RESUMO
Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS). Low plus intermediate Sokal score correlated to optimal imatinib responses, as well as OS at 8-years, thus confirming the established role of Sokal score as a prognostic factor in CML patients. Low ABCB1 and high OCT1 mRNA levels were associated with an optimal molecular response, while the inverse levels were associated with non-responders (warning and failure) patients. Our results suggest that ABCB1 and OCT1 mRNA expressions may present biological relevance to identify responder and non-responder patients to imatinib treatment.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Transportador 1 de Cátions Orgânicos/genética , RNA Mensageiro/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Adolescente , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos , Feminino , Hospitais Comunitários , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging.
Assuntos
Humanos , Acetato Quinase , Citogenética , Leucemia Mielogênica Crônica BCR-ABL Positiva , Monitoramento Ambiental , Mutação , Reação em Cadeia da Polimerase , TirosinaRESUMO
Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging.
RESUMO
Point mutations in the kinase domain of BCR-ABL were described in 40-90% of patients with chronic myeloid leukemia (CML) resistant to Imatinib. We herein describe the development of a rapid allele-specific (AS)-RT-PCR assay to identify the T315I mutation, which confers full resistance to all available tyrosine-kinase inhibitors (TKI). The mutation status of 65 patients with resistant CML was evaluated, and the T315I was detected in 3/65 (4.6%). Comparisons between sequencing and AS-RT-PCR results, as well as serial dilutions experiments proved that the method is specific and reproducible, with maximum sensitivity of 1 × 10(-3). The developed assay is a convenient and easy tool to be used in research of CML resistance for rapid mutation screening and, together with sequencing, may be included in efficient strategies for early detection of TKI resistance in patients with CML.
Assuntos
Técnicas de Laboratório Clínico/métodos , Resistência a Medicamentos , Inibidores Enzimáticos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcr/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Alelos , Substituição de Aminoácidos/genética , Diagnóstico Precoce , Humanos , Mutação de Sentido Incorreto , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Prediction of biological behavior is crucial for selection of new therapeutic modalities in GIST. Here, we aimed to assess whether KIT and PDGFRA mutations have survival impact in gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS: Fifty-five Brazilian patients with completely resected GIST were examined for KIT and PDGFRA mutations. The 5-year disease-free survival (DFS) was analyzed. RESULTS: KIT and PDGFRA mutations were identified in 74.5% and 7.3% of patients, respectively. The 5-year DFS rate for all patients was 52.8%. The 5-year DFS rate was lower in patients with tumors having in-frame deletions or concomitant in-frame deletions and insertions affecting codons 557-558 than in patients with tumors having other exon 11 KIT mutations (p=0.023). Conversely, when the patients with concomitant deletion-insertion mutations affecting codons 557-558 were excluded from the analysis, deletions involving codons 557-558 had no influence on 5-year DFS rates. CONCLUSION: Our findings indicate that a specific KIT mutation may be associated with unfavorable behavior in GIST. This finding may have implications on selecting patients for adjuvant therapy.
Assuntos
Tumores do Estroma Gastrointestinal/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Idoso , Códon , Éxons , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for tumor suppressor gene silencing in several malignancies. We determined the methylation status of nine tumor suppressor genes in 68 newly diagnosed MM patients by methylation-specific PCR. The frequency of promoter hypermethylation for individual genes was: CDH1, 50%; p16 INK4a, 42.8%; p15 INK4b, 16.2%; SHP1, 14.7%; ER and BNIP3, 13.2%; RAR beta, 11.8%; DAPK 5.9%; and MGMT 0%. Overall, 79% of patients presented at least one hypermethylated gene. By univariate analysis, hypermethylation of DAPK (P < 0.001) and RAR beta (P = 0.01) genes were identified as adverse prognostic features. Median OS of patients with hypermethylation in DAPK (4 months) and RAR beta (34 months) was significantly lower than in patients without hypermethylation (median survival not reached), with values of P < 0.001 and P = 0.01, respectively. Our data suggest that DAPK and RAR beta hypermethylation are adverse prognostic factors in MM. The relevance of these findings as poor prognosis indicators requires confirmation in a larger sample with longer follow-ups.
Assuntos
Metilação de DNA/fisiologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Antígenos CD , Proteínas Reguladoras de Apoptose/genética , Caderinas/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas Quinases Associadas com Morte Celular , Feminino , Inativação Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Estrogênio/genética , Receptores do Ácido Retinoico/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Hodgkin lymphoma (HL) shows a bimodal distribution with a first peak in developing countries during childhood. The causative role and prognostic significance of Epstein-Barr virus (EBV) association in patients with HL is controversial. Our aim was to perform a comparative study of EBV association in 2 Latin American pediatric HL series, and to correlate it with patient's survival. Epstein-Barr encoded RNAs in situ hybridization and latent membrane protein 1 immunohistochemistry were performed on formalin-fixed, paraffin-embedded HL biopsies from 176 pediatric patients from 2 public institutions from Argentina and Southeast Brazil. Mixed cellularity subtype was prevalent in Argentine HL (Arg HL) (52%) and nodular sclerosis subtype in Brazilian HL (BR HL) (83%). EBV expression was detected in 52% of cases, namely 54% Arg HL and 48% Br HL. EBV was significantly associated with mixed cellularity subtype in both populations. In Arg HL, EBV positivity was significantly higher in patientsAssuntos
Infecções por Vírus Epstein-Barr/epidemiologia
, Doença de Hodgkin/epidemiologia
, Adolescente
, Argentina/epidemiologia
, Biópsia
, Brasil/epidemiologia
, Criança
, Pré-Escolar
, Infecções por Vírus Epstein-Barr/complicações
, Feminino
, Doença de Hodgkin/classificação
, Doença de Hodgkin/complicações
, Doença de Hodgkin/mortalidade
, Doença de Hodgkin/patologia
, Humanos
, Masculino
, Estadiamento de Neoplasias
, Análise de Sobrevida
, Resultado do Tratamento
RESUMO
Burkitt lymphoma/leukaemia (BL/L) is a heterogeneous disease with respect to epidemiological patterns and cell origin. The occurrence of BL/L with an immature phenotype raises the question whether this phenotype might be a consequence of early B-cell transformation or, alternatively, a secondary feature of transformed, mature B cells. It also poses important clinical questions regarding diagnosis and therapeutic procedures. Here we describe the case of a 4-yr-old child with BL/L and FAB L3 morphology, with phenotypic and genotypic characteristics of a CD10+ precursor B-cell acute lymphoid leukaemia (ALL) associated with t(8;14)(q24;q32). Molecular analysis showed expression of RAG1 and RAG2 and an unmutated VDJCmu immunoglobulin rearrangement coinciding with a lack of AICDA expression, indicating an immature B-cell origin. His clinical response suggested that FAB L3 ALL with MYC rearrangement and an aberrant precursor B-cell phenotype is clinically similar to BL/L. Moreover, short, intensive chemotherapeutic protocols seemed to be beneficial. This case also allowed us to refine the description of cellular and molecular variants of BL/L regarding the cell origin and pathogenesis of this biologically heterogeneous disease.