RESUMO
The production of hematopoietic cells is under the tight control of distinct growth factors. As therapeutic agents, granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoiesis-stimulating agents (TSA) are in routine clinical use. Granulocyte colony-stimulating factor is used to prevent febrile neutropenia or to increase dose-density in chemotherapy regimens. Despite a reduced duration of neutropenia, randomized controlled trials have documented only a modest clinical benefit. A clinical advantage of dose-dense chemotherapy has been shown only in specific chemotherapy regimens. Clinical practice guidelines recommend the use of G-CSF for patients with a high risk of adverse outcome of febrile neutropenia. Erythropoiesis-stimulating agents (ESAs) are used as an alternative to blood transfusion in patients with chemotherapy-induced anemia. However, recent meta-analyses of clinical studies suggest that their use was associated with an increased risk of all-cause mortality and serious adverse events. Thrombopoiesis-stimulating agents have been introduced recently into the market for patients with immune thrombocytopenic purpura. Prior to the use of TSA in other conditions such as chemotherapy-induced thrombocytopenia the lessons learned with G-CSF and ESAs should be taken into account.
Assuntos
Anemia/etiologia , Anemia/prevenção & controle , Antineoplásicos/efeitos adversos , Fatores de Crescimento de Células Hematopoéticas/administração & dosagem , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamenteRESUMO
The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group conducted a survey to obtain information about the frequency, presentation, and treatment of mycobacterial infection (MBI) in stem cell transplant (SCT) recipients. Among 29 centers, MBI was diagnosed in 0.79% of 1513 allogeneic and 0.23% of 3012 autologous SCT recipients during 1994-1998 a median of 160 days after transplantation. The mean interval between first symptoms and diagnosis was 29 days and was still longer for patients with atypical MBI or recipients of corticosteroid therapy. The prevalence of MBI was highest among those who received matched unrelated or mismatched STCs from related donors. Of 31 patients, 20 had tuberculosis, 8 had atypical MBI, and 3 had diagnoses based on histological findings only. Five patients (16%) died, all of whom had received an allogeneic SCT. Because of the increased numbers of unmatched donors and transplantation programs in countries with a high prevalence of tuberculosis, constant vigilance is required to early detect MBI in SCT recipients.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Mycobacterium/epidemiologia , Infecções Oportunistas/epidemiologia , Tuberculose/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium/diagnóstico , Infecções Oportunistas/diagnóstico , Estudos Retrospectivos , Transplante de Células-Tronco , Tuberculose/diagnósticoRESUMO
It is unknown whether the addition of antithymocyte globulin (ATG) to reduced-intensity conditioning with busulfan (BU) and fludarabine (FLU) is beneficial in HLA-identical sibling transplantation. Therefore, we analyzed retrospectively data on 83 patients, who received peripheral blood stem cells from HLA-identical siblings after conditioning with either 8 mg/kg BU and 150 mg/m2 FLU (n=45) or 8 mg/kg BU, 180 mg/m2 FLU and 40 mg/kg ATG (n=38). Graft-versus-host disease (GVHD) prophylaxis consisted of CSA alone (n=32) or a combination with either MTX or MMF (n=51). The median age was 52 years. Graft failure occurred in two patients after BU/FLU and in three after BU/FLU/ATG (P=0.66). After conditioning with BU/FLU, platelet recovery was significantly faster (P=0.017), and less platelet (P<0.001) and red blood cell (P=0.002) support was needed. Incidences of acute GVHD grades II and IV were 46 and 49%, respectively. Limited chronic GVHD occurred more often after BU/FLU compared to BU/FLU/ATG (54 vs 23%, P=0.02). The overall survival, non-relapse and relapse mortality did not differ significantly. We conclude that in peripheral blood stem cell transplantation from HLA-identical siblings after reduced-intensity conditioning with BU and FLU, ATG has no major impact on the rate of graft rejection and acute GVHD, but it reduces the incidence of limited chronic GVHD.
Assuntos
Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Doença Aguda , Adulto , Idoso , Doença Crônica , Terapia Combinada , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/mortalidade , Hematopoese , Teste de Histocompatibilidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Transplante Homólogo , Falha de TratamentoRESUMO
Since the incidence of cytomegalovirus (CMV) infections after hematopoietic stem cell transplantation (HSCT) may depend on the intensity of the pretreatment, we studied the incidence of CMV infections after reduced-intensity compared to myeloablative conditioning. A total of 82 patients with matched related or unrelated donors were prospectively monitored for CMV infections after HSCT by CMV-PCR techniques, CMV-antigenemia and clinical observation. A total of 45 patients received reduced-intensity conditioning consisting of fludarabine, busulfan and ATG and 37 patients received myeloablative conditioning. Leukocyte engraftment occurred after a median of 15 vs 18 days (P=0.012) and platelet engraftment after 12 days vs 20 days (P=0.001), respectively. Acute graft-versus-host disease (GVHD) grade II-IV was observed in 58 vs 54% patients (P=0.737), respectively. The onset and peak values of CMV-antigenemia and DNAemia and the incidence of CMV infections did not differ statistically significantly between the two treatment groups. Multivariate analysis confirmed CMV seropositivity of the recipient (P=0.035), acute GVHD II-IV (P=0.001) but not the type of conditioning as significant risk factors for CMV-antigenemia. In conclusion, the kinetics of CMV-antigenemia and DNAemia and the incidence of CMV infections were not statistically different in patients who received HSCT after reduced-intensity conditioning with fludarabine, busulfan and ATG compared to myeloablative conditioning.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Infecções por Citomegalovirus/mortalidade , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Fosfoproteínas/sangue , Reação em Cadeia da Polimerase , Probabilidade , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Condicionamento Pré-Transplante/normas , Transplante Homólogo , Resultado do Tratamento , Proteínas da Matriz Viral/sangueRESUMO
PURPOSE: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.
Assuntos
Bussulfano/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto , Idoso , Criança , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Probabilidade , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Taxa de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
The referral of critically ill cancer patients to an intensive care unit (ICU) is a matter of controversial debate. This study was conducted by an interdisciplinary clinical group to evaluate the outcome of ICU treatment in cancer patients according to their characteristics at the time of referral. A retrospective analysis was used to identify relevant subgroups among 189 consecutive cancer patients referred as emergencies to one of four ICUs during a 2-year period. Reasons for ICU referral were pneumonia (29.6%), sepsis (27.0%), fungal infection (11.1%), another infection (9.5%), gastrointestinal emergency (16.9%), treatment-related organ toxicity (6.9%), or other, non-infectious complications (43.9%). Vasopressor support was required in 50.3%, mechanical ventilation in 49.7%, and haemodialysis/-filtration in 26.5% of the patients. Overall, 41.3% died during ICU treatment, 12.2% died after transfer from ICU to a non-ICU ward, and 35.4% were discharged alive. Sepsis, mechanical ventilation, vasopressor support, renal replacement therapy and neutropenia were independent risk factors for fatal outcome, but no single risk factor unequivocally predicted death. All patients with fungal infection who required vasopressor support and either had sepsis (n=13) or needed mechanical ventilation (n=14) died during ICU treatment, while all non-septic patients. who did not require mechanical ventilation, were younger than 74 years of age and had a non-infectious underlying complication (n=29), survived. This analysis may help to early identify relevant subgroups of cancer patients with different prognoses under ICU treatment. A prospective study to confirm the predictive usefulness of this approach is needed. Cancer patients should not be excluded from referral to the intensive care unit in an emergency solely due to their underlying malignant disease or a single unfavourable prognostic factor.
Assuntos
Cuidados Críticos , Neoplasias/terapia , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Árvores de Decisões , Emergências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/terapia , Neutropenia/terapia , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Fatores de Risco , Sepse/terapia , Análise de Sobrevida , Resultado do TratamentoAssuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Reação em Cadeia da Polimerase/normas , Toxoplasmose/diagnóstico , Animais , Humanos , Reação em Cadeia da Polimerase/métodos , Estudos Prospectivos , Controle de Qualidade , Kit de Reagentes para Diagnóstico/normas , Toxoplasmose/epidemiologiaRESUMO
OBJECTIVE: A new quantitative polymerase chain reaction (real-time PCR) was designed to detect Toxoplasma DNA in human body fluid samples. METHODS: Real-time fluorescence detection of amplification product formation on the basis of the TaqMan-System was established with Toxoplasma 18S rDNA as a target gene. RESULTS: The method provides a high sensitivity comparable to conventional nested PCR procedures and generates quantitative data when detecting toxoplasmic DNA in human blood, cerebrospinal or amniotic fluid. Moreover, data were obtained investigating blood samples from an immunocompromised patient with reactivated toxoplasmosis after allogeneic bone marrow transplantation, monitoring the therapeutic effect. CONCLUSIONS: The potential application of this method to detect Toxoplasma DNA in body fluids and to follow the development of parasitemia under therapy could be demonstrated.
Assuntos
Líquidos Corporais/parasitologia , DNA de Protozoário/análise , Reação em Cadeia da Polimerase/métodos , Toxoplasma/isolamento & purificação , Toxoplasmose/parasitologia , Animais , Transplante de Medula Óssea/efeitos adversos , Humanos , Taq Polimerase/metabolismo , Toxoplasma/genéticaRESUMO
A combined PCR assay was developed for the detection and typing of human polyomavirus (huPoV) in clinical samples, consisting of (i) a qualitative seminested PCR assay (snPCR) to discriminate between huPoV BK and JC and (ii) a high-throughput, quantitative TaqMan PCR assay (TM-PCR) for the general detection of huPoV. The TM-PCR detects huPoV DNA in a linear range from 10(7) to 10(1) copies per assay. In reproducibility runs, the inter- and intra-assay variabilities were < or =60 and < or =50%, respectively. The snPCR assay uses a set of four primers for the same region of the BK and JC viral genomes. In the first round of amplification, two general primers were used; in the second round, one of these general primers and two additional, BK- or JC-specific primers were used simultaneously to produce amplicons of different sizes specific for BK virus (246 bp) and JC virus (199 bp), respectively. We tested different urine dilutions in order to determine the inhibitory effects of urine on PCR amplification. Furthermore, we compared the use of native urine with DNA purified by different preparation procedures. Our results show, that a 1:10 dilution of the urine led to complete reduction of the amplification inhibition found with 6% of undiluted urine samples. In a clinical study including 600 urine specimens, our assay turned out to be fast, cheap, and reliable in both qualitative and quantitative aspects.
Assuntos
Vírus BK/classificação , Transplante de Medula Óssea , Vírus JC/classificação , Reação em Cadeia da Polimerase/métodos , Urina/virologia , Vírus BK/isolamento & purificação , Calibragem , Primers do DNA , DNA Viral/urina , Humanos , Vírus JC/isolamento & purificação , Plasmídeos , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Transplante HomólogoRESUMO
Hemorrhagic cystitis (HC) is a common complication following high-dose chemotherapy and bone marrow transplantation, and the treatment of virus-associated HC remains to be optimized. This is the first report on the successful use of cidofovir in a patient with HC and polyoma viruria concomitant with CMV reactivation after allogeneic BMT. Treatment led to a significant decrease in viruria and to sustained suppression of CMV reactivation. Administered with probenecid and hydration, cidofovir was well tolerated, and there were no side-effects.
Assuntos
Antivirais/uso terapêutico , Vírus BK , Cistite/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Citomegalovirus/crescimento & desenvolvimento , Citosina/uso terapêutico , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Cidofovir , Cistite/virologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/urina , Citosina/análogos & derivados , Hematúria/etiologia , Hematúria/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/urina , Ativação Viral/efeitos dos fármacosRESUMO
Toxoplasmosis in bone marrow transplant recipients is a rare but serious complication and if untreated, almost uniformly fatal. The diagnosis, however, remains difficult. We therefore compared serial determination of antibody titers specific for T. gondii before and after transplantation, serial PCR for T. gondii DNA in serum, PCR and nested PCR for T. gondii DNA in various tissues, conventional histology and immunohistochemistry for detection of parasites in three patients with autopsy-confirmed toxoplasmosis after bone marrow transplantation. Immunohistochemistry demonstrated the presence of parasites in 13 out of 20 organs investigated (65%), whereas PCR detected T. gondii-specific DNA in 15 out of 20 organs (75%). Immunohistochemistry revealed concordant results to PCR data in 60% of the specimens. With the use of a nested PCR protocol, eight out of nine samples (89%) were positive for T. gondii-specific DNA. The combination of both methods detected the presence of parasites in 90% of the specimens. Serial PCR in serum did not yield positive results. Neither PCR nor immunohistochemistry was able to detect parasites in all organs investigated, but both methods together improved sensitivity to 90% and consequently, should be used jointly to maximize diagnostic precision. Bone Marrow Transplantation (2000) 25, 1257-1262.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Toxoplasma/isolamento & purificação , Toxoplasmose/diagnóstico , Toxoplasmose/etiologia , Adulto , Animais , Humanos , Imuno-Histoquímica , Masculino , Reação em Cadeia da Polimerase , Transplante HomólogoRESUMO
Therapy with colony-stimulating factors has been extended beyond their use in accelerating myeloid cell recovery to take advantage of their immune function-enhancing properties. Studies in animal models and with human subjects suggest a potential role as adjunctive therapy in infections of non-neutropenic hosts, including those with sepsis. Granulocyte colony-stimulating factor may play a pivotal role in the induction of lipopolysaccharide desensitization by nontoxic lipid A analogues proposed for the prevention of sepsis; granulocyte macrophage colony-stimulating factor may be useful in reversing the immune paralysis described in later stages of sepsis. Significant issues of exogenous colony-stimulating factor therapy must be addressed, however: the optimal timing, dose, and clinical context (e.g., type of immunosuppression, duration of infection-inciting stimulus) as well as tissue-specificity of the activities and net effect of potentially conflicting responses (e.g., immune restorative and procoagulant effects of granulocyte macrophage colony-stimulating factor). Resolution of these issues will require carefully designed clinical studies with meticulous monitoring of immunologic parameters.
Assuntos
Infecções Bacterianas/prevenção & controle , Fatores de Crescimento de Células Hematopoéticas/fisiologia , Sepse/prevenção & controle , Animais , Fator Estimulador de Colônias de Granulócitos/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Humanos , Fator Estimulador de Colônias de Macrófagos/fisiologia , Neutropenia/prevenção & controleRESUMO
When given in the presence of gamma interferon (IFN-gamma), otherwise nontoxic doses of lipopolysaccharide (LPS or endotoxin) become highly lethal for mice. The mechanisms of this synergistic toxicity are not known. We considered the possibility that an interaction between the LPS-induced NF-kappaB and IFN-gamma-induced JAK-STAT pathways at the pretranscriptional level may enhance the LPS-induced signals. To test this hypothesis, we incubated murine macrophage RAW 264.7 cells with IFN-gamma for 2 h before addition of different doses of LPS. Consistent with the synergistic induction of inducible nitric oxide synthase mRNA and nitric oxide production by a combination of LPS and IFN-gamma, IFN-gamma strongly augmented LPS-induced NF-kappaB activation and accelerated the binding of NF-kappaB to DNA to as early as 5 min. In agreement with this, IFN-gamma pretreatment promoted rapid degradation of IkappaB-alpha but not that of IkappaB-beta. Inhibition of protein synthesis during IFN-gamma treatment suppressed LPS-initiated NF-kappaB binding. A rapidly induced protein appeared to be involved in IFN-gamma priming. Preincubation of cells with antibodies to tumor necrosis factor alpha or the interleukin-1 receptor partially reduced the priming effect of IFN-gamma. In a complementary manner, LPS enhanced the activation of signal-transducing activator of transcription 1 by IFN-gamma. These data suggest novel mechanisms for the synergy between IFN-gamma and LPS by which they cross-regulate the signal-transducing molecules. Through this mechanism, IFN-gamma may transform a given dose of LPS into a lethal stimulus capable of causing sepsis. It may also serve a beneficial purpose by enabling the host to respond quickly to relatively low doses of LPS and thereby activating antibacterial defenses.
Assuntos
Adjuvantes Imunológicos/fisiologia , Proteínas I-kappa B , Interferon gama/fisiologia , Interleucina-1/fisiologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/imunologia , Linhagem Celular , Cicloeximida/farmacologia , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/imunologia , Inibidores da Síntese de Proteínas/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Alveolar macrophages (AM) play an important role in antimicrobial defense mechanisms of the lung. It therefore seems reasonable to use macrophage colony-stimulating factor (M-CSF) to enhance local resistance mechanisms. However, little is known about the in vivo activity of M-CSF on macrophages in various organs. We determined the effect of a single subcutaneous dose of M-CSF (10, 50, 100, and 500 ng, respectively) on the number and functional status of AM as well as of macrophages in liver and spleen of mice. Organs were investigated immunohistochemically on days 1 and 3 after injection using monoclonal antibodies specific for F4/80, Ia antigen, and MAC-1. We found a significant increase in the number of F4/80+ AM, Kupffer cells, and splenic macrophages reaching its maximum 24 h after injection of low doses (10 and 50 ng per mouse, respectively) of M-CSF and decreasing to a level seen in untreated mice at 72 h after M-CSF in liver and spleen, whereas at a dose of 50 ng per mouse the number of AM remained high. In contrast, the numbers of AM, Kupffer cells, and splenic macrophages did not increase significantly when high doses were used (500 ng). The expression of Ia antigen and MAC-1 was increased on macrophages in the spleen but not on AM or Kupffer cells. TNF-alpha was elevated in bronchoalveolar (BAL) fluid after 3 h and IL-6 at 6, 12, and 24 h after M-CSF injection in dose-dependent manner. Nitric oxide production was not increased after injection of M-CSF. Our results point to regional differences in the response of macrophages to M-CSF. These may caused by differences in the M-CSF-induced production of TNF-alpha and IL-6. These findings may be important for the therapeutic use of M-CSF in microbial infections.