[show abstract][hide abstract] ABSTRACT: Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare clonal hematopoietic diseases presented in the childhood. Both diseases exhibit abnormal karyotype and/or monosomy of chromosome 7 in a subgroup of patients. We screened for copy number variations (CNVs) by array-comparative genomic hybridization (aCHG) the DNA from bone marrow of six MDS and four JMML pediatric patients. Array-CGH analysis identified five cases (50 %) with monosomy 7, disclosing the chromosome 7 monosomy in two patients whose samples could not be evaluated by other methods. We identified CNVs in six patients, one of which displayed loss of LMO2, an oncogene that plays a central role in hematopoietic development. Our results suggest that array-CGH is a reliable and accurate technique to identify genomic alterations in MDS and JMML.
Medical Oncology 12/2013; 30(4):734. · 2.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Medulloblastomas (MBs) are the most frequent brain tumors in children and remained a major therapeutic challenge. Clinical and histopathological features are used for disease classification and patient prognostication. Currently, several molecular studies using transcriptomic and genomic approaches suggested the existence of four molecular subtypes, increasing the complexity, and knowledge of MB biology. Despite these significant advances, the molecular basis of MBs is not fully understood. MicroRNAs (miRNAs) are a group of small nonprotein coding RNA molecules that target genes by inducing mRNA degradation or translational repression. They represent an evolutionary conserved mechanism that controls fundamental cellular processes, such as development, differentiation, metabolism, proliferation, and apoptosis. Aberrant expression of miRNAs correlates with various cancers. This altered expression can arise from mutation, methylation, deletion, and gain of miRNA-encoding regions. We here review the knowledge of miRNAs in MBs. The expression patterns of miRNAs in MBs were comprehensively evaluated and their diagnostic, prognostic, and therapeutic biomarker role assessed. miRNAs are important players in MB tumorigenesis and their therapeutic exploitation can constitute an alternative approach to this devastating disease.
Pediatric Hematology and Oncology 03/2013; · 0.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 01/2013; · 1.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Susceptibility to acute lymphoblastic leukemia can be highly influenced by genetic polymorphisms in metabolizing enzyme genes of environmental carcinogens. This study aimed to evaluate the impact of the CYP3A5 and NAT2 metabolizing enzyme polymorphisms on the risk of childhood acute lymphoblastic leukemia. The analysis was conducted on 204 ALL patients and in 364 controls from a Brazilian population, using PCR-RFLP. The CYP3A5 3 polymorphic homozygous genotype was more frequent among ALL patients and the 3 allele variant was significantly associated with increased risk of childhood ALL (OR = 0.29; 95% CI, 0.14-0.60). The homozygous polymorphic genotype for the 6 allele variant was extremely rare and found in only two individuals. The heterozygous frequencies were similar for the ALL group and the control group. No significant differences were observed between the groups analyzed regarding NAT2 variant polymorphisms. None of the polymorphisms analyzed was related to treatment outcome. The results suggest that CYP3A5 3 polymorphism may play an important role in the risk of childhood ALL.
Molecular and Cellular Biochemistry 01/2012; 364(1-2):217-23. · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to evaluate the frequency of polymorphisms in the TYMS, XRCC1, and ERCC2 DNA repair genes in pediatric patients with acute lymphoblastic leukemia using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) approaches. The study was conducted in 206 patients and 364 controls from a Brazilian population. No significant differences were observed among the analyzed groups regarding XRCC1 codon 399 and codon 194 and ERCC2 codon 751 and codon 312 polymorphisms. The TYMS 3R variant allele was significantly associated with a reduced risk of childhood ALL, represented by the sum of heterozygous and polymorphic homozygous genotypes (odds ratio 0.60; 95% confidence interval 0.37-0.99). The results suggest that polymorphism in TYMS may play a protective role against the development of childhood ALL.
[show abstract][hide abstract] ABSTRACT: PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.
Journal of Clinical Oncology 03/2010; 28(11):1911-8. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: In 1988, we formed a consortium of Brazilian institutions to develop uniform standards for the diagnostic assessment and multidisciplinary treatment of children and adolescents with germ cell tumors. We also implemented the first childhood Brazilian germ cell tumor protocol, GCT-91, evaluating two-agent chemotherapy with cisplatin and etoposide (PE). We now report on the clinical characteristics and survival of children and adolescents with germ cell tumors treated on this protocol.
From May 1991 to April 2000, 115 patients (106 assessable patients) were enrolled onto the Brazilian protocol with a diagnosis of germ cell tumor.
Patients were treated with surgery only (n = 35) and chemotherapy (n = 71). Important prognostic factors included stage (P = .025), surgical procedure at diagnosis according to resectability (P < .032), and abnormal lactate dehydrogenase value at diagnosis (P < .001).
The improvement in survival by the introduction of a standard protocol is an important achievement. This is of particular importance for smaller institutions with previous limited experience in the treatment of childhood germ cell tumors. In addition, the results of a two-agent regimen with PE were favorable (5-year overall survival rate is 83.3% for patients in the high-risk group [n = 36] who received PE v 58.8% for patients in the high-risk patients group who received PE plus ifosfamide, vinblastine, and bleomycin [n = 17; P = .017]). Thus for selected patients, complex three-agent regimens may not be necessary to achieve long-term survival, even for some patients with advanced disease.
Journal of Clinical Oncology 01/2009; 27(8):1297-303. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mortality from childhood leukemia has declined substantially in developed countries but less markedly in the developing world. This study was designed to describe mortality trends in childhood leukemia and the impact of social inequalities on these trends in Brazil from 1980 to 2002.
Cancer mortality data by cause and estimates of resident population stratified by age and sex were obtained from the Brazilian Mortality Information System (SIM) for the years 1980 to 2002. Age-standardized (ages 0-19 years) mortality rates were calculated by the direct method using the 1960 world standard population. Trends were modeled using linear regression with 3-year moving average rates as the dependent variable and with the midpoint of the calendar year interval (1991) as the independent variable. The Index of Social Exclusion was used to classify the 27 Brazilian states. Pearson correlation was used to describe the correlation between social exclusion and variations in mortality in each state.
Age-standardized mortality rates for boys decreased from 2.05 per 100,000 habitants in 1984 to 1.44 100,000 habitants in 1995, whereas the observed corresponding decline among girls was from 1.60 per 100,000 habitants in 1986 to 1.14 per 100,000 habitants in 1995. Statistically significant declining trends in mortality rates were observed for boys (adjusted correlation coefficient [r(2)] = 0.68; P < .001) and girls (adjusted r(2) = 0.62; P < .001). Significant negative correlations between social inequality and changes in mortality were noted for boys (r = -0.66; P = .001) and for girls (r = -0.78; P < .001).
A consistent decrease in mortality rates from childhood leukemia was noted in Brazil. Higher decreases in mortality were observed in more developed states, possibly reflecting better health care.
Cancer 10/2007; 110(8):1823-31. · 5.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Using cDNA microarray assays we have observed a clear difference in the gene expression pattern between bone marrow stromal cells obtained from healthy children (CT) and from pediatric patients with either myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) associated with MDS (MDS-AML). The global gene function profiling analysis indicated that in the pediatric MDS microenvironment the disease stages may be characterized mainly by underexpression of genes associated with biological processes such as transport. Furthermore, a subset of downregulated genes related to endocytosis and protein secretion was able to discriminate MDS from MDS-AML.
Leukemia Research 06/2007; 31(5):579-89. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Myelodysplastic syndrome is a clonal hematopoietic stem cell disorder that presents a poor survival for patients treated with standard therapies other than stem-cell transplantation. Multi-drug resistance (MDR) to simultaneous drugs used in chemotherapy is a major concern in the treatment of cancer and also in MDS. ATP-binding cassette (ABC) transporters are involved in the main mechanism that confers drug resistance to cells. Increased expression of drug resistance genes, such as MDR1, MRP1 and LRP, is involved with multi-drug resistance in MDS. The expression of these drug efflux transporters acts in synergy with other alterations, such as epigenetic events, increases in multidrug resistance in MDS. Methylation, the main epigenetic mechanism is widely explored in other hematological malignancies; however, in MDS, this mechanism is poorly investigated. Clinical trials evaluated or are under ongoing evaluation of drugs that abrogated ABC transporters action or reversed the abnormal methylation of some genes in MDS. In this report, we explore the data available in the field of drug resistance and methylation both in pediatric and adult MDS.
Current pharmaceutical biotechnology 05/2007; 8(2):77-81. · 3.40 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aberrant methylation of gene promoter region is responsible for inappropriate gene silencing, and it has been associated to initiation and progression of cancer. Aberrant promoter methylation is frequently observed in adult patients with myelodysplastic syndrome (MDS), but in pediatric patients it has been poorly investigated.
We examined the promoter methylation status of 13 genes in bone marrow cells collected at diagnosis of 21 pediatric patients with MDS (subtype RAEB or RAEB-t). For this analysis, we performed sodium bisulfite treatment of genomic DNA, followed by methylation specific PCR (MSP).
In pediatric MDS samples, we observed two genes frequently methylated: CALCA was methylated in 85.7% (18/21) of the analyzed samples and CDKN2B in 50% (6/12).
Our findings indicate that CALCA and CDKN2B are frequently methylated in pediatric MDS. It suggests that aberrant methylation in pediatric MDS seems to be similar to adult MDS, thus pediatric patients could be also benefited with treatment using demethylating agents.
Leukemia Research 03/2007; 31(2):175-81. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Promoter hypermethylation occurs early in leukemogenesis and seems to be associated with poor prognosis in acute lymphoblastic leukemia (ALL). The methylation status of the promoter region of six genes was analyzed in 71 children with ALL using methylation specific PCR (MSP). Calcitonin (CALCA) and E-cadherin (CDH1) were the most frequently methylated genes in this group of patients. Considering the patients with central nervous system (CNS) infiltration, the estimated 2-year overall survival (OS) was 20% for those with methylation in CALCA promoter and 85% for those without (p=0.001). Our results suggest that the hypermethylation of CALCA promoter is a promising prognostic marker and may predict a higher risk for ALL patients with CNS infiltration.
Leukemia Research 08/2006; 30(7):891-4. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are few publications reporting health-related quality of life (HRQL) in developing nations. Most instruments measuring HRQL have been developed in English-speaking countries. These instruments need to be culturally adapted for use in non-English-speaking countries. The HUI2 and HUI3 are generic, preference-based systems for describing health status and HRQL. Developed in Canada, the systems have been translated into more than a dozen languages and used worldwide in hundreds of studies of clinical and general populations.
The Brazilian-Portuguese translation of the HUI systems was supervised by senior HUInc staff having experience with both the HUI systems and translations. The process included two independent forward translations of the multi-attribute health status classification systems and related questionnaires, consensus between translators on a forward translation, back-translation by two independent translators of the forward translation, and review of the back-translations by original developers of the HUI. The final questionnaires were tested by surveying a sample of convenience of 50 patients recruited at the Centro de Tratamento e Pesquisa-Hospital do Cancer in São Paulo, Brazil.
Fifty patients were enrolled in the study. No assessor, patient or nurse or physician, reported problems answering the HUI questionnaires. No significant differences were found in mean overall HUI2 or HUI3 utility scores among types of assessors. Variability in scores are similar to those from other studies in Latin America and Canada.
Test results provide preliminary evidence that the Brazilian-Portuguese translation is acceptable, understandable, reliable and valid for assessing health-status and HRQL among survivors of cancer in childhood in Brazil.
Quality of Life Research 07/2005; 14(5):1407-12. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cancer patients receiving chemotherapy are exposed to high doses of cytotoxic and genotoxic drugs which, in some cases, can lead to treatment related leukemia. Since this only occurs in a minority of patients, however, it is possible some individuals are predisposed due to genetic polymorphisms in genes for enzymes that mediate drug metabolism. To address this possibility we measured the genotoxicity of chemotherapeutic agents in patients receiving treatment for ALL by the frequency of the Vgamma/Jbeta trans-rearrangement in their peripheral blood leukocytes and compared this with CYP3A4 genotype. CYP3A4 is the most abundant of the cytochrome P450 (CYP) enzyme in the liver and intestine which contains a common -392A>G substitution in the promoter region (CYP3A4*1B allele). We found a significant increase in the frequency of rearrangements during chemotherapy only in patients homozygous for the wild type CYP3A4*1A allele. This provides a direct link between CYP3A4 genotype and susceptibility to drug genotoxicity thus strengthening the possibility that predisposition to treatment related leukemia may be measurable by simple genetic testing.
Leukemia Research 01/2005; 28(12):1281-6. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Therapy strategies for myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) vary considerably.
To review the treatment of Brazilian children who were diagnosed with MDS or JMML in the past decade and reported to the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED).
Of 173 children reported to the BCG-MDS-PED from January 1997 to January 2003 with a suspected diagnosis of MDS or JMML, 91 had the diagnosis confirmed after central review of the bone marrow aspirate and biopsy. Information on previous treatments was available for 78 MDS/JMML patients. Treatment varied from different schedules of low-dose (14%) and standard-dose chemotherapy (50%), granulocyte-colony-stimulating factor (G-CSF 7%), interferon (5%), steroids (2%) and erythropoietin (2%) to allogeneic stem-cell transplantation (SCT) (14%). No survival advantage could be demonstrated based on Hasle's classification or based on treatment.
This report reflects the current practice in treating Brazilian children with MDS/JMML without specific Cooperative Group guidelines. Treatment modalities were very heterogeneous. The strategies for implementing a national protocol should consider international guidelines and focus on local experience and available resources.
Leukemia Research 10/2004; 28(9):933-9. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: We studied bone marrow stromal cell cultures from patients with childhood myelodysplastic syndromes (MDS, refractory anemia with excess of blasts, RAEB) and from matched normal donors. Stromal cell monolayers were characterized as myofibroblasts by the expression of smooth muscle alpha-actin, collagen IV, laminin and fibronectin. When normal cord blood cells were plated onto myelodysplastic stromas, a pathologic cell differentiation was observed, indicating altered myelosupportive properties. cDNA array analysis showed that patient stromas expressed increased levels of thrombospondin-1, collagen-I alpha2-chain, osteoblast-specific factor-2 and osteonectin, indicating the presence of increased osteoblast content, as confirmed by enhanced alkaline phosphatase synthesis. Alterations in the myelodysplastic stroma environment might contribute to abnormal hematopoiesis in this pathology.
Leukemia Research 09/2004; 28(8):831-44. · 2.76 Impact Factor