RESUMO
The effects of inter-unit HLA-match on early outcomes with regards to double cord blood transplantation have not been established. Therefore, we studied the effect of inter-unit HLA-mismatching on the outcomes of 449 patients with acute leukemia after double cord blood transplantation. Patients were divided into two groups: one group that included transplantations with inter-unit mismatch at 2 or less HLA-loci (n=381) and the other group with inter-unit mismatch at 3 or 4 HLA-loci (n=68). HLA-match considered low resolution matching at HLA-A and -B loci and allele-level at HLA-DRB1, the accepted standard for selecting units for double cord blood transplants. Patients', disease, and transplant characteristics were similar in the two groups. We observed no effect of the degree of inter-unit HLA-mismatch on neutrophil (Hazard Ratio 1.27, P=0.11) or platelet (Hazard Ratio 0.1.13, P=0.42) recovery, acute graft-versus-host disease (Hazard Ratio 1.17, P=0.36), treatment-related mortality (Hazard Ratio 0.92, P=0.75), relapse (Hazard Ratio 1.18, P=0.49), treatment failure (Hazard Ratio 0.99, P=0.98), or overall survival (Hazard Ratio 0.98, P=0.91). There were no differences in the proportion of transplants with engraftment of both units by three months (5% after transplantation of units with inter-unit mismatch at ≤2 HLA-loci and 4% after transplantation of units with inter-unit mismatch at 3 or 4 HLA-loci). Our observations support the elimination of inter-unit HLA-mismatch criterion when selecting cord blood units in favor of optimizing selection based on individual unit characteristics.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Teste de Histocompatibilidade , Leucemia Mieloide/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doença Aguda , Adulto , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Antígenos HLA-A/análise , Antígenos HLA-A/genética , Antígenos HLA-B/análise , Antígenos HLA-B/genética , Cadeias HLA-DRB1/análise , Cadeias HLA-DRB1/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Modelos de Riscos ProporcionaisRESUMO
Data on Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) in adults in the United States remain very limited. A cluster of four cases of EBV-HLH was observed in a 4-month period at a tertiary center in Los Angeles County (LA County) and the clinical and molecular characteristics identified in these cases are being described. EBV typing, immunophenotypic and molecular genetic studies were performed. Diagnostic criteria that may be used to identify EBV as a cause of HLH in adults are also being suggested. Finally, the crude incidence rate for HLH in LA County was determined and was compared to the worldwide crude incidence rate for HLH. The cases each occurred in young male adult residents of California and were associated with evidence of EBV reactivation and ferritin levels of >20,000 µg/L. A higher rate of cases of EBV-HLH in 2010 was found at UCLA Medical Center than for 2007-2009 (4.9/10,000 hospital discharges vs. 0.14/10,000 hospital discharges, respectively; P = 0.0017). The cases were associated with EBV type 1, and the insertion of the codon CTC (leucine) was found in numerous of the EBNA-2 gene sequences. The annual incidence of secondary, non-familial HLH was estimated to be 0.9 cases per million persons >15 years of age in LA County. Although EBV-HLH is a rare disease, the incidence in adults in Western countries may be underestimated.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Linfo-Histiocitose Hemofagocítica/etiologia , Adulto , Sequência de Aminoácidos , DNA Viral/análise , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Herpesvirus Humano 4/classificação , Humanos , Los Angeles/epidemiologia , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Proteínas da Matriz Viral/genética , Proteínas Virais/genética , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45-7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0-14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.
RESUMO
Based on favorable results from randomized clinical trials, oral posaconazole has been approved for prophylaxis in neutropenic patients and stem cell transplantation (SCT) recipients. However, routine use of a prophylactic drug may yield different results than those from clinical trials. We collected data on the efficacy, safety, breakthrough infections, and antimicrobial resistance associated with standard long-term posaconazole prophylaxis in adult allogeneic SCT recipients at the UCLA Medical Center. Oral posaconazole (200 mg 3 times daily) was started on day 1 after SCT and continued until day 100. After day 100, posaconazole was continued in patients who still required corticosteroids for prevention or treatment of graft-versus-host disease. From January 2007 through December 2008, 106 consecutive patients received prophylactic posaconazole. Breakthrough invasive fungal infections on posaconazole occurred in 8 patients (7.5%) within 6 months after SCT; 3 additional patients developed invasive fungal infection after discontinuation of prophylactic posaconazole. The infective organisms were Candida (8 cases), Aspergillus (2 cases), and Aspergillus plus Coccidioides immitis (1 case). There were no Zygomycetes infections. Only 2 (both Candida glabrata) of 9 infecting isolates tested were resistant to posaconazole (minimal inhibitory concentration >1 µg/mL). Mortality from invasive fungal infection occurred in 4 patients (3.7%). Except for nausea in 9 patients, no clinical adverse event or laboratory abnormality could be attributed to posaconazole. Mean peak and trough plasma posaconazole concentrations were relatively low (<400 ng/mL) in neutropenic patients with oral mucositis and other factors possibly affecting optimal absorption of posaconazole. These results demonstrate that standard long-term oral posaconazole prophylaxis after allogeneic SCT is safe and associated with few invasive mold infections. However, breakthrough infections caused by posaconazole-susceptible organisms (frequently Candida) may occur at currently recommended prophylactic doses. Thus, strategies to improve posaconazole exposure, including the use of higher doses, administration with an acidic beverage, and restriction of proton pump inhibitors, need to be considered when using prophylactic posaconazole.
Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Neoplasias Hematológicas/terapia , Micoses/prevenção & controle , Transplante de Células-Tronco , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Adolescente , Adulto , Feminino , Neoplasias Hematológicas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/mortalidade , Estudos Retrospectivos , Fatores de Tempo , Transplante Homólogo , Adulto JovemRESUMO
We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize stem cells in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Patients with NHL and MM underwent mobilization with G-CSF (10 microg/kg/day) for up to 9 days and plerixafor (240 microg/kg/day), which started on the evening of day 4. Apheresis began on day 5 and continued daily until either >or= 5 x 10(6) CD34/kg were collected or to a maximum of 5 aphereses. Toxicities, increase in circulating CD34 cells/microL before and after the first dose of plerixafor, percentage of patients collecting >or= 5 x 10(6) CD34/kg, total CD34 cells/kg collected, engraftment, and exploratory efficacy analyses in heavily pretreated patients were examined. Six sites enrolled 49 patients (NHL, 23; MM, 26). All completed mobilization and 47 of 49 (96%) underwent transplant. Circulating CD34 cells/microL increased by 2.5-fold (1.3-6.0-fold) after the first plerixafor dose. The median CD34 cells/kg collected was 5.9 x 10(6) (1.5-22.5) in 2 (1-5) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (8-16) and 14.5 (7-39) days, respectively. Adverse events primarily were mild nausea and diarrhea (n=24). Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34 cells/microL was 2.5 (1.4-5.0) after plerixafor, similar to minimally pretreated patients. Plerixafor and G-CSF increased circulating CD34 cells/microL and led to the adequate collection of stem cells for autotransplant in 96% of the patients. This combination may have particular value in heavily pretreated patients.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Adulto , Idoso , Antígenos CD34 , Benzilaminas , Remoção de Componentes Sanguíneos , Contagem de Células , Ciclamos , Quimioterapia Combinada , Feminino , Sobrevivência de Enxerto , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/normas , Células-Tronco Hematopoéticas/citologia , Compostos Heterocíclicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores CXCR4/antagonistas & inibidoresRESUMO
The prognosis of patients with hematopoietic stem cell transplants (HSCTs) who require admission to the intensive care unit (ICU) has been regarded as extremely poor. We sought to re-evaluate recent outcomes and predictive factors in a retrospective cohort study. Among the 605 adult patients that received an HSCT between 2001 and 2006, 154 required admission to the ICU. Of these, 47% were discharged from the ICU, 36% were discharged from the hospital, and 19% survived 6 months. Allogeneic transplant, mechanical ventilation, vasopressor-use, and neutropenia were each associated with increased mortality, and the mortality of patients with all four characteristics was 100%. Hemodialysis was also associated with increased mortality in a Kaplan-Meier analysis but did not appear important in a multivariate tree analysis. A final Cox model confirmed that allogeneic transplant, mechanical ventilation, and vasopressor-use were each independent risk factors for mortality in the 6 months following ICU admission.
RESUMO
Treatment for steroid-resistant acute graft-versus-host disease (GVHD) has had limited success. ABX-CBL is a hybridoma-generated murine IgM monoclonal antibody against the CD147 antigen, weakly expressed on human leukocytes and up-regulated on activated lymphocytes. A prospective, multicenter, open-label, randomized clinical trial comparing ABX-CBL to antithymocyte globulin (ATG) for treatment of steroid-resistant acute GVHD was conducted in 95 patients at 21 centers. Forty-eight patients received ABX-CBL daily for 14 consecutive days followed by up to 6 weeks of ABX-CBL twice weekly. Forty-seven patients received equine ATG, 30 mg/kg every other day for a total of 6 doses with additional courses as needed. By day 180, overall improvement was similar in the patients receiving ABX-CBL and in those receiving ATG (56% versus 57%, P = .91). Patient survival at 18 months was less favorable on ABX-CBL than on ATG (35% versus 45%), with the 95% confidence interval ruling out that ABX-CBL provides at least a 10.4% improvement. Data from this trial suggest that ABX-CBL does not offer an improvement over ATG in the treatment of acute steroid-resistant GVHD. This prospective, multicenter, randomized clinical trial for steroid-resistant acute GVHD serves as a model for future evaluation of new agents.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Basigina/imunologia , Resistência a Medicamentos/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Esteroides/farmacologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Soro Antilinfocitário/efeitos adversos , Soro Antilinfocitário/imunologia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Taxa de Sobrevida , Fatores de TempoAssuntos
Doenças Autoimunes/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Condicionamento Pré-Transplante/métodos , Doenças Autoimunes/mortalidade , Humanos , Imunossupressores/uso terapêutico , Linfócitos/efeitos dos fármacos , Agonistas Mieloablativos/uso terapêutico , Taxa de Sobrevida , Transplante AutólogoRESUMO
In 87 patients with aplastic anemia who failed to respond to immunosuppressive treatment, we determined the minimal dose of total body irradiation (TBI) required when added to antithymocyte globulin (ATG, 30 mg/kg x 3) plus cyclophosphamide (CY, 50 mg/kg x 4) to achieve engraftment of unrelated donor marrow. TBI was started at 3 x 200 cGy, to be escalated or deescalated in steps of 200 cGy depending on graft failure or toxicity. Patients were aged 1.3 to 53.5 years (median, 18.6 years). The interval from diagnosis to transplantation was 3 to 328 months (median, 14.6 months). Donors were HLA-A, -B, -C, -DR, and -DQ identical for 62 patients, and nonidentical for 1 to 3 HLA loci at the antigen or allele level for 25. The dose-limiting toxicity was diffuse pulmonary injury. The optimum TBI dose was 1 x 200 cGy. Nine patients did not tolerate ATG and were prepared with CY + TBI. Graft failure occurred in 5% of patients. With a median follow-up of 7 years, 38 (61%) of 62 HLA-identical, and 10 (40%) of 25 HLA-nonidentical transplant recipients are surviving. The highest survival rate with HLA-identical transplants was observed at 200 cGy TBI. Thus, low-dose TBI + CY + ATG conditioning resulted in excellent outcome of unrelated transplants in patients with aplastic anemia who had received multiple transfusions.
Assuntos
Anemia Aplástica/cirurgia , Transplante de Medula Óssea/imunologia , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Transfusão de Sangue , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/cirurgia , Feminino , Teste de Histocompatibilidade , Humanos , Doadores Vivos , Masculino , Análise de Sobrevida , Falha de TratamentoRESUMO
The optimal postremission treatment for elderly patients with acute myelogenous leukemia (AML) is presently unknown, but recent studies report the feasibility of autologous stem cell transplantation in this population. To better understand the long-term outcome of autologous transplantation in AML patients > or =60 years of age, we evaluated high-dose chemoradiotherapy preparative conditioning followed by transplantation of peripheral blood progenitor cells procured after a single cycle of cytarabine-based consolidation chemotherapy as postremission therapy in 27 patients aged 60 to 71 years (median age, 65 years) with newly diagnosed AML in first complete remission (CR). The median follow-up from CR for all patients was 13.6 months (range, 6.0-123.1 months). The median follow-up from remission for surviving patients was 81 months (range, 41.4-123.1 months). Seven patients are alive in continuous CR, 19 died from relapse, and 1 died as a result of treatment-related infection. Leukemia-free survival and overall survival are 10.3 and 13.4 months, respectively. Actuarial leukemia-free and overall survival at 3 years are 25% +/- 9% and 28% +/- 9%, respectively. Our results demonstrate that autologous transplantation of peripheral blood progenitor cells is well tolerated and feasible for patients > or =60 years of age with AML in first CR. Future investigation should focus on a randomized study evaluating a larger group of elderly patients in first CR comparing autologous stem cell transplantation with conventional cytarabine-based consolidation chemotherapy to identify the optimal postremission therapy.
Assuntos
Leucemia Mieloide Aguda/mortalidade , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Idoso , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Recidiva , Indução de Remissão , Taxa de Sobrevida , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Transplante AutólogoRESUMO
Management of patients with multiple-relapsed lymphoma meets with little success. The optimal use of available drugs in this situation is often unknown. Gemcitabine has documented efficacy in this setting. Pharmacodynamic data suggest that the optimal use may involve a fixed-rate infusion and coadministration with platinum compounds. In this study we explored the use of gemcitabine starting at a dose of 800 mg/m(2) administered at a fixed infusion rate of 10 mg/m(2) per minute with cisplatin 35 mg/m(2) intravenously, both given on day 1, and dexamethasone 20 mg daily for 4 days; the treatment was given every 2 weeks (days 1 and 15 of a 28-day cycle) for the treatment of relapsed Hodgkin's and non-Hodgkin's lymphoma. Dose escalation of gemcitabine was allowed according to phase I criteria. Twenty-two patients with a median of 4 prior treatments were enrolled (Hodgkin's lymphoma, n = 7; B-cell non-Hodgkin's lymphoma, n = 9; T-cell non-Hodgkin's lymphoma, n = 6). Ten patients had relapsed after prior autologous transplantation. Grade 4 thrombocytopenia and neutropenia were the dose-limiting toxicities and occurred in 9 patients (41%) and 4 patients (18%), respectively. Initial dose escalation of gemcitabine was not possible. Responses were observed in 45% of the patients: 2 of 5 with T-cell non-Hodgkin's lymphoma (1 patient withdrew after first treatment and was evaluable only for toxicity), 4 of 7 with Hodgkin's lymphoma, and 4 of 9 with B-cell non-Hodgkin's lymphoma. The coadministration of gemcitabine 800 mg over 80 minutes with low-dose cisplatin and dexamethasone is feasible and sufficiently active in a heavily pretreated patient population with lymphoma.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/toxicidade , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/toxicidade , Dexametasona/uso terapêutico , Linfoma/tratamento farmacológico , Adulto , Idoso , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Infusões Intravenosas , Linfoma/classificação , Linfoma/patologia , Linfoma de Células B/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Grupos Raciais , Recidiva , GencitabinaRESUMO
Graft versus host disease is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Galectin-1, a mammalian lectin that modulates T cell function and apoptosis, has been shown to be immunomodulatory in animal models of autoimmune disease. We investigated the efficacy of galectin-1 in a murine model of graft versus host disease and found that 68% of galectin-1-treated mice survived, compared to 3% of vehicle-treated mice. Galectin-1-treated animals also had reduced inflammatory infiltrates in tissues compared to animals treated with vehicle alone. Galectin-1 did not affect engraftment of donor hematopoietic cells. However, galectin-1-treated animals demonstrated increased cellularity in bone marrow and spleen with increased numbers of splenic B cells and CD4 T cells compared to those animals treated with vehicle alone. Galectin-1 treatment also significantly improved reconstitution of normal splenic architecture following transplant. Production of type I cytokines interleukin-2 (IL-2) and interferon-gamma was reduced in splenocytes derived from galectin-1-treated transplanted mice when compared to animals treated with vehicle alone, while production of the type II cytokines, IL-4 and IL-10, was similar between the two groups of animals. Although splenocytes from galectin-1-treated transplanted animals responded to both third party antigens and leukemic challenge, host alloreactivity was significantly reduced when compared to cells from vehicle-treated animals. These results demonstrate that galectin-1 therapy is capable of increasing survival and suppressing the graft versus host immune response without compromising engraftment or immune reconstitution following allogeneic hematopoietic stem cell transplant.
Assuntos
Adjuvantes Imunológicos/farmacologia , Transplante de Medula Óssea/imunologia , Galectina 1/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Transplante de Medula Óssea/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Histocitoquímica , Interferon gama/biossíntese , Interferon gama/sangue , Interleucina-2/biossíntese , Interleucina-2/sangue , Interleucina-4/sangue , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos AKR , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Células Th1/efeitos dos fármacos , Células Th1/imunologiaRESUMO
Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE-/-OPN+/+, ApoE-/-OPN+/-, and ApoE-/-OPN-/- mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE-/-OPN+/+ mice, ApoE-/-OPN+/- and ApoE-/-OPN-/- mice developed less Ang II-accelerated atherosclerosis. ApoE-/- mice transplanted with bone marrow derived from ApoE-/-OPN-/- mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE-/-OPN+/+ cells. Aortae from Ang II-infused ApoE-/-OPN-/- mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE-/-OPN-/- mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.
Assuntos
Angiotensina II/farmacologia , Aneurisma da Aorta Abdominal/etiologia , Arteriosclerose/etiologia , Sialoglicoproteínas/fisiologia , Animais , Aneurisma da Aorta Abdominal/terapia , Apolipoproteínas E/fisiologia , Arteriosclerose/terapia , Movimento Celular , Sobrevivência Celular , Quimiocina CCL2/fisiologia , Citocinas/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Leucócitos/fisiologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Osteopontina , RNA Mensageiro/análise , Receptores CCR2 , Receptores de Quimiocinas/fisiologia , Sialoglicoproteínas/genéticaRESUMO
BACKGROUND: Allogeneic hematopoietic stem-cell transplant recipients often receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole and toxicity with amphotericin B, alternative prophylactic regimens have become necessary. OBJECTIVE: To compare the efficacy and safety of intravenous and oral itraconazole with the efficacy and safety of intravenous and oral fluconazole for long-term prophylaxis of fungal infections. DESIGN: Open-label, multicenter, randomized trial. SETTING: Five transplantation centers in the United States. PATIENTS: 140 patients undergoing allogeneic hematopoietic stem-cell transplantation. INTERVENTION: Itraconazole (200 mg intravenously every 12 hours for 2 days followed by 200 mg intravenously every 24 hours or a 200-mg oral solution every 12 hours) or fluconazole (400 mg intravenously or orally every 24 hours) from day 1 until day 100 after transplantation. MEASUREMENTS: Proven invasive or superficial fungal infection, drug-related side effects, mortality from fungal infection, and overall mortality. RESULTS: Proven invasive fungal infections occurred in 6 of 71 itraconazole recipients (9%) and in 17 of 67 fluconazole recipients (25%) during the first 180 days after transplantation (difference, -16 percentage points [95% CI, -29.2 to -4.7 percentage points]; P = 0.01). Superficial fungal infections occurred in 3 of 71 itraconazole recipients (4%) and in 2 of 67 fluconazole recipients (3%). In a multivariable analysis using factors known to affect the risk for invasive fungal infection after hematopoietic stem-cell transplantation, prophylaxis with itraconazole was still associated with fewer invasive fungal infections (odds ratio, 0.300 [CI, 0.111 to 0.814]; P = 0.02) caused by either yeasts or molds. More fungal pathogens were found to be resistant to fluconazole than to itraconazole. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea, or abdominal pain) in patients given itraconazole (24% vs. 9%; difference, 15 percentage points [CI, 2.9 to 27.0 percentage points]; P = 0.02), both itraconazole and fluconazole were well tolerated. The overall mortality rate was similar in each group (32 of 71 patients in the itraconazole group [45%] vs. 28 of 67 patients in the fluconazole group [42%]; difference, 3 percentage points [CI, -13.2 to 19.8 percentage points]; P > 0.2), but fewer deaths were related to fungal infection in patients given itraconazole (6 of 71 [9%]) than in patients given fluconazole (12 of 67 [18%]) (difference, 9 percentage points [CI, -20.6 to 1.8 percentage points]; P = 0.13). CONCLUSION: Itraconazole is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic hematopoietic stem-cell transplantation. Except for gastrointestinal side effects, itraconazole is well tolerated.
Assuntos
Antifúngicos/administração & dosagem , Fluconazol/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Itraconazol/administração & dosagem , Micoses/prevenção & controle , Administração Oral , Adolescente , Adulto , Antifúngicos/efeitos adversos , Antifúngicos/sangue , Feminino , Fluconazol/efeitos adversos , Humanos , Injeções Intravenosas , Itraconazol/efeitos adversos , Itraconazol/sangue , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/prevenção & controle , Análise de SobrevidaRESUMO
In this multicenter, randomized study, cytomegalovirus (CMV)-seropositive patients who received an allogeneic bone marrow transplant were provided high-dose intravenous acyclovir (500 mg/m(2) q8h) from the day of transplantation until engraftment. The patients were then randomly assigned to receive either oral valacyclovir, 2 g q.i.d. (n=83), or intravenous ganciclovir, 5 mg/kg q12h for 1 week, then 6 mg/kg once daily for 5 days per week (n=85), until day 100 after transplantation. CMV infection occurred in 12% of the patients who received valacyclovir and in 19% of the patients who received ganciclovir (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.391-2.778; P=.934). CMV disease developed in only 2 patients who received valacyclovir and in 1 patient who received ganciclovir (HR, 1.943; 95% CI, 0.176-21.44; P=.588). Oral valacyclovir can be an effective alternative to intravenous ganciclovir for prophylaxis of CMV disease after bone marrow transplantation.
Assuntos
Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Transplante de Medula Óssea , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Aciclovir/efeitos adversos , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Infecções Bacterianas/mortalidade , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/mortalidade , Feminino , Ganciclovir/efeitos adversos , Humanos , Injeções Intravenosas , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Micoses/mortalidade , Sepse/mortalidade , Análise de Sobrevida , Transplante Homólogo , Valaciclovir , Valina/efeitos adversosRESUMO
Hepcidin is a liver-made peptide proposed to be a central regulator of intestinal iron absorption and iron recycling by macrophages. In animal models, hepcidin is induced by inflammation and iron loading, but its regulation in humans has not been studied. We report that urinary excretion of hepcidin was greatly increased in patients with iron overload, infections, or inflammatory diseases. Hepcidin excretion correlated well with serum ferritin levels, which are regulated by similar pathologic stimuli. In vitro iron loading of primary human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA, suggesting that in vivo regulation of hepcidin expression by iron stores involves complex indirect effects. Hepcidin mRNA was dramatically induced by interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor alpha (TNF-alpha), demonstrating that human hepcidin is a type II acute-phase reactant. The linkage of hepcidin induction to inflammation in humans supports its proposed role as a key mediator of anemia of inflammation.
Assuntos
Proteínas de Fase Aguda/urina , Anemia/urina , Peptídeos Catiônicos Antimicrobianos/urina , Inflamação/urina , Proteínas de Fase Aguda/classificação , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/fisiologia , Estudos de Casos e Controles , Ferritinas/sangue , Hepatócitos/citologia , Hepatócitos/metabolismo , Hepcidinas , Humanos , Infecções/urina , Interleucina-1/farmacologia , Interleucina-6/farmacologia , Ferro/farmacologia , Sobrecarga de Ferro/urina , RNA Mensageiro/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Treatment with the anti-CD20 antibody rituximab prior to stem cell collection may lead to tumor-free stem cell collections in patients with B-cell lymphoma undergoing autologous stem cell transplantation. To test the feasibility of obtaining polymerase chain reaction (PCR)-negative stem cell collection, 30 patients with a variety of B-cell lymphomas were enrolled in a protocol employing a common MINE (mitoxantrone/ifosfamide/etoposide) salvage regimen with rituximab (in vivo purging). Rituximab 400 mg/m2 was administered weekly for 3 weeks on days 1, 6, and 8 in relation to the last MINE cycle, which was followed by growth factor-stimulated peripheral stem cell collection. The median number of CD34(+) cells/kg was 2.5 million cells/kg collected over a median of 5 days. Polymerase chain reaction amplification for the t (14;18) or the heavy-chain gene rearrangement was performed prior to treatment and on the leukapheresis sample. Out of 15 patients who had a positive PCR signal prior to treatment, 10 had PCR-negative stem cell collections, whereas 5 had PCR-positive stem cell collections. After high-dose chemotherapy and stem cell transplant, all patients with a PCR-positive signal pretreatment became PCR negative. We conclude that rituximab may increase the yield of tumor-free stem cells. Higher rates of PCR negativity have been reported when more intense and protracted chemoimmunotherapy regimens have been employed. The magnitude of clinical benefit and the significance of the PCR analysis in stem cells after rituximab requires larger studies.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/administração & dosagem , Ifosfamida/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Linfoma/tratamento farmacológico , Mesna/administração & dosagem , Mitoxantrona/administração & dosagem , Terapia de Salvação , Adulto , Idoso , Anticorpos Monoclonais Murinos , Antígenos CD20/biossíntese , Antígenos CD34/biossíntese , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Recidiva , Indução de Remissão , Rituximab , Células-Tronco/citologia , Fatores de TempoRESUMO
BACKGROUND: Calcification is a common complication of atherosclerosis and other chronic inflammatory processes that involves infiltration of monocytes and accumulation of macrophages. METHODS AND RESULTS: To determine whether these cells modulate vascular calcification in vitro, calcifying vascular cells (CVCs), a subpopulation of osteoblast-like cells derived from the artery wall, were cocultured with human peripheral blood monocytes for 5 days. Results showed that alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation, was significantly greater in cocultures than in cultures of CVCs or monocytes alone. Both ALP activity and matrix mineralization increased in proportion to the number of monocytes added. Activation of monocyte/macrophages (M/Ms) by oxidized LDL further increased ALP activity in cocultures. However, neither conditioned medium from oxidized-LDL-activated M/Ms or transwell coculture had this effect on CVCs, which suggests a need for cell-to-cell contact. In contrast, conditioned medium from lipopolysaccharide-activated M/Ms increased ALP activity of CVCs. ELISA showed that lipopolysaccharide-activated M/Ms secreted tumor necrosis factor-alpha, and neutralizing antibody to tumor necrosis factor-alpha attenuated the induction of ALP activity by the conditioned media. CONCLUSIONS: These results suggest that M/Ms enhance in vitro vascular calcification via 2 independent mechanisms: cell-cell interaction and production of soluble factors such as tumor necrosis factor-alpha.
Assuntos
Aorta/metabolismo , Calcinose/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Osteoblastos/enzimologia , Fosfatase Alcalina/metabolismo , Animais , Aorta/citologia , Arteriosclerose/complicações , Calcinose/complicações , Bovinos , Comunicação Celular/efeitos dos fármacos , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Lipoproteínas LDL/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Osteoblastos/citologia , Células-Tronco/citologia , Células-Tronco/enzimologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Lipid oxidation products promote atherosclerosis and may also affect osteoporosis. We showed previously that oxidized lipids including 8-isoprostaglandin E2 (isoPGE2) inhibit osteoblastic differentiation of preosteoblasts. Since osteoporosis is mediated both by decreased osteoblastic bone formation and by increased osteoclastic bone resorption, we assessed whether oxidized lipids regulate the osteoclastic potential of marrow hematopoietic cells. Treatment of marrow-derived preosteoclasts with isoPGE2 enhanced osteoclastic differentiation as evidenced by increased tartrate-resistant acid phosphatase (TRAP) activity and multinucleation, which were inhibited by calcitonin, and increased numbers of resorption pits. The enhanced osteoclastic differentiation by isoPGE2 was observed whether preosteoclasts were in coculture with stromal cells or in monoculture in the presence of receptor-activated NFkappaB ligand (RANKL) and macrophage colony-stimulating factor. Receptor antagonist studies suggest that isoPGE2 effects were mediated by prostaglandin receptor subtypes EP2/DP on preosteoclasts and subtype EP1 and thromboxane receptors on stromal/osteoblast cells. The enhanced TRAP activity was also inhibited by cAMP-dependent protein kinase inhibitors, and isoPGE2 elevated intracellular cAMP levels of preosteoclast monocultures. Other oxidized lipids also enhanced the TRAP activity of preosteoclast monocultures. These data suggest that isoPGE2 enhances osteoclastic differentiation of marrow preosteoclasts and that this regulation occurs via the cAMP-dependent protein kinase pathway.