Acute myeloid leukemia in children and adolescents in Brazilian institutions : reality and challenges.

Objective: To describe the outcome of acute myeloid leukemia (AML) among children treated in Brazilian institutions. Methods: A structured online questionnaire was sent to pediatric oncologists affiliated to the Brazilian Society of Pediatric Oncology. The physicians and institutions were unidentified. Results: One hundred and four pediatric oncologists in all Brazilian regions answered the questionnaire. The treatment-related mortality rate was reported to be higher than 30% by 29.8% of the participants. Difficulty in accessing the intensive care unit (ICU) was reported by 54.8%. About 85% had access to cytogenetics, 78% to molecular testing, 94% to the measurement of residual disease by flow cytometry. About 90% of participants reported access to HSCT, but 86% of them had difficulties in providing HSCT timely. About 95% of the respondents indicated the need to create a national treatment protocol, and 89.4% are willing to collaborate with a national study group. Conclusion: Our study demonstrated large gaps in the treatment of pediatric AML in Brazil. To improve outcome, a national protocol will have to consider the regional differences and adapt the management according to the local resources

Estudo epidemiológico do câncer infantojuvenil em centro de referência do Oeste do Estado do Pará / Epidemiological profile of childhood cancer in patients attended at the regional hospital of Santarém-PA in the period from 2013 to 2015

O câncer infantojuvenil representa a primeira causa de morte por doença entre crianças e adolescentes. Assim o conhecimento do perfil clínico-epidemiológico das crianças e dos adolescentes com câncer é importante para definir as estratégias de ação. Este trabalho descreve o perfil epidemiológico dos pacientes atendidos no Serviço de Oncologia pediátrica do Hospital Regional do Baixo Amazonas. Foram incluídos 42 pacientes de 0 a 19 anos, que obtiveram o diagnóstico de doença neoplásica entre janeiro de 2013 e agosto de 2015. A população estudada teve em sua maioria pacientes do sexo masculino com uma média de idade de 7,97 anos, eram pardos e 52,38% eram provenientes de Santarém-Pa, a neoplasia mais prevalente foi leucemia, tendo sido a quimioterapia o tratamento mais utilizado, a maioria dos pacientes obteve diagnóstico entre 1 e 2 meses após início dos sintomas, e uma vez diagnosticados, iniciaram o tratamento em menos de 15 dias. Apesar de a caracterização proposta ter sido alcançada, as possíveis relações prognósticas não obtiveram significância estatística devido aleatoriedade e diversidade da amostra

Estudo epidemiológico do câncer infantojuvenil em centro de referência do oeste do Estado do Pará / Epidemiological profile of childhood cancer in patients attended at the regional hospital of Santarém-PA in the period from 2013 to 2015

O câncer infantojuvenil representa a primeira causa de morte por doença entre crianças e adolescentes. Assim o conhecimento do perfil clínico-epidemiológico das crianças e dos adolescentes com câncer é importante para definir as estratégias de ação. Este trabalho descreve o perfil epidemiológico dos pacientes atendidos no Serviço de Oncologia pediátrica do Hospital Regional do Baixo Amazonas. Foram incluídos 42 pacientes de 0 a 19 anos, que obtiveram o diagnóstico de doença neoplásica entre janeiro de 2013 e agosto de 2015. A população estudada teve em sua maioria pacientes do sexo masculino com uma média de idade de 7,97 anos, eram pardos e 52,38% eram provenientes de Santarém-Pa, a neoplasia mais prevalente foi leucemia, tendo sido a quimioterapia o tratamento mais utilizado, a maioria dos pacientes obteve diagnóstico entre 1 e 2 meses após início dos sintomas, e uma vez diagnosticados, iniciaram o tratamento em menos de 15 dias. Apesar de a caracterização proposta ter sido alcançada, as possíveis relações prognósticas não obtiveram significância estatística devido aleatoriedade e diversidade da amostra

Identifying novel genetic alterations in pediatric acute lymphoblastic leukemia based on copy number analysis

National Counsel of Technological and Scientific Development (CNPq), grant n° 460185/2014–4 and Amazon Foundation for Research Support (FAPESPA), grant n° PPSUS/2013.Federal University of Pará. Oncology Research Center. Belém, PA, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Octávio Lobo Children’s Cancer Hospital. Belém, PA, Brazil.Octávio Lobo Children’s Cancer Hospital. Belém, PA, Brazil.Federal University of Pará. Oncology Research Center. Belém, PA, Brazil.Federal University of Pará. Oncology Research Center. Belém, PA, Brazil.Federal University of Pará. Oncology Research Center. Belém, PA, Brazil.Federal University of Pará. Oncology Research Center. Belém, PA, Brazil.Copy number variations (CNVs) analysis may reveal molecular biomarkers and provide information on the pathogenesis of acute lymphoblastic leukemia (ALL). We investigated the gene copy number in childhood ALL by microarray and select three new recurrent CNVs to evaluate by real-time PCR assay: DMBT1, KIAA0125 and PRDM16 were selected due to high frequency of CNVs in ALL samples and based on their potential biological functions in carcinogenesis described in the literature. DBMT1 deletion was associated with patients with chromosomal translocations and is a potential tumor suppressor; KIAA0125 and PRDM16 may act as an oncogene despite having a paradoxical behavior in carcinogenesis. This study reinforces that microarrays/aCGH is it is a powerful tool for detection of genomic aberrations, which may be used in the risk stratificatio

Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient’s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population

Telomerase (hTERT) Overexpression Reveals a Promising Prognostic Biomarker and Therapeutical Target in Different Clinical Subtypes of Pediatric Acute Lymphoblastic Leukaemia

Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system defined as a clonal expansion of an abnormal lymphoid precursor cell. It mostly affects children under five years of age and is the most common tumor to afflict pediatric patients. The expression of the human telomerase gene (hTERT) in patients with ALL has been studied as a biomarker and could become a new therapeutic target. We evaluate the role of hTERT gene expression in ALL pediatric patients, through quantitative real-time PCR technique, and the possible correlation between hTERT expression and clinical variables: gender, age, white blood cells (WBC), gene fusions, and immunophenotyping. The analysis between healthy controls and ALL patients (N = 244) was statistically significant (p < 0.001), demonstrating hTERT overexpression in these patients. In comparison with the usual set of clinical variables, the data were not statistically significant (p > 0.05), indicating that hTERT is equally overexpressed among patients regardless of gender, age, gene fusions, and immunophenotyping. Moreover, patients who presented a higher hTERT expression level had a significant (p < 0.0001) lower overall survival rate. In summary, hTERT expression emerges as an important molecular pathway in leukemogenesis regardless patient’s clinical variables, thus, the data here presented pointed it as a valuable biomarker in pediatric acute lymphoblastic leukemia and a promising target for new therapeutic and prognostic measures

Correlation of Genetic Variants and the Incidence, Prevalence and Mortality Rates of Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, representing about 30–35% of cases. Its etiology is complex and not fully understood. ALL is influenced by genetic variants, and their frequencies (Fq) vary in different ethnic groups, which consequently could influence the epidemiology of this cancer worldwide. The aim of this study was to investigate the correlation between the genetic variants and their impacts on incidence (IC), mortality (MT), and prevalence (PV) rates of ALL in different world populations. Methods: Sixty variants were selected from the literature with Genome Wide Association studies (GWAS). Information regarding allele Fq was selected from the 1000 Genomes platform. Epidemiological data were taken from the Global Burden of disease visualisations (GBD) Compare website. Statistical analyses were calculated in RStudio v.3.5.1 software. Results: Four variants demonstrated significant results in correlations with epidemiological data for ALL. The PAX5 gene variant (rs2297105) had an indirect relationship with PV and IC of ALL, showing that an increased Fq of this variant is related to low rates of both. An increased Fq of rs915172 in EPB4IL2 gene was also correlated with a lower IC of ALL. The rs1048943 of the CYP1A1 gene and the rs3088440 polymorphism of the CDKN2A gene were shown to have a direct proportional relationship with MT rate, showing that an increased Fq of these variants correlates with a worse prognosis worldwide. Conclusion: Our study points out four important variants for understanding the IC, PV, and MT rates for ALL. The ascertainment of these data may help to choose molecular markers to investigate the susceptibility and prognosis of ALL

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil.

IntroductionThe nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil.MethodsThe entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software.ResultsFour NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world.ConclusionOur findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines

Effect of American genomic ancestry on severe toxicities in children with acute lymphoblastic leukemia in the Amazon region

Abstract Background Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system characterized by a clonal expansion of abnormal lymphocyte precursor cells. ALL is the most common form of cancer in children, but despite advances in treatment, it can still be fatal. Ethnic differences influence survival rates, and genomic ancestry plays an important role, especially in mixed-race populations such as Latin America. This study aims to analyze the influence of genomic ancestry on toxicity in children with ALL in the Amazon region. Methods The study included 171 patients (protocol number 119,649/2012—Ethics Committee) with ALL treated at a pediatric treatment center in Belém do Pará, in the Brazilian Amazon. The patients were submitted to the BFM protocol of induction therapy for ALL. Toxicity was assessed based on laboratory tests and adverse events, classified according to the CTC-NCI guide. Genomic ancestry was determined using autosomal informative markers. Results The majority of children (94.74%) developed some type of toxicity during treatment, 87.04% of which were severe. Infectious toxicity was the most common, present in 84.8% of cases, 77.24% of which were severe. Amerindian ancestry showed an association with the risk of severe general toxicity and severe infectious toxicity, with a contribution of 35.0% demonstrating a significant increase in risk. In addition, post-induction refractoriness and relapse were also associated with an increased risk of death. Conclusion This study highlights the influence of Amerindian genomic ancestry on response to therapy and toxicity in children with ALL in the Amazon region. Understanding these associations can contribute to personalizing treatment and improving clinical outcomes