RESUMO
AIM: to investigate the methylation status of the SOX7 and p15NK4b genes and Wnt signaling pathway antagonists in patients with acute myeloid leukemia (AML) in order to assess the association of the rate of aberrant methylation (AM) with the morphological variant and pattern of chromosomal aberrations, as well as the impact of the methylation status on survival. SUBJECTS AND METHODS: The data of 57 AML patients aged 20 to 79 years were analyzed. The methylation status of the genes was studied by methylation-specific polymerase chain reaction. RESULTS: The signs of the AM of ≥1 gene were detected in 52 (91.2%) of the 57 patients. The most common finding was AM of simultaneously 2 or 3 genes: in 29.8 and 21.1% of the patients, respectively. Concurrent methylation of 3-5 genes proved to be a more frequent finding in AML patients with myelodysplasia: in 7 (70%) of 10 patients. The proportion of patients with methylation of 5 genes was considerably higher in a group of patients with a complex karyotype: 50% versus 8.3% among other patients (odds ratio: 11.0; 95% confidence interval 2.0 to 61.6; p=0.01). There were no differences in the median overall and relapse-free survival rates in patients with a normal karyotype and without FLT3 and NPM mutations, who received induction therapy, in relation to the number of genes with AM. CONCLUSION: AM of the p15NK4b and SOX7 genes and Wnt signaling pathway antagonists is detected in the majority of patients with AML, which allows hypomethylating agents to be recommended for the treatment of patients who cannot use intensive cytostatic therapy for different reasons. The detection of a large number of genes with the aberrant methylation status in most AML patients with myelodysplasia or a complex karyotype serves as the basis for initiating trials to evaluate the efficiency of a combination of 5-azacytidine and cytostatics.
Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Metilação de DNA/genética , Leucemia Mieloide Aguda/genética , Regiões Promotoras Genéticas/genética , Fatores de Transcrição SOXF/genética , Via de Sinalização Wnt/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Secondary myeloid neoplasia may be a complication of intensive cytostatic therapy. The most common types of secondary neoplasias are acute myeloid leukemia and myelodysplastic syndrome. The development of secondary atypical chronic myeloid leukemia (aCML) is an extremely rare phenomenon. The paper describes transformation of secondary myelodysplastic syndrome to aCML 6 months after its diagnosis. The development of aCML was accompanied by additional chromosomal aberration as monosomy of chromosome 17. No mutations in the JAK2, MPL, and CalR genes were detected. It is concluded that the clinical course of secondary myeloid neoplasias is variable.
Assuntos
Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Síndromes Mielodisplásicas/patologia , Idoso , Aberrações Cromossômicas , Cromossomos Humanos Par 17 , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genéticaRESUMO
This rare type of acute leukemia, blast cells of which express myeloid and/or lymphoid markers, is mainly diagnosed using flow cytometric findings. The paper describes a clinical case of mixed-phenotype acute leukemia, in which B-cell lymphoid antigen expressions were revealed by a flow cytometric technique, while bone marrow morphological specimens showed the signs of myeloid differentiation specific to blast cells. It is concluded that there is a need for a comprehensive examination of patients with new-onset acute leukemia and for an aggregate analysis of flow cytometric results with morphological and cytochemical findings.
Assuntos
Antígenos de Neoplasias/metabolismo , Linfócitos B/imunologia , Leucemia/diagnóstico , Células-Tronco/patologia , Doença Aguda , Adulto , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Feminino , Citometria de Fluxo , Humanos , Leucemia/imunologia , FenótipoRESUMO
AIM: To characterize the clinical and hematological variability of acute myeloid leukemia (AML) with t(8;21) and to identify the signs associated with the likelihood of its relapse. SUBJECTS AND METHODS: The results of examining 44 patients aged 11 to 70 years were analyzed; the efficiency of treatment was evaluated in 36. Their karyotypes were studied using the standard GTG method. Polymerase chain reaction (PCR) was employed to assess the mutational status of the FLT3, NPM1, NRAS and c-Kit genes. Qualitative PCR was used to reveal the chimeric transcript RUNX1/RUNX1T1. RESULTS: The M2 variant was verified using the French-American-British classification in 82% of cases. One patient was diagnosed with secondary AML. Additional chromosomal aberrations were found in 50% of the patients. The most common breakages were loss of one of the sex chromosomes (34.1%) and damage of chromosome 9 (16.6%). Gene mutations were detected in single cases. Following 2 7+3 induction chemotherapy (CT) cycles, complete remission (CR) was achieved in 97% of cases (3 patients with cytopenia died). Eight (25%) patients developed a relapse mainly within the first 7 months after achieving CR. The characteristic signs of relapse cases were the inefficiency of the first cycle of remission induction (RI), the absence of high-dose consolidation, damage of chromosome 9, D816V mutation in exone 17 of the c-Kit gene. Antirecurrent CT was ineffective in 5 patients. The median overall survival (OS) in patients with early recurrence was 10 months. That in the patients who were recorded to have CR was not achieved; 5-year OS was 57.8%. Chromosome 9 aberration was ascertained to have a negative impact on OS parameters (p=0.003). CONCLUSION: Patients with AML with t(8;21) is a group heterogeneous with respect to age, the morphological nature of blast cells, the pattern of the disease, the presence and type of additional chromosomal aberrations, mutations in individual genes, and clinical course. Those who are unresponsive to the first RI cycle and have additional chromosome 9 damages should be regarded as potential candidates for allogeneic hematopoietic stem cell transplantation.
Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Heterogeneidade Genética , Leucemia Mieloide Aguda/genética , Translocação Genética/genética , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Intervalo Livre de Doença , Humanos , Quimioterapia de Indução , Cariotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Mutação , Nucleofosmina , Recidiva , Adulto JovemRESUMO
AIM: To identify a category of persons with very low overall survival (OS) rates, whose intensive chemotherapy is unreasonable, amongst the patients with acute myeloid leukemia (AML) with extended forms of myelodysplastic syndrome (MDS) and complex karyotype. MATERIALS AND METHODS: OS rates were retrospectively analyzed in 41 patients with AML and 26 with MDS; their median age was 61 years (range 15 to 77 years). Thirty-four (50.7%) patients received standard induction courses; 19 (28.4%) patients had low-intensity therapy. Restraining therapy was used to treat 14 (20.9%) patients. The length of follow-up was 1.5 to 171 months. RESULTS: Irrespective of the type of disease, the median OS was 6 months. A difference in OS was found when the patients were divided into 4 age groups: those who were under 40 years of age (n = 11 ), 41-60 years (n = 21), 61-69 years (n = 21), and > or = 70 years (n = 14). With age, the median OS decreased from 9.5 to 4 months (p = 0.041). Multivariate analysis revealed that the intensity of induction courses was the cause that affected OS. High comorbidity index and, first of all, cardiovascular diseases were the main reason for discontinuing standard chemotherapy courses in patients aged 70 years or older. CONCLUSION: Standard induction courses of cytostatic therapy are not indicated for patients aged > or = 70 years with AML and extended stages of MDS with complex karyotype and high comorbidity index.
Assuntos
Antineoplásicos/uso terapêutico , Cariótipo , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Comorbidade , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
AIM: To estimate the extent of FLT3 and NPM1 gene mutations and the impact of mutations of FLT3-ITD on the survival of patients with acute myeloid leukemias (AML). MATERIALS AND METHODS: The nucleus-containing cells of bone marrow and blood were studied in 43 patients with AML. Polymerase chain reaction analysis of total genomic DNA was applied. RESULTS: Mutations of FLT3-ITD, FLT3-TDK, and the NPM1 gene were found in 16 (37.2%) patients. A total of 19 mutations were revealed. There were 8 mutations of FLT3-ITD, 5 of FLT3-TKD, and 6 in the NPM1 gene. Single damages to genes were detected in 13 patients: FLT3-ITD in 6 (13.9%), FLT3-TKD in 4 (9.3%), and NPM1 in 3 (7%). Three (7%) patients exhibited 2 mutations simultaneously: in the NPM1 and FLT3-ITD in 2 (4.7%) and in the NPM1 gene and FLT3-TKD in 1 (2.3%). In AML patients with a normal karyotype and the FLT3-ITD-/NPM1 and FLT3-ITD+/ NPM-T genotypes, median overall survival was 17.3 versus 8 months (p = 0.069); and event-free survival (EFS) was 11 versus 5 months (p = 0.026). Univariate analysis established the negative impact of FLT3-1TD mutation on EFS. CONCLUSION: The findings allow AML patients with a normal karyotype and the FLT3-ITD-/NPM-genotypes to be identified as a poor prognosis group.
Assuntos
DNA/genética , Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Federação Russa/epidemiologia , Taxa de Sobrevida/tendências , Adulto JovemRESUMO
Two FLT3-ITD mutations, one FLT3-TKD) and five NPM1 mutations were detected in 7 patients with de novo myelodysplastic syndrome (MDS) out of 44 cases of MDS and MDS/mixed myeloid diseases. Expression of one of the three investigated mutations was identified: 4 in gene NPM1 (9.1%) and 2--FLT3-ITD (4.5%); simultaneous FLT3-ITD and NPM1 mutation--1 (2.3%); no progression in NPM1 within 9-20 months--3, although with chromosome 7 damage--2. It was suggested that NPM1 mutation without complex karyotype may serve as marker of relatively favorable course.
Assuntos
Doenças da Medula Óssea/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Idoso , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Valor Preditivo dos Testes , Prognóstico , Fatores de TempoRESUMO
Lymphocyte subpopulation composition and spontaneous production of tumor necrosis factor-alpha (TNF-alpha) by blood cells were studied in 22 and 15 patients with myelodysplastic syndrome (MDS), respectively, who were under immunosuppressive therapy (IST). Patients with hematological response revealed a significantly increased cytotoxic CD8+ lymphocyte concentration and TNF-alpha production. A direct correlation between TNF-alpha production rate and CD8+ lymphocyte level was established. Maximum cytokine-producing activity of blood cells was identified in MDS patients with enhanced erythroid response. The study established a great diversity of MDS, its hypoplastic variants and the prognostic value of spontaneous production of tumor necrosis factor-alpha (TNF-alpha) by blood cells as marker of IST efficacy.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Subpopulações de Linfócitos , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/terapia , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Subpopulações de Linfócitos B , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Subpopulações de Linfócitos TRESUMO
AIM: To examine prognostic potential of the number of bone marrow (BM) blasts and cell karyotype as risk factors of transformation of myelodysplastic syndrome (MDS) in acute myeloblastic leukemia AML. MATERIAL AND METHOD: The analysis of examination was made for 72 patients with primary MDS in the groups formed by number of blasts in BM, karyotype and IPSS variant. MDS was diagnosed by WHO criteria. Transformation into AML was established in blastosis > 20% in peripheral blood and/or BM. The karyotype was studied according to GTG technique. RESULTS: More frequent progression of MDS was seen in patients with blastosis > 10%, unfavourable karyotype and high IPSS risk. The least number of leukemic transformations occurred in karyotype of intermediate prognosis while disease-free survival in patients with karyotype of good prognosis was similar to that of patients with unfavourable karyotype. The number of blasts in BM and IPSS variant appeared to be prognostic markers of duration of leukemia-free survival in one-factor analysis. The multifactorial analysis found out one factor of MDS transformation in AML: number of blasts in BM puncture biopsy. CONCLUSION: Prognostic priority of the number of BM blasts as a risk factor of MDS progression compared to karyotype is explained by biological heterogenicity of MDS.
Assuntos
Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Células da Medula Óssea/patologia , Aberrações Cromossômicas , Progressão da Doença , Intervalo Livre de Doença , Seguimentos , Humanos , Cariotipagem , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Taxa de SobrevidaRESUMO
Whole bone marrow fragments of trepanobiopsies of the upper flaring portion of the ilium were cultivated over 1 to 8 weeks in a liquid phase of the agar drop-liquid medium system. Fifty-two hematological patients and controls were examined in order to study the character of regeneration of different stromal cells and their role in the production of stimulants of precursor cells of granulomonocytopoiesis. It was shown that during cultivation of bone marrow fragments precursors of the stromal cells form a monolayer at the dish bottom, forming a capsule around the fragments and proliferating inside the medullary lacunae. Endosteum is the main source of the regeneration of the stromal elements. The studies did not reveal any relationship between the colony-stimulating activity of the trepanobiopsies and the area occupied in them by sinuses, fibrous and osseous tissue. A positive correlation was established between the CSA and the number of fatty cells. The magnitude of the area of the stromal cell monolayer did not influence colony formation. Based on the data obtained the authors suggest that fatty acids are the main producers of the CSA within the system under consideration.
Assuntos
Células da Medula Óssea , Granulócitos/citologia , Hematopoese , Monócitos/citologia , Ensaio de Unidades Formadoras de Colônias , Fatores Estimuladores de Colônias/metabolismo , Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Mastócitos/metabolismoRESUMO
The authors describe the results of the cloning of hemopoietic cells from 85 patients with different patterns of nonlymphoblastic leukemias in the agar drop--liquid medium system. It is shown that measurement of the colony-stimulating activity of hemopoietic cells and their growth pattern as well as morphological study of the cultures can be employed in practical hematology for making diagnosis and differential diagnosis, for evaluation of the treatment efficacy and prediction of the disease prognosis. The presence of blast colonies, an increase in the number of cell aggregations is regarded as an unfavourable prognostic criterion. Elevation of the colony-stimulating activity of hemopoietic cells is evidence of a more favourable prognosis.
Assuntos
Doenças Hematológicas/diagnóstico , Hematopoese , Células-Tronco Hematopoéticas/patologia , Leucemia/diagnóstico , Células Clonais/patologia , Diagnóstico Diferencial , Doenças Hematológicas/patologia , Humanos , Leucemia/patologia , PrognósticoRESUMO
A pilot study of anticytocine therapy (PCD) was carried out in 9 patients with primary myelodysplastic syndrome (MDS). After 12 weeks, 2 patients (22%) showed hematological response cutting down the need for washed-out erythrocyte transfusions by half or more. MDS progression at different stages was reported in 4; transformation to acute myeloleukemia--2. PCD treatment is indicated in MDS patients, aged over 65, with a less than 10% blast level of the bone marrow, and without any risks of tumor progression.
Assuntos
Medula Óssea/efeitos dos fármacos , Citosina/antagonistas & inibidores , Fármacos Hematológicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Progressão da Doença , Transfusão de Eritrócitos , Feminino , Fármacos Hematológicos/farmacologia , Humanos , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIM: To characterize patients with mixed myeloid neoplasias with proliferation of neutrophils, platelets and eosinophils. MATERIAL AND METHODS: Examination and treatment results were analysed for patients with atypical myeloid leukemia (n = 4), myelodysplastic syndrome (MDS, n = 1) and thrombocytosis, MDS and eosinophilia (n = 1). The examination included morphological, histological, cytogenetic and molecular tests. RESULTS: One patient with atypical chronic myeloid leukemia was prior diagnosed to have primarily MDS with a typical aberration of chromosome 5. Two other patients had an initial morphological picture of resistant anemia with blast excess, signs of myeloproliferation and extramedullary hemopoiesis. One and two months after the first examination they received transfusions of erythrocytic mass. Just then they were found to have splenomegaly and leukocytosis due to proliferating and maturating forms of neutrophils. The course of the disease in patients with MDS, thrombocytosis and normal karyotype and in patients with MDS, eosinophilia and combined chromosomal breaks including translocation (3;12)(q21;p13) was characterized by resistance to standard programs of polychemotherapy and transformation into acute myeloblastic leukemia. CONCLUSION: In some cases atypical CML is a stage of a natural course of MDS. Some MDS variants with eosinophilia and thrombocytosis should be referred to the group of mixed myeloid neoplasias.
Assuntos
Eosinofilia/fisiopatologia , Leucemia Mielomonocítica Crônica/fisiopatologia , Síndromes Mielodisplásicas/fisiopatologia , Trombocitose/fisiopatologia , Adulto , Idoso , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 3 , Eosinofilia/classificação , Eosinofilia/complicações , Feminino , Hematopoese Extramedular , Humanos , Leucemia Mielomonocítica Crônica/classificação , Leucemia Mielomonocítica Crônica/complicações , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/complicações , Trombocitose/classificação , Trombocitose/complicações , Translocação GenéticaRESUMO
The treatment of 77 children suffering from acquired aplastic anemia (AAA) in the Petersburg Pediatric Hematological Center allowed the authors to distinguish three groups of patients according to the disease severity: severe, moderate and mild. The groups differed by clinicohematological parameters and treatment results. With reference to the above classification conventional combined treatment with hormones and splenectomy is uneffective in groups 1 and 2, but is able to induce remission in half the patients with mild disease. Immunosuppression with antilymphocytic globulin and large-dose methylprednisolone markedly contributed to survival prolongation in severe and moderate AAA (69 and 90% of cases with long-term remissions, respectively), being a failure in group 1 patients who are primarily scheduled for bone marrow transplantation.
Assuntos
Anemia Aplástica/classificação , Anemia Aplástica/terapia , Anemia Aplástica/sangue , Anemia Aplástica/etiologia , Anemia Aplástica/mortalidade , Transplante de Medula Óssea , Criança , Terapia Combinada , Quimioterapia Combinada , Humanos , Terapia de Imunossupressão , Prognóstico , Federação Russa/epidemiologiaRESUMO
Prognostic significance of the ratio of MMP-2 and MMP-9 activities (MMP-2/MMP-9) have been investigated in bone marrow plasma (BMP) of 53 patients with acute myeloid leukemia (AML) using the method of zymography. During BMP collection 33 patients were diagnosed with complete remission (CR) and 22 patients without CR. The ratio MMP-2/MMP-9 was approximately 1.00 (the upper limit was equal 1.77) in the 75% of patients. At the same time the ratio was more than 3 times higher in 13 patients (25%): their minimal value was 1.80 (p < 0.001). In the group with high ratio MMP-2/MMP-9 only 3 patients were with CR, and 10 patients with resistant variant of AML. The median of the overall survival (OS) of these 10 patients was significantly lower than OS of other investigated AML patients (7.0 vs 33.5 months p < 0.001). Thus the high MMP-2/MMP-9 ratio (> or = 1.8) may be associated with unfavorable course of AML.