile of the microRNAs previously described as associated with childhood ALL, miR-92a, miR-100, miR-125a-5p, miR-128a, miR-181b, miR-196b and let-7e, and their association with biological/prognostic features in 128 consecutive samples of childhood acute lymphoblastic leukemia (ALL) by quantitative real-time PCR. A significant association was observed between higher expression levels of miR-196b and T-ALL, miR-100 and patients with low white blood cell count at diagnosis and t(12;21) positive ALL. These findings suggest a potential activity of these microRNAs in pediatric ALL biology.
    Leukemia research 11/2011; 36(3):293-8. · 2.36 Impact Factor
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    ABSTRACT: The interaction of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells (BMSCs) has a positive impact on ALL resistance to chemotherapy. We investigated the modulation of a series of putative asparaginase-resistance/sensitivity genes in B-precursor ALL cells upon coculture with BMSCs. Coculture with stromal cells resulted in increased insulin-like growth factor (IGF)-binding protein 7 (IGFBP7) expression by ALL cells. Assays with IGFBP7 knockdown ALL and stromal cell lines, or with addition of recombinant rIGFBP7 (rIGFBP7) to the culture medium, showed that IGFBP7 acts as a positive regulator of ALL and stromal cells growth, and significantly enhances in-vitro resistance of ALL to asparaginase. In these assays, IGFBP7 function occurred mainly in an insulin- and stromal-dependent manner. ALL cells were found to contribute substantially to extracellular IGFBP7 levels in the conditioned coculture medium. Diagnostic BM plasma from children with ALL had higher levels of IGFBP7 than controls. IGFBP7, in an insulin/IGF-dependent manner, enhanced asparagine synthetase expression and asparagine secretion by BMSCs, thus providing a stromal-dependent mechanism by which IGFBP7 protects ALL cells against asparaginase in this coculture system. Importantly, higher IGFBP7 mRNA levels were associated with lower leukemia-free survival (Cox regression model, P=0.003) in precursor B-cell Ph(-) ALL patients (n=147) treated with a contemporary polychemotherapy protocol.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2011; 26(5):1001-11. · 10.16 Impact Factor
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    ABSTRACT: Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cell leukemogenesis, paving the way for therapeutic targeting of IL-7R-mediated signaling in T-ALL.
    Nature Genetics 09/2011; 43(10):932-9. · 35.21 Impact Factor
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    ABSTRACT: CTNNB1/β-catenin mutations and activation of Wnt/β-catenin pathway are frequent in adult adrenocortical tumors (ACT), but data on childhood ACT are lacking. The aim of the study was to investigate the presence of Wnt/β-catenin pathway abnormalities in childhood ACT. Clinicopathological findings and outcome of 62 childhood ACT patients were analyzed regarding CTNNB1 mutations and the expression of Wnt-related genes (CTNNB1; WNT4, a Wnt ligand; SFRP1, DKK3, and AXIN1, Wnt inhibitors; TCF7, a transcription factor; and MYC and WISP2, target genes) by quantitative PCR and immunohistochemistry. CTNNB1-activating mutations were found in only four of 62 ACT (6%), all of them harboring TP53 mutation. There was association between the presence of CTNNB1 mutations and death (P = 0.02). Diffuse β-catenin accumulation was found in 71% of ACT, even in ACT without CTNNB1 mutations. Compared to normal adrenals, ACT presented increased expression of CTNNB1 (P = 0.008) and underexpression of Wnt inhibitor genes: DKK3 (P < 0.0001), SFRP1 (P = 0.05), and AXIN1 (P = 0.04). With regard to Wnt/β-catenin target genes, ACT presented increased expression of WISP2 but lower expression of MYC. Higher overall survival was associated with underexpression of SFRP1 (P = 0.01), WNT4 (P = 0.004), and TCF7 (P < 0.01). CTNNB1 mutations are not common in childhood ACT but appear to associate with poor prognosis. Nevertheless, most ACT exhibit increased expression of β-catenin and WISP2 and reduced expression of Wnt inhibitor genes (DKK3, SFRP1, and AXIN1). Thus, in addition to CTNNB1 mutations, other genetic events affecting the Wnt/β-catenin pathway may be involved in childhood adrenocortical tumorigenesis.
    The Journal of clinical endocrinology and metabolism 08/2011; 96(10):3106-14. · 6.50 Impact Factor
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    ABSTRACT: Oral mucositis is a common collateral effect among the secondary complications resulting from chemotherapy. The objective of this study was to prospectively evaluate the association of HSV-1, Candida spp., and oral bacteria on the severity of oral mucositis in pediatric acute lymphoblastic leukemia (ALL). Seventy-one prospective patients were included. Analyses of oral microbiota were conducted on days 14 (D14) and 56 (D56) of the Brazilian GBTLI-99 treatment protocol. Herpes simplex virus (HSV) identification was performed by PCR followed by DNA sequencing analysis. Bacteria and fungi identification was obtained by standard microbiological culture tests. HSV-1 was found in 10.37% of individual patient samples. One sample was positive for HSV-4. On D14, we found an association between the severity of mucositis and the presence of HSV (p = 0.0347) and Candida spp. (p = 0.0078). At D56, we found an association between the severity of mucositis and the presence of HSV on D14 (p < 0.0001) and HSV presence (p = 0.0317). The presence of HSV, mainly HSV-1, and Candida spp. was associated with mucositis severity in pediatric ALL. No association could be found between bacterial CFU and severity of mucositis.
    Supportive Care in Cancer 05/2011; 20(5):1101-7. · 2.09 Impact Factor
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    ABSTRACT: The interactions of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival. In the present study, we proposed to identify and investigate the role of molecules critically involved in leukemia--microenvironment crosstalk. Gene expression profiling analyses of BM mesenchymal stem cells (BMMSC) were performed following stimulation by ALL cells. CCL2 and IL-8 plasma levels were evaluated from ALL patients and controls. Expression of the CCL2 and IL-8 receptors in ALL was determined by RT-PCR. The biological effects of CCL2, IL-8 or its neutralizing antibodies in primary precursor-B ALL and BMMSC cells were evaluated using in vitro assays. Leukemia stimulation of BMMSC upregulated the expression of several inflammatory chemokines, including CCL2 and IL-8. The BM plasma levels of CCL2 and IL-8 in children at diagnosis were significantly higher than in healthy controls (P < 0.001). Functional studies revealed that CCL2 and IL-8 enhanced the capacity of BMMSC to support adhesion of ALL cells. CCL2 and IL-8 were also found to enhance BMMSC survival and to increase their proliferation. ALL cells were not directly affected by CCL2 or IL-8. The leukemic BM microenvironment had increased levels of CCL2 and IL-8. These chemokines are known to have suppressive effects in normal hematopoiesis. Our data indicate that CCL2 and IL-8 have a positive impact on BMMSC survival, proliferation, and adhesiveness to ALL cells. Leukemia-associated CCL2 and IL-8 upregulation may represent one possible mechanism of microenvironment perversion in favor of ALL cells.
    Pediatric Blood & Cancer 04/2011; 56(4):568-77. · 2.35 Impact Factor
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    BMC Cancer 01/2011; 11:152. · 3.33 Impact Factor
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    ABSTRACT: Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements function as specific markers for minimal residual disease (MRD), which is one of the best predictors of outcome in childhood acute lymphoblastic leukemia (ALL). We recently reported on the prognostic value of MRD during the induction of remission through a simplified PCR method. Here, we report on gene rearrangement frequencies and offer guidelines for the application of the technique. Two hundred thirty-three children had DNA extracted from bone marrow. Ig and TCR gene rearrangements were amplified using consensus primers and conventional PCR. PCR products were submitted to homo/heteroduplex analysis. A computer program was designed to define combinations of targets for clonal detection using a minimum set of primers and reactions. At least one clonal marker could be detected in 98% of the patients, and two markers in approximately 80%. The most commonly rearranged genes in precursor B-cell ALL were IgH (75%), TCRD (59%), IgK (55%), and TCRG (54%). The most commonly rearranged genes for T-ALL were TCRG (100%) and TCRD (24%). The sensitivity of primers was limited to the detection of 1 leukemic cell among 100 normal cells. We propose that eight PCR reactions per ALL subtype would allow for the detection of two markers in most cases. In addition, these reactions are suitable for MRD monitoring, especially when aiming the selection of patients with high MRD levels (≥ 10(-2)) at the end of induction therapy. Such an approach would be very useful in centers with limited financial resources.
    Pediatric Blood & Cancer 12/2010; 55(7):1278-86. · 2.35 Impact Factor
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    ABSTRACT: The inherited, low-penetrance arginine-to-histidine substitution at codon 337 (R337H) of the tumor protein 53 gene (TP53) is clustered in southeast Brazil (estimated frequency, 0.3%). Although its tumorigenic effect initially appeared to be tissue-specific, recent evidence suggests its association with a broader range of tumors. Therefore, the authors of this report investigated the spectrum of pediatric malignancies associated with the TP53 R337H mutation at a single referral institution in southeast Brazil. Genomic DNA samples from 493 children with malignancies were screened for the R337H mutation. Available tumor samples from carriers were investigated for loss of heterozygosity (LOH) and nuclear p53 accumulation. Clinical data were obtained from medical records. Sixty-five of 70 patients (93%) with adrenocortical tumors (ACTs), 9 of 13 patients (69%) with choroid plexus carcinoma (CPC), and 3 of 41 patients (7.3%) with osteosarcoma carried the mutation. The proportion of CPC to choroid plexus papilloma (CPP) was much higher than that reported elsewhere. Osteosarcoma in carriers had a significantly poorer outcome (P = .02). The mutation was not identified in patients who had acute lymphoblastic leukemia (ALL) (n = 187), recurrent ALL (n = 49), acute myeloid leukemia (n = 44), lymphoma (n = 30), non-CPC central nervous system tumors (n = 26), Ewing sarcoma (n = 25), or rhabdomyosarcoma (n = 8). Among the tumors that were available for analysis, LOH with retention of the mutant allele was confirmed in 21 of 21 ACTs, in 2 of 2 CPCs, and in 2 of 3 osteosarcomas that were positive for R337H. CPCs and osteosarcomas that were positive for R337H had marked nuclear accumulation of p53. The current findings demonstrated compellingly that the TP53 R337H mutation is associated not only with ACT but also with CPC and, to a lesser extent, with osteosarcoma, both of which are core-component tumors of the Li-Fraumeni syndrome.
    Cancer 12/2010; 117(10):2228-35. · 5.20 Impact Factor
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    ABSTRACT: Intensive chemotherapy regimens can result in severe toxicities, particularly those that involve the digestive systems, leading to morbidity and mortality in this group of patients. Acute enterocolitis can be a frequent complication. The authors performed a retrospective review or patients treated at their institution to ascertain the prognostic value of the clinical symptoms and signs of acute enterocolitis, the corresponding abdominal ultrasonographic findings, and the impact of previous chemotherapy. Amongst 1159 patients with cancer treated at the Centro Infantil Boldrini from 2003 to 2007, 188 (16.2%) patients had 1 or more episode of enterocolitis. An intestinal wall thickness of >or=3 mm on ultrasound was considered diagnostic of enterocolitis. There were 231 episodes of enterocolitis with a death rate of 11.7%. Previous therapy with cytarabine and the presence of abdominal distention affected survival. An intestinal wall thickness of >or=10 mm in the ultrasonographic examination was associated with greater mortality. In multivariate analysis, age, gender, tumor type, degree of neutropenia, intestinal wall thickness, and number of intestinal segments were not statistically significant difference. In children and young adults with cancer and enterocolitis, the clinical findings of 4 or more symptoms and presence of abdominal distention were associated with higher risk of death. Use of cytarabine and an intestinal wall thickness of >or=10 mm were associated with a higher death rate.
    Pediatric Hematology and Oncology 09/2010; 27(6):462-70. · 0.90 Impact Factor
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    ABSTRACT: Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment, including haematological malignancies. We evaluated the mRNA gene expression profile of 12 HDAC genes by quantitative real-time polymerase chain reaction in 94 consecutive childhood acute lymphoblastic leukaemia (ALL) samples and its association with clinical/biological features and survival. ALL samples showed higher expression levels of HDAC2, HDAC3, HDAC8, HDAC6 and HDAC7 when compared to normal bone marrow samples. HDAC1 and HDAC4 showed high expression in T-ALL and HDAC5 was highly expressed in B-lineage ALL. Higher than median expression levels of HDAC3 were associated with a significantly lower 5-year event-free survival (EFS) in the overall group of patients (P = 0·03) and in T-ALL patients (P = 0.01). HDAC7 and HADC9 expression levels higher than median were associated with a lower 5-year EFS in the overall group (P = 0.04 and P = 0.003, respectively) and in B-lineage CD10-positive patients (P = 0.009 and P = 0·005, respectively). Our data suggest that higher expression of HDAC7 and HDAC9 is associated with poor prognosis in childhood ALL and could be promising therapeutic targets for the treatment of refractory childhood ALL.
    British Journal of Haematology 09/2010; 150(6):665-73. · 4.94 Impact Factor
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    ABSTRACT: SUMMARY: Denys-Drash syndrome (DDS, Online Mendelian Inheritance in Man number 194080) is a rare human developmental disease generally occurring in 46,XY individuals characterized by the combination of disorder of sex development, early onset nephropathy, and Wilms' tumor (WT). DDS is mainly caused by mutations in the WT1 gene. This report describes a novel WT1 gene mutation in a DDS patient. Sequencing the WT1 gene revealed a heterozygous transversion CAT>AAT within exon 8, causing the substitution of an asparagine for a histidine at residue 377. The p.H377N mutation is predicted to diminish the WT1 protein DNA-binding affinity as it might disrupt the normal zinc finger 2 conformation.
    Journal of Pediatric Hematology/Oncology 08/2010; 32(6):486-8. · 0.97 Impact Factor

Publication Stats

306 Citations
167.66 Total Impact Points

Institutions

  • 2010–2013
    • University of São Paulo
      • Ribeirão Preto School of Medicine (FMRP)
      São Paulo, Estado de Sao Paulo, Brazil
  • 2004–2013
    • Centro Infantil Boldrini
      • Molecular Biology Laboratory
      San Paulo, São Paulo, Brazil
  • 2010–2011
    • University of Campinas
      • Departamento de Pediatria
      Conceição de Campinas, São Paulo, Brazil