Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B/terapia , Insuficiência Renal , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Insuficiência Renal/etiologia , Insuficiência Renal/terapia , Índice de Gravidade de DoençaAssuntos
ADP-Ribosil Ciclase 1 , Antígenos CD34 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Antígenos Comuns de Leucócito , Glicoproteínas de Membrana , Mieloma Múltiplo , Adulto , Autoenxertos , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapiaRESUMO
The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.
Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aldeído Desidrogenase/metabolismo , Alcinos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Criança , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Fenótipo , Compostos de Sulfidrila/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCRbright) or low levels (NCRdull) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a specific NK cells transcriptomic signature in patients with AML. However, in vitro NK cells expansion erased this signature and up-regulated expression of central molecules of NK functions, such as NCR, NKG2D and also ETS-1, regardless of their origin, i.e., AML-NK vs HD-NK. ETS-1 transcription factor was shown to bind to a specific and common region in the NCRs promoters, thus appearing as a good candidate to explain the coordinated regulation of three NCRs. Such results are encouraging regarding in vitro AML-NK cytotoxicity restoration and provide a new conceptual support for innovative cellular therapy based on in vitro NK cells expansion before their reinfusion in AML patients.
Assuntos
Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Receptores Desencadeadores da Citotoxicidade Natural/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Citotoxicidade Imunológica , Feminino , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Receptores Desencadeadores da Citotoxicidade Natural/genética , Análise Serial de Tecidos , Transcriptoma , Adulto JovemRESUMO
OBJECTIVE: To study the efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing induction chemotherapy for acute myeloid leukemia. PATIENTS AND METHODS: A prospective observational single-center study of 41 patients from the hematology department between May 2012 and April 2015. Micafungin was administered once daily from the first day of induction chemotherapy to the end of the neutropenic phase. RESULTS: Neither Candida nor Aspergillus infection was documented in our 41 patients from the first day of micafungin infusion to the end of the neutropenic phase. Patients were followed for three months after discontinuation of micafungin and none of them contracted an invasive fungal infection. Only one patient presented with grade III-IV hepatic and ionic toxicities. CONCLUSION: Micafungin is associated with a good safety profile and is an interesting option for preventing invasive fungal infections in the high-risk population of patients presenting with hematological disorders.
Assuntos
Antifúngicos/uso terapêutico , Equinocandinas/uso terapêutico , Leucemia Mieloide Aguda/complicações , Lipopeptídeos/uso terapêutico , Micoses/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções Bacterianas/etiologia , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Equinocandinas/administração & dosagem , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/complicações , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Lipopeptídeos/administração & dosagem , Masculino , Micafungina , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemAssuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Infecções por Vírus Epstein-Barr/imunologia , Sangue Fetal/imunologia , Herpesvirus Humano 4/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Adolescente , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Infecções por Vírus Epstein-Barr/etiologia , Feminino , HumanosAssuntos
Imunoglobulina D/análise , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/fisiopatologia , Proteínas do Mieloma/análise , Síndrome da Veia Cava Superior/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína de Bence Jones/urina , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/fisiopatologia , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/tratamento farmacológico , Recidiva , Tomografia Computadorizada por Raios XRESUMO
Hemolytic disease of the newborn caused by maternal isoimmunization has been decreasing over the past 10 years because of prophylactic treatment with anti-RH1 (anti-D) immunoglobulin. Nevertheless, there is an increase in the incidence of both relative and absolute numbers of non-RH1 red-cell maternofetal isoimmunizations, essentially anti-RH4 (anti-c), anti-RH3 (anti-E), and anti-Kell. In 8 to 14% of cases, multispecificity antibodies are present, the most common combination being the association of anti-RH3 and -4. Despite absence of specific prophylactic therapy, anti-RH4 isoimmunization could be as severe as anti-RH1 ; as for anti-RH3, it is usually associated with mild to moderate clinical manifestations. Nevertheless, there are few publications on anti-RH3, -4 maternofetal isoimmunization with a bias toward the most severe cases being reported. We report here a case of nonsevere maternofetal anti-RH3, -4 isoimmunization complicated with severe hyperbilirubinemia and delayed profound anemia. Hyperbilirubinemia was controlled using intensive phototherapy. Although anemia was absent at birth, it appeared progressively with a nadir at 7.8 g/dL at 1-month postnatal age. Blood counts were monitored for 3 months but the patient did not require red blood cell transfusion. This report underlines the need for a prolonged and rigorous pediatric follow-up of children born in the context of maternofetal isoimmunization after the acute neonatal period. Furthermore, it stresses the necessity of DAT testing in all pregnant women, even those who are RH1-positive.