RESUMO
The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in self-renewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose long-term expansion exclusively on human HSCs, not on progenitors. This was associated with an enhanced cobblestone formation under bone marrow stromal cells of STAT5-transduced HSCs. Hypoxia-induced factor 2α (HIF2α) was identified as a STAT5 target gene in HSCs, and chromatin immunoprecipitation studies revealed STAT5 binding to a site 344 base pairs upstream of the start codon of HIF2α. Lentiviral RNA interference (RNAi)-mediated down-modulation of HIF2α impaired STAT5-induced long-term expansion and HSC frequencies, whereas differentiation was not affected. Glucose uptake was elevated in STAT5-activated HSCs, and several genes associated with glucose metabolism were up-regulated by STAT5 in an HIF2α-dependent manner. Our studies indicate that pathways normally activated under hypoxia might be used by STAT5 under higher oxygen conditions to maintain and/or impose HSC self-renewal properties.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células-Tronco Hematopoéticas/metabolismo , Fator de Transcrição STAT5/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/fisiologia , Humanos , Recém-Nascido , Modelos Biológicos , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/fisiologia , Oxigênio/farmacologia , Gravidez , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismoRESUMO
In human hematopoietic malignancies, RAS mutations are frequently observed. Yet, little is known about signal transduction pathways that mediate KRAS-induced phenotypes in human CD34(+) stem/progenitor cells. When cultured on bone marrow stroma, we observed that KRAS(G12V)-transduced cord blood (CB) CD34(+) cells displayed a strong proliferative advantage over control cells, which coincided with increased early cobblestone (CAFC) formation and induction of myelomonocytic differentiation. However, the KRAS(G12V)-induced proliferative advantage was transient. By week three no progenitors remained in KRAS(G12V)-transduced cultures and cells were all terminally differentiated into monocytes/macrophages. In line with these results, LTC-IC frequencies were strongly reduced. Both the ERK and p38 MAPK pathways, but not JNK, were activated by KRAS(G12V) and we observed that proliferation and CAFC formation were mediated via ERK, while differentiation was predominantly mediated via p38. Interestingly, we observed that KRAS(G12V)-induced proliferation and CAFC formation, but not differentiation, were largely mediated via secreted factors, since these phenotypes could be recapitulated by treating non-transduced cells with conditioned medium harvested from KRAS(G12V)-transduced cultures. Multiplex cytokine arrays and genome-wide gene expression profiling were performed to gain further insight into the mechanisms by which oncogenic KRAS(G12V) can contribute to the process of leukemic transformation. Thus, angiopoietin-like 6 (ANGPTL6) was identified as an important factor in the KRAS(G12V) secretome that enhanced proliferation of human CB CD34(+) cells.
Assuntos
Antígenos CD34 , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Monócitos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas ras/metabolismo , Substituição de Aminoácidos , Proteína 6 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/genética , Angiopoietinas/metabolismo , Linhagem Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Citocinas/biossíntese , Citocinas/genética , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/citologia , Humanos , Leucemia/genética , Leucemia/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Monócitos/citologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Transdução Genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas ras/genéticaRESUMO
We report the use of PCR techniques on a formalin-fixed and paraffin-embedded tissue specimen for direct detection of one dominant azole resistance mechanism in a case of disseminated invasive aspergillosis. Rapid detection of mutations associated with azole resistance directly in tissue significantly reduces diagnostic delay.
Assuntos
Antifúngicos/farmacologia , Aspergilose/diagnóstico , Aspergillus/efeitos dos fármacos , Azóis/farmacologia , Técnicas de Laboratório Clínico/métodos , Farmacorresistência Fúngica , Reação em Cadeia da Polimerase/métodos , Aspergilose/microbiologia , Aspergillus/genética , Aspergillus/isolamento & purificação , Primers do DNA/genética , DNA Fúngico/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. DESIGN AND METHODS: Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1 to 7) in 162 patients with chronic myeloid leukemia. RESULTS: With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50-0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96-2.68, P=0.07) and 1.66 (95% confidence interval, 1.02-2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%. CONCLUSIONS: The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses (Clinicaltrials.Gov Identifier: NCT00028847).
Assuntos
Citarabina/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Benzamidas , Análise Citogenética , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Mucin1 is a membrane glycoprotein that is overexpressed in a variety of human cancers. Here, we analyzed the role of Mucin1 in human hematopoietic stem/progenitor cells as well as in acute myeloid leukemia (AML) cells. MATERIALS AND METHODS: Mucin1 expression was determined within the normal stem cell and progenitor compartment, as well as in the AML CD34+ and CD34- subfractions of patient samples. Stem cells were enumerated in long-term culture-initiating cell (LTC-IC) assays in limiting dilution and progenitor frequencies in colony-forming cell (CFC) assays in methylcellulose, and consequences of elevated Mucin1 expression were studied using retroviral overexpression systems in cord blood (CB) CD34+ cells. RESULTS: Ten percent of CB and 5% of peripheral blood CD34+ cells expressed Mucin1. Retroviral overexpression of Mucin1 in CB CD34+ cells resulted in elevated stem cell and progenitor frequencies as determined in LTC-IC and CFC assays without affecting differentiation, which coincided with increased proliferation. Overexpression of intercellular adhesion molecule-1, a ligand for Mucin1, in MS5 stromal cells further increased LTC-IC frequencies. Mucin1 overexpression was associated with increased nuclear factor-kappaB p50 nuclear translocation, suggesting that Mucin1-induced phenotypes involve increased cell survival mechanisms. Finally, we observed increased Mucin1 expression in 70% of the AML cases (n=24), suggesting that elevated Mucin1 levels might be involved in regulating the proliferative potential of the immature leukemic compartment as well. CONCLUSIONS: Our data indicate that hematopoietic stem cells as well as CD34+ AML subfractions are enriched for Mucin1 expression, and that overexpression of Mucin1 in CB cells is sufficient to increase both progenitor and LTC-IC frequencies.
Assuntos
Sangue Fetal/fisiologia , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Mucina-1/genética , Células-Tronco/fisiologia , Antígenos CD/análise , Antígenos CD34/análise , Ensaio de Unidades Formadoras de Colônias , Primers do DNA , Citometria de Fluxo , Humanos , Recém-Nascido , Molécula 1 de Adesão Intercelular/genética , Leucemia Mieloide Aguda/patologia , Reação em Cadeia da Polimerase , Retroviridae/genética , Regulação para CimaRESUMO
PURPOSE: To investigate the feasibility of withholding antibiotics and early discharge for patients with chemotherapy-induced neutropenia and fever at low risk of bacterial infection by a new risk assessment model. PATIENTS AND METHODS: Outpatients with febrile neutropenia were allocated to one of three groups by a risk assessment model combining objective clinical parameters and plasma interleukin 8 level. Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk. Based on their interleukin-8 level, remaining patients were allocated to low or medium risk for bacterial infection. Medium-risk and high-risk patients received standard antibiotic therapy, whereas low-risk patients did not receive antibiotics and were discharged from hospital after 12 hours of a febrile observation. End points were the feasibility of the treatment protocol. RESULTS: Of 196 assessable episodes, 76 (39%) were classified as high risk, 84 (43%) as medium risk, and 36 (18%) as low risk. There were no treatment failures in the low-risk group (95% CI, 0% to 10%). Therefore, sensitivity of our risk assessment model was 100% (95% CI, 90% to 100%), the specificity, positive, and negative predictive values were 21%, 13%, and 100%, respectively. Median duration of hospitalization was 3 days in the low-risk group versus 7 days in the medium- and high-risk groups (P < .0001). The incremental costs of the experimental treatment protocol amounted to a saving of 471 (US $572) for every potentially low-risk patient. CONCLUSION: This risk assessment model appears to identify febrile neutropenic patients at low risk for bacterial infection. Antibiotics can be withheld in well-defined neutropenic patients with fever.
Assuntos
Antibacterianos/administração & dosagem , Antineoplásicos/efeitos adversos , Febre/prevenção & controle , Neoplasias/tratamento farmacológico , Neutropenia/prevenção & controle , Adolescente , Adulto , Idoso , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Febre/etiologia , Humanos , Lactente , Recém-Nascido , Interleucina-8 , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Alta do Paciente , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de RiscoRESUMO
PURPOSE: Patients with acute lymphoblastic leukemia (ALL) are treated with a variety of chemotherapeutic drugs, which can be transported by six multidrug resistance-associated proteins (MRP). These MRPs have strongly overlapping functional activities. The aim of this study was to investigate the expression levels of MRP1 to MRP6 and study their effect on prognosis. EXPERIMENTAL DESIGN: The mRNA expression levels of MRP1 to MRP6 were analyzed by quantitative real-time PCR in leukemic blasts of 105 de novo ALL patients (adults, n=49; children, n=56) including 70% B-lineage and 30% T-lineage ALL patients. RESULTS: Adults showed a higher expressions of MRP1 (P=0.008), MRP2 (P=0.026), and MRP3 (P=0.039) than children. Interestingly, this difference disappeared when patients were categorized based on clinical outcome. Relapsed patients showed a higher expression of all MRP genes, except MRP4. For the total group of ALL patients, the expressions of MRP1, MRP2, MRP3, MRP5, and MRP6 predicted relapse. Moreover, high expression of all MRP genes, except MRP4, was associated with a reduced relapse-free survival in children and adults (MRP1, P=0.005; MRP2, P=0.008; MRP3, P=0.001; MRP5, P=0.016; MRP6, P=0.037). CONCLUSIONS: The present study shows that a subset of ALL patients with high MRP expression has an unfavorable prognosis independently of age.
Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adulto , Criança , Feminino , Expressão Gênica , Humanos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , RNA Neoplásico/química , RecidivaRESUMO
OBJECTIVE: Hematopoietic stem cells (HSC) are considered to display a quiescent state with low turnover rate. We investigated the cell-cycle kinetics of HSC after a single dose of cytarabine (Ara-C). MATERIALS AND METHODS: We analyzed by flow cytometry the cell-cycle status of lin(low)sca-1(+)c-kit(+) (LSK) stem cells isolated from the bone marrow of C57Bl/6 mice sacrificed at 0, 2, 4, 6, 8, 12, 20, 48, 72, and 96 hours after intraperitoneal injection of Ara-C (100 mg/kg) using 7-aminoactinomycin-D (7-AAD) for DNA staining. In vivo bromodeoxyuridine (BrdU) incorporation and Ki-67 expression in HCS were also measured. RESULTS: Two hours after administration of Ara-C, LSK cells ceased to incorporate BrdU. At 4 hours, a decrease of S-phase cells from 10% at baseline to 4% was found (p < 0.05), followed by a rapid increase of BrdU and 7-AAD incorporation reaching a maximum of 28% S-phase cells at 20 hours (p < 0.001). Ki-67 expression suggested recruitment of 20% of cells from G0 into cell cycle. The total number of LSK cells increased 2.5-fold within this short time interval. After 72 hours, a recovery of cell cycling to baseline levels was observed. CONCLUSION: This data shows that a single injection of Ara-C first rapidly induced S-phase arrest in HSC for up to 4 hours. Subsequently, an unexpectedly rapid activation of HCS with recruitment of G0 cells into cell cycle was observed. The mechanism of cell-cycle activation of LSK cells remains unknown, but reduction of the number of differentiated end cell did not appear to be the primary trigger.
Assuntos
Ciclo Celular/efeitos dos fármacos , Citarabina/farmacologia , Células-Tronco/citologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/efeitos dos fármacosRESUMO
OBJECTIVE: Cancer patients with febrile neutropenia after chemotherapy have a variable risk of bacterial infection. Especially Gram-negative bacteremia is associated with high mortality and/or morbidity. Early diagnosis of patients with Gram-negative bacteremia at the onset of febrile neutropenia is potentially useful in tailoring therapy. DESIGN AND SETTING: Prospective study at the Department of Pediatric Oncology and Internal Medicine of a university hospital. PATIENTS: Were analyzed 66 febrile neutropenic episodes in 57 adults and children. Patients were divided into four groups: those with Gram-negative bacteremia, Gram-positive bacteremia, clinical sepsis, or fever of unknown origin. MEASUREMENTS AND RESULTS: Plasma lipopolysaccharide-binding protein (LBP) and C-reactive protein (CRP) concentrations were determined. LBP at the onset of febrile neutropenia was significantly higher in patients with Gram-negative bacteremia than those with fever of unknown origin and those with Gram-positive bacteremia. Using a cutoff value for LBP proved to have much greater sensitivity, specificity, and positive and negative predictive value for Gram-negative bacteremia than the best cutoff value for CRP. CONCLUSIONS: An initial high LBP level might predict Gram-negative bacteremia in cancer patients with febrile neutropenia. These results may have potential clinical impact by allowing therapy to be initiated for these patients at a very early stage.
Assuntos
Proteínas de Fase Aguda , Antineoplásicos/efeitos adversos , Proteínas de Transporte/sangue , Infecções por Bactérias Gram-Negativas/sangue , Glicoproteínas de Membrana , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Adolescente , Adulto , Idoso , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Feminino , Febre de Causa Desconhecida/sangue , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Negativas/mortalidade , Infecções por Bactérias Gram-Positivas/sangue , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/complicações , Estudos ProspectivosRESUMO
There is a distinct difference in prognosis between childhood versus adult acute lymphoblastic leukaemia (ALL). To define whether multidrug resistance (MDR) genes might contribute to this distinction, the expression and functional activity of P-glycoprotein (P-gp) and MDR associated proteins (MRP) were determined with RT-PCR (MDR-1, MRP1, MRP2, MRP3) and flow cytometry (P-gp and MRP). Patient samples were obtained from 36 children and 35 adults with de novo ALL. Of these patients, 38 showed a T-lineage and 33 showed a B-lineage immunophenotype. In the samples, large variability in P-gp activity (0.8-4.9) and MRP activity (1.1-13.9) was observed. Most T-ALL patients with high P-gp activity were adults (89%). The mRNA expression of MDR-1 correlated weakly with P-gp activity. In contrast, MRP activity did not correlate with the mRNA expression of MRP1, MRP2 and MRP3. In T-ALL, a worse overall survival and event-free survival was observed with increasing P-gp activity. P-gp activity had no prognostic impact in B-lineage ALL. In addition, high MRP activity did not influence treatment outcome in either T- or B-lineage ALL. Multivariate Cox regression analysis, showed P-gp activity to be the only unfavourable prognostic factor for overall survival in T-ALL. In conclusion, this study demonstrates the prognostic relevance of P-gp activity in T-ALL. Since the majority of the patients with high P-gp activity were adults, P-gp might contribute to the poor prognosis of adult T-ALL.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Proteínas de Membrana Transportadoras , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Leucemia de Células B/diagnóstico , Leucemia de Células B/genética , Leucemia de Células B/mortalidade , Leucemia de Células T/diagnóstico , Leucemia de Células T/genética , Leucemia de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , RNA Mensageiro/análise , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de SobrevidaAssuntos
Anticonvulsivantes/farmacologia , Antifúngicos/farmacocinética , Fenitoína/farmacologia , Pirimidinas/farmacocinética , Triazóis/farmacocinética , Anticonvulsivantes/administração & dosagem , Área Sob a Curva , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenitoína/administração & dosagem , Aspergilose Pulmonar/tratamento farmacológico , VoriconazolRESUMO
BACKGROUND: Treatment options in older acute myeloid leukaemia (AML) patients include intensive chemotherapy, best supportive care (BSC), and hypomethylating agents. Currently, limited data is available on hypomethylating agents in older AML patients in unselected patient populations. METHODS: To compare the effectiveness of azacitidine with conventional therapy, we collected data of 227 consecutive AML patients (≥60 years) who were treated with azacitidine (N = 26), intensive chemotherapy (N = 90), or BSC (N = 97). RESULTS: Azacitidine-treated patients were older and had more comorbidities, but lower white blood cell- and bone marrow blast counts compared with intensive chemotherapy patients. Complete or partial response was achieved in 42% of azacitidine-treated patients and in 73% of intensive chemotherapy patients (P = 0.005). However, the overall survival (OS) was similar (1-year-OS 57% versus 56%, P = 0.93; 2-year-OS 35% versus 35%, P = 0.92), and remained similar after correction for risk factors in a multivariate analysis. Patients treated with BSC had an inferior OS (1-year- and 2-year-OS 16% and 2%, P < 0.001). Compared to intensive chemotherapy, azacitidine-treated patients spent less days in the hospital (median in first three months 0.5 versus 56, P < 0.001), and needed less red blood cell and platelet transfusions (median per month 2.7 versus 7, P < 0.001 and 0.3 versus 5, P < 0.001) in the first three months. CONCLUSIONS: Azacitidine treatment is associated with a comparable OS but higher tolerability in a subgroup of older AML patients compared with intensive chemotherapy. Patients receiving BSC had a poor prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Azacitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated whether CML patients in molecular response(4.5) (MR(4.5), quantitative reverse-transcription polymerase chain reaction (RQ-PCR)) after previous combination therapy with imatinib and cytarabine may discontinue imatinib treatment safely. PATIENTS AND METHODS: Thirty-three patients from the HOVON 51 study with an MR(4.5) for at least 2 years who were still on imatinib treatment were randomised between continuation of imatinib (arm A, n=18) or discontinuation of imatinib (arm B, n=15). RESULTS: After a median follow up of 36 months since randomisation, 3 patients (17%) in arm A and 10 patients (67%) in arm B had a molecular relapse. All 3 relapsing patients in arm A had also stopped imatinib after randomisation. All but one relapsing patient relapsed within 7 months after discontinuation of imatinib. The molecular relapse rate at 12 and 24 months after randomisation was 0% and 6% (arm A) and 53% and 67% (arm B) respectively. As-treated analysis revealed 56% and 61% relapses at 1 and 2 years since cessation in patients who discontinued imatinib, in contrast to 0% of patients who continued imatinib. All evaluable patients remained sensitive to imatinib after reinitiation and regained a molecular response. CONCLUSION: Our data suggest that discontinuation of imatinib is safe in patients with durable MR(4.5).
Assuntos
Benzamidas/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Bélgica , Benzamidas/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Mesilato de Imatinib , Masculino , Recidiva Local de Neoplasia/diagnóstico , Países Baixos , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Taxa de Sobrevida , Resultado do TratamentoRESUMO
There has been a large increase in the incidence of invasive fungal infections (IFIs) over the past decades, largely because of the increasing size of the population at risk. One of the major risk groups for IFIs are patients with haematological malignancies treated with cytotoxic chemotherapy or undergoing haematopoietic stem cell transplantation. These IFIs are associated with high morbidity and mortality rates. Consequently, as the diagnosis of IFIs is difficult, antifungal prophylaxis is desirable in high-risk patients. Furthermore, as the economic impact of IFIs is also significant, it is important to assess the cost benefit and cost effectiveness of each prophylactic agent in order to aid decisions concerning which prophylactic agent provides the best value for limited healthcare resources. This article systematically reviews the available pharmacoeconomic evidence regarding antifungal prophylaxis in immunocompromised patients treated for haematological malignancies. Furthermore, specific points of interest concerning economic analyses of antifungal prophylaxis are briefly discussed. Considering the available evidence, antifungal prophylaxis in immunocompromised patients treated for haematological malignancies seems to be an intervention with favourable cost-benefit, cost-effectiveness and cost-saving potential. Furthermore, recently introduced antifungal agents seem to be attractive alternatives to fluconazole from a pharmacoeconomic point of view. However, due to wide heterogeneity in patient characteristics, underlying diseases, hospital settings and study methods in the included economic studies, as well as the lack of 'head-to-head' trials, it is difficult to find clear evidence of the economic advantages of a single prophylactic agent. Furthermore, we show that the results of cost-effectiveness analyses are highly dependent on several crucial factors that influence the baseline IFI incidence rates and, therefore, differ per patient population or region.
Assuntos
Antifúngicos/economia , Hospedeiro Imunocomprometido , Micoses/prevenção & controle , Antifúngicos/uso terapêutico , Antineoplásicos/efeitos adversos , Análise Custo-Benefício , Farmacoeconomia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Micoses/etiologiaRESUMO
AIM: To demonstrate whether serum Interleukin-8 (IL-8) is a relevant parameter to select hospitalised patients with chemotherapy-induced neutropenic fever with low or high probability of infection. RESULTS: 90 assessable febrile episodes in 73 patients were evaluated; 46% of the febrile episodes were microbiologically documented infection (MDI), 8% clinical documented infection (CDI), and 47% fever of unknown origin (FUO). Median IL-8 level was lower in the FUO group compared to CDI and MDI (p<0.0005). In 45 of 48 episodes (94%) with CDI/MDI, IL-8 level at the start was > or =60 ng/l while in 18 of 21 episodes (86%) with IL-8 level <60 ng/l, no infectious cause was demonstrated. FUO and CDI/MDI patients with IL-8 > or =60 ng/l and responsive on antibiotic treatment showed a decline of IL-8 levels within days in contrast to non-responding patients. CONCLUSIONS: Serum IL-8 level can be a useful marker to identify hospitalised FUO patients with low probability of infection.
Assuntos
Antineoplásicos/efeitos adversos , Febre de Causa Desconhecida/etiologia , Interleucina-8/sangue , Neutropenia/induzido quimicamente , Adulto , Idoso , Antibacterianos/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Feminino , Febre de Causa Desconhecida/tratamento farmacológico , Febre de Causa Desconhecida/microbiologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/complicações , Infecções Oportunistas/complicações , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Estudos Prospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: B-cell expression of ZAP-70, normally expressed in T and NK cells, correlates with poor prognosis in B-CLL. Poor discrimination between ZAP-70 positive and negative cells hampers routine application of flow cytometry. We examined the usefulness of FACS Lysing Solution. METHODS: ZAP-70 expression in 65 healthy volunteers was measured by four-color flow cytometry, comparing FACS Lysing Solution for fixation and permeabilization with the Fix & Perm kit. Separation between ZAP-70 positive T cells and negative B cells was based on a ratio of median ZAP-70 staining of T cells to B cells. In 25 B-CLL patients, ZAP-70 expression was estimated using the lower limit of the fluorescence range corresponding with 98% of ZAP-70 positive T cells as threshold marker as well as a ratio of B-CLL cell to internal T-cell median ZAP-70 staining. RESULTS: Use of FACS Lysing Solution resulted in approximately fourfold increased separation between ZAP-70 positive T cells and negative B cells, when compared with the Fix & Perm kit. In B-CLL samples, ZAP-70 negative and positive B-cell expression could be clearly discerned. CONCLUSIONS: FACS Lysing Solution is a simple procedure that markedly improves discrimination between ZAP-70 positive and negative cells.
Assuntos
Biomarcadores Tumorais/metabolismo , Citometria de Fluxo/métodos , Leucemia Linfocítica Crônica de Células B/metabolismo , Kit de Reagentes para Diagnóstico , Soluções/farmacologia , Proteína-Tirosina Quinase ZAP-70/metabolismo , Reações Antígeno-Anticorpo , Linfócitos B/química , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Separação Celular , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Soluções/química , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Proteína-Tirosina Quinase ZAP-70/química , Proteína-Tirosina Quinase ZAP-70/imunologiaRESUMO
Rhodococcus equi, mainly known from veterinary medicine as a pathogen in domestic animals, can also cause infections in immunocompromised humans, especially in those with defects in cellular immunity. Alemtuzumab, an anti-CD52 monoclonal antibody, causes lymphocytopenia by eliminating CD52-positive cells. We report a patient in whom Rhodococcus equi infection developed after alemtuzumab therapy.
Assuntos
Infecções por Actinomycetales/etiologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/efeitos adversos , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Rhodococcus equi , Infecções por Actinomycetales/microbiologia , Idoso , Alemtuzumab , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados , Humanos , Hospedeiro Imunocomprometido , Abscesso Pulmonar/tratamento farmacológico , Abscesso Pulmonar/microbiologia , MasculinoRESUMO
The Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) collaborative study group evaluated outcome of patients (pts) with acute myeloid leukemia (AML) in first remission (CR1) entered in 3 consecutive studies according to a donor versus no-donor comparison. Between 1987 and 2004, 2287 pts were entered in these studies of whom 1032 pts (45%) without FAB M3 or t(15;17) were in CR1 after 2 cycles of chemotherapy, received consolidation treatment, and were younger than 55 years of age and therefore eligible for allogeneic hematopoietic stem cell transplantation (allo-SCT). An HLA-identical sibling donor was available for 326 pts (32%), whereas 599 pts (58%) lacked such a donor, and information was not available in 107 pts. Compliance with allo-SCT was 82% (268 of 326). Cumulative incidences of relapse were, respectively, 32% versus 59% for pts with versus those without a donor (P < .001). Despite more treatment-related mortality (TRM) in the donor group (21% versus 4%, P < .001), disease-free survival (DFS) appeared significantly better in the donor group (48% +/- 3% versus 37% +/- 2% in the no-donor group, P < .001). Following risk-group analysis, DFS was significantly better for pts with a donor and an intermediate- (P = .01) or poor-risk profile (P = .003) and also better in pts younger than 40 years of age (P < .001). We evaluated our results and those of the previous MRC, BGMT, and EORTC studies in a meta-analysis, which revealed a significant benefit of 12% in overall survival (OS) by donor availability for all patients with AML in CR1 without a favorable cytogenetic profile.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Doadores Vivos , Condicionamento Pré-Transplante , Adolescente , Adulto , Fatores Etários , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Teste de Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Transplante HomólogoRESUMO
PURPOSE: Cloretazine (VNP40101M) is a sulfonylhydrazine alkylating agent with significant antileukemia activity. A multicenter phase II study of cloretazine was conducted in patients 60 years of age or older with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Cloretazine 600 mg/m2 was administered as a single intravenous infusion. Patients were stratified by age, performance score, cytogenetic risk category, type of AML, and comorbidity. RESULTS: One hundred four patients, median age 72 years (range, 60 to 84 years), were treated on study. Performance status was 2 in 31 patients (30%) and no patient had a favorable karyotype. Forty-seven patients (45%) had cardiac disease, 25 patients (24%) had hepatic disease, and 19 patients (18%) had pulmonary disease, defined as per the Hematopoietic Cell Transplantation-Specific Comorbidity Index, at study entry. The overall response rate was 32%, with 29 patients (28%) achieving complete response (CR) and four patients (4%) achieving CR with incomplete platelet recovery. Response rates in 44 de novo AML patients, 45 secondary AML patients, and 15 high-risk MDS patients were 50%, 11%, and 40%, respectively. Response by cytogenetic risk category was 39% in 56 patients with intermediate cytogenetic risk and 24% in 46 patients with unfavorable cytogenetic risk. Nineteen (18%) patients died within 30 days of receiving cloretazine therapy. Median overall survival was 94 days, with a 1-year survival of 14%; the median duration of survival was 147 days, with a 1-year survival of 28% for those who achieved CR. CONCLUSION: Cloretazine has significant activity and modest extramedullary toxicity in elderly patients with AML or high-risk MDS. Response rates remain consistent despite increasing age and comorbidity.