RESUMO
PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Feminino , Citometria de Fluxo , Genes bcl-2 , Humanos , Linfoma Folicular/imunologia , Linfoma Folicular/mortalidade , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Rituximab , Subpopulações de Linfócitos T/imunologia , Vidarabina/efeitos adversosRESUMO
Percutaneous coronary intervention of chronic total occlusions (CTO) is associated with a significantly higher incidence of reocclusion and restenosis compared with non-total occlusions. Randomized and observational trials have demonstrated the effectiveness of intracoronary brachytherapy (ICBT) for the prevention of recurrent in-stent restenosis. However, limited data are available on the effectiveness of ICBT in patients with totally occluded in-stent restenosis. The authors assessed the long-term outcome of patients treated with intracoronary gamma radiation for totally occluded in-stent restenotic lesions. Percutaneous coronary intervention and subsequent catheter-based irradiation with iridium-192 was performed in 100 patients (103 vessels) with diffuse in-stent restenosis. At baseline, CTO of the target vessel at the site of the stent was present in 15 vessels (14.5%). Follow-up data were collected during follow-up visits and from telephone interviews. Repeat coronary angiography was performed in symptomatic patients with clinical restenosis. Clinical and angiographic characteristics were similar between the two groups, although there was a trend towards more unstable angina at the index procedure in CTO patients (66.7% versus 41.4%; p = 0.12) compared with patients without non-total occlusions. A higher percentage of patients (53.3%) with CTO required longer radiation sources (14 seeds, covering a length of 55 mm), compared with 23.9% of patients with non-total occlusion (p = 0.04). With a mean follow-up period of 47.5 +/- 24.0 months, major adverse cardiac events (MACE) were observed in 10 of 15 patients (66.7%) with CTO compared with 25 out of 88 patients (28.4%) without CTO (p = 0.009). According to multivariate analysis, total occlusion of the target vessel at baseline was the single independent predictor of MACE at one-year follow-up (relative risk 16.2, 95% confidence interval 4.2-62.9; p < 0.0001). This study shows that the use of gamma radiation for the prevention of recurrence of in-stent restenosis in patients with CTO does not seem to be as effective as in patients with non-total occlusions. Furthermore, CTO was an independent predictor of worse outcome at long-term follow-up in this study.
Assuntos
Braquiterapia/métodos , Reestenose Coronária/radioterapia , Stents , Angiografia Coronária , Feminino , Seguimentos , Humanos , Radioisótopos de Irídio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos , Fatores de TempoRESUMO
We examined the incidence, risk factors and associated mortality of acute renal failure requiring dialysis (Renal Bearman Grade [BG] 3) in a 3-year cohort of 97 consecutive allogeneic blood and marrow transplantation (alloBMT) patients. In all, 20 (21%) developed Renal BG3 (all died by day +132) and 77 (79%) developed renal insufficiency (Renal BG1-2). Renal BG3 was a contributing or primary cause of death in 18 (90%) patients who continued to require dialysis at time of death. The two Renal BG3 patients whose deaths were not related to renal failure died on day +103 of hemorrhage and day +132 of underlying disease. By univariate analysis, age, unrelated donor, veno-occlusive disease (VOD) and grade III-IV acute graft-versus-host disease with hepatic involvement were significantly associated with Renal BG3. The multivariate model of time to Renal BG3 determined only a prior diagnosis of severe acute GVHD (RR=4.1, 95% CI 1.6-10.3, P=0.003) and VOD (RR=9.1, 95% CI 3.5-23.7, P<0.001) as significant independent predictors. Renal BG3 is generally considered a conditioning regimen-related toxicity. This study demonstrates that Renal BG3 is most commonly a complication of hepatic co-morbidities after allogeneic blood and marrow transplantation and identifies patients with a very poor prognosis.
Assuntos
Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Transfusão de Sangue/métodos , Transplante de Medula Óssea , Injúria Renal Aguda/mortalidade , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/terapia , Hepatopatia Veno-Oclusiva/prevenção & controle , Hepatopatia Veno-Oclusiva/terapia , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Rituximab is used for in vivo tumor cell purging for non-Hodgkin's lymphoma (NHL) patients prior to autologous peripheral blood stem cell transplantation (PBSCT). However, its effects on PBSC mobilization and function are poorly understood. We compared the mobilization characteristics and engraftment kinetics of 13 NHL patients receiving and 34 NHL patients not receiving rituximab 6 months before PBSC mobilization. In the rituximab group, there was a significantly longer time to neutrophil engraftment (P=0.0466), a trend toward the need for BM harvest to supplement low-yield PBSC collections (31 vs 9%, P=0.08) and a significantly increased rate of bacteremia episodes (62 vs 26%, P=0.025). Median progression-free survival (PFS) and overall survival (OS) were significantly longer in the rituximab compared to the nonrituximab patients (P=0.049 and 0.042, respectively). However, patients in the nonrituximab group were at high risk for recurrence and expected to have shorter survival. Rituximab used within 6 months prior to collection may have a detrimental effect on PBSC mobilization and engraftment. However, rituximab is a major therapeutic breakthrough for NHL treatment and this negative effect may be offset by improved survival. Further studies are warranted in larger populations to determine the impact of rituximab on engraftment, PFS and OS.
Assuntos
Anticorpos Monoclonais/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Mobilização de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/terapia , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Bacteriemia/induzido quimicamente , Estudos de Coortes , Avaliação de Medicamentos , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Recidiva , Rituximab , Análise de SobrevidaRESUMO
Respiratory syncytial virus (RSV) infection is an important cause of respiratory mortality in immunosuppressed patients, including bone marrow transplant (BMT) recipients. The presence of lower respiratory tract infection and infection in the pre-engraftment phase of BMT is believed to confer a poor prognosis. Three patients who underwent allogeneic BMT at our institution developed RSV pneumonia over 1 year post BMT, with the underlying disease in remission. All three were hypoxic with extensive pulmonary disease at presentation. Treatment consisted of aerosolized ribavirin and intravenous immune globulin with successful clearing of viral shedding and excellent clinical outcomes. RSV infection is probably less severe in the late post-BMT period, but needs to be considered early in the differential diagnosis of pulmonary infiltrates in this patient population.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Vírus Respiratório Sincicial/etiologia , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Ribavirina/administração & dosagem , Fatores de Tempo , Transplante Homólogo/efeitos adversosRESUMO
This retrospective cohort study of 462 consecutive adult allogeneic and autologous blood or marrow transplantation (BMT) patients compared the incidence of hepatic veno-occlusive disease (VOD) after BMT with three prophylactic regimens. Patients receiving heparin (Hep), heparin + prostaglandin E1 (Hep + PGE1) or low molecular weight heparin (LMWH) as a prophylactic VOD regimen were compared to a historical cohort receiving no VOD prophylaxis. Of 462 BMT patients, VOD was diagnosed in 22% (31 of 142) of the no prophylaxis group, 11% (11 of 104) of the Hep, 12% (13 of 110) in the Hep + PGE1 and 4% (four of 106) of the LMWH group (P = 0.0002). VOD was the primary cause of death in 20% (12 of 59). By multivariate logistic regression, independent risk factors for developing VOD were: no VOD prophylactic regimen, unrelated allogeneic BMT, Karnofsky performance score (KPS) < 80 and aspartate aminotransferase (AST) > or =50 U/l. There was no increase in the rate of death due to hemorrhagic events or VOD in any prophylaxis group compared to the control group. Prospective randomized trials of Hep vs LMWH vs placebo are warranted to assess the efficacy of heparin compounds in the prevention of VOD.
Assuntos
Transfusão de Sangue , Transplante de Medula Óssea , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/prevenção & controle , Adulto , Idoso , Estudos de Coortes , Dinoprostona/administração & dosagem , Feminino , Heparina/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Type 1 von Willebrand disease (vWD) is generally regarded clinically as 'mild' and the obstetrical-gynaecological features have not been fully described. We administered a patient questionnaire and provider survey of the medical and quality of life aspects of childbirth and menstruation to 99 type 1 vWD patients and compared the patients presently menstruating (n=81) to a cohort of 150 menstruating females in the general population. The following measurements had a statistically higher proportion in the vWD group: number of tampons/towels used for a typical menstrual cycle (P=0. 002); percentage reporting that clothes are stained by menses (P = 0. 001); past or present history of anaemia (P = 0.001); childbirth-related bleeding (P=0.001); and childbirth-related bleeding necessitating RBC transfusion (P=0.002). Quality of life assessment of the impact of menses in both of the above cohorts was measured by a Likert scale using seven quality of life parameters. Compared to the control group, the vWD patients had a significantly higher score, with P-values of < 0.0001 for each parameter. Hormonal interventions for menorrhagia in the vWD patients were < or = 50% effective. Menorrhagia resulted in red blood cell transfusions in 6% of patients, dilatation and curettage in 17% and hysterectomy in 13%. Despite the common connotation of type 1 vWD as clinically 'mild', childbirth and the monthly challenge to haemostasis presented by menstruation result in a substantial degree of morbidity in females with type 1 vWD. These results support the rationale for ongoing international efforts to increase awareness of vWD as a cause for menorrhagia and to improve the quality of life in females with known vWD.
Assuntos
Doenças dos Genitais Femininos/fisiopatologia , Genitália Feminina/fisiopatologia , Doenças de von Willebrand/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Feminino , Doenças dos Genitais Femininos/etiologia , Humanos , Trabalho de Parto , Menstruação , Pessoa de Meia-Idade , Gravidez , Qualidade de Vida , Inquéritos e Questionários , Doenças de von Willebrand/complicaçõesRESUMO
PURPOSE: The drastic increase in the incidence of non-Hodgkin's lymphoma in patients infected with HIV-1 is testimony to the fact that our immune system is critical for the prevention of certain malignancies. Preclinical and clinical studies were conducted to (1) gain further insight into defects in immunity that can lead to malignant transformation and (2) determine if certain immune deficiencies could be corrected by cytokines delivered at doses that result in near-physiologic concentrations in vivo. METHODS: We have used the severe combined immune deficient mouse engrafted with human peripheral blood leukocytes from healthy individuals who are seropositive for the Epstein-Barr virus to study the spontaneous development of malignant Epstein-Barr virus-positive human B-cell lymphoproliferative disorder. RESULTS: We have demonstrated in this model that, in the absence of CD4+ T cells, cytokine replacement with low-dose interleukin (IL)-2 therapy can prevent Epstein-Barr virus-positive human B-cell lymphoproliferative disorder by interacting with mouse natural killer and human CD8+ T cells. We review our clinical experience with administration of low-dose IL-2 therapy in patients with HIV-1-related cancer, noting minimal toxicity and significant immune modulation. We provide evidence that this therapy can favorably alter the type 1 cytokine profile in vivo in these patients, and improve the cellular response to infectious insults in vitro. CONCLUSION: Early clinical studies with low-dose IL-2 therapy in patients with HIV-1-related lymphoma suggest that this therapy may have a role in the prevention and treatment of this disease.
Assuntos
HIV-1 , Interleucina-2/uso terapêutico , Linfoma Relacionado a AIDS/terapia , Animais , Humanos , Interferon gama/biossíntese , Interleucina-2/efeitos adversos , Células Matadoras Naturais/imunologia , Linfoma Relacionado a AIDS/imunologia , Camundongos , Camundongos SCIDRESUMO
OBJECTIVE: Kaposi's sarcoma, the most common malignancy in AIDS patients, often presents with painful cutaneous lesions that are difficult to treat effectively despite a wide variety of therapeutic approaches. We used photodynamic therapy in an attempt to provide effective palliative treatment for this disease. METHODS: Photodynamic therapy utilizes the activation by light of a photosensitizing drug that preferentially accumulates in tumor tissue such as Kaposi's sarcoma. We enrolled 25 patients who received 1.0 mg/kg of Photofrin 48 h before exposure to 100-400 J/cm2 of 630 nm light. RESULTS: Of the 348 lesions treated, 289 were evaluable: 32.5% had complete clinical response, 63.3% had partial clinical response and 4.2% were clinical failures. There was a strong correlation between response and light dose: 54% of lesions achieved a complete clinical response at optimum light dose (> 250 J/cm2). There was no correlation of response with CD4 cell count nor was there a change in CD4 cell count post-treatment. At 400 J/cm2 full field scabbing and necrosis occurred in 90% of the treated fields. Thus, the maximum tolerated dose was determined to be 300 J/cm2. At light doses of 250 J/cm2 and below the toxicities were limited to erythema and edema in the treatment field. Forty-three biopsies were taken 0.5 h to 4 months post-treatment. These showed little change in the B and T cell infiltrates identified. Kaposi's sarcoma cells disappeared post-treatment in certain lesions. CONCLUSION: Photofrin is effective palliative treatment for HIV-associated Kaposi's sarcoma.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Éter de Diematoporfirina/uso terapêutico , Fotoquimioterapia , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Humanos , Masculino , Cuidados Paliativos , Fotoquimioterapia/efeitos adversos , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologiaRESUMO
The combination of carmustine, cisplatin, dacarbazine, interferon, and low-dose tamoxifen is widely used in treating metastatic melanoma and was originally reported to achieve a 20% complete response rate. Among 29 patients who completed the authors' phase II study with the regimen, five (17%) achieved complete remission, and the median duration of response was 8 months (range, 2-14 months). The aim of the study was to evaluate briefly the value and toxicity of this regimen in treating metastatic malignant melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/secundário , Carmustina/administração & dosagem , Cisplatino/administração & dosagem , Dacarbazina/administração & dosagem , Feminino , Humanos , Interferon-alfa/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Tamoxifeno/administração & dosagemRESUMO
Human NK cells have been shown to produce cytokines (e.g., IFN-gamma and TNF-alpha) and the chemokine macrophage inflammatory protein (MIP)-1alpha following stimulation with the combination of two monokines, IL-15 plus IL-12. The C-C chemokines MIP-1alpha, MIP-1beta, and RANTES have been identified as the major soluble macrophage-tropic HIV-1-suppressive factors produced by CD8+ T cells, which exert their action at the level of viral entry. Here, we demonstrate that monokine-activated NK cells, isolated from both normal and HIV-1+ donors, produce similar amounts of MIP-1alpha, MIP-1beta, and RANTES protein, in vitro. Further, supernatants of monokine-activated NK cells obtained from both normal donors and AIDS patients showed potent (routinely > or = 90%) suppressive activity against HIV-1 replication in vitro, compared with unstimulated control supernatants. NK cell supernatants inhibited both macrophage-tropic HIV-1(NFN-SX) and T cell-tropic HIV-1(NL4-3) replication in vitro, but not dual-tropic HIV-1(89.6). Importantly, the C-C chemokines MIP-1alpha, MIP-1beta, and RANTES were responsible only for a fraction of the HIV-1-suppressive activity exhibited by NK cell supernatants against macrophage-tropic HIV-1. Collectively these data indicate that NK cells from normal and HIV-1+ donors produce C-C chemokines and other unidentified factors that can inhibit both macrophage- and T cell-tropic HIV-1 replication in vitro. Since NK cells can be expanded in patients with HIV-1, AIDS, and AIDS malignancy in vivo, this cell type may have an important role in the in vivo regulation of HIV-1 infection.
Assuntos
Quimiocinas CC/biossíntese , Soropositividade para HIV/imunologia , HIV-1/imunologia , Tolerância Imunológica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Sistema Livre de Células/imunologia , Células Cultivadas , Soropositividade para HIV/virologia , HIV-1/fisiologia , Humanos , Ativação Linfocitária , Macrófagos/imunologia , Macrófagos/virologia , Linfócitos T/imunologia , Linfócitos T/virologia , Replicação Viral/imunologiaRESUMO
Proglumide, a cholecystokinin (CCK) antagonist, has been shown to have agonist effects at extremely low doses on both endogenous and exogenous opioid systems. To determine the effectiveness and the side effects of proglumide as an opioid agonist, a double-blind crossover study was conducted in 60 patients with cancer pain who were treated with opioid analgesics. Forty-three patients completed both treatment arms: (a) full analgesic dose plus placebo (the patient's usual analgesic dose, individualized to drug dose and route) and (b) one-half analgesic dose plus 50 mg of proglumide. An analysis of eight pain descriptors was performed to determine whether or not these treatments were associated with a difference in patients' pain perception. The level of patient anxiety differed between the two arms, but was inconsistent over time. There were no side effects detected with proglumide, as determined by clinical monitoring and patient questionnaire. No differences in pain perception were detected between the study arms. The latter finding is consistent with an augmentation of morphine analgesia, but without additional controls, the equivalency of the two arms cannot be determined with certainty. Nonetheless, this study suggests that proglumide may have use as an opioid adjunct in patients with cancer pain.
Assuntos
Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Neoplasias/complicações , Dor/tratamento farmacológico , Proglumida/uso terapêutico , Receptores da Colecistocinina/antagonistas & inibidores , Estudos Cross-Over , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Dor/etiologiaRESUMO
BACKGROUND: The T-cell stimulatory function of accessory cells isolated from peripheral blood lymphocytes of AIDS patients has been reported to be suppressed. These patients also have elevated levels of the immunosuppressive factor transforming growth factor (TGF)-beta1 in their serum and plasma. OBJECTIVE: To explore the role of TGF-beta1 in the loss of accessory cell function of peripheral blood lymphocytes from AIDS patients. METHODS: Fluorescent labeled anti-TGF-beta1 and confocal microscopy were used to detect the presence of TGF-beta1 on the cell membrane of dendritic cells. To assess the role of TGF-beta1 in the inhibition of accessory cell function in AIDS, antibodies against TGF-beta1 or the TGF-beta1 type III receptor, beta-glycan, were added to a mixed lymphocyte reaction. RESULTS: TGF-beta1 was detected on the cell membrane of dendritic cells isolated from AIDS patients. The addition of blocking antibodies against either TGF-beta1 or beta-glycan restored the T-cell stimulatory function to accessory cells from these patients. CONCLUSIONS: T-cell stimulatory function was not irreversibly lost in AIDS patients. Our data suggested that beta-glycan-TGF-beta1 immunosuppressive complexes may contribute to the suppression of accessory cell function in these patients.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Células Apresentadoras de Antígenos/imunologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/fisiologia , Anticorpos/imunologia , Células Dendríticas/química , Células Dendríticas/imunologia , Humanos , Tolerância Imunológica , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Testes de Neutralização , Proteoglicanas/imunologia , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta/imunologia , Tripsina/farmacologiaRESUMO
This study was undertaken to determine if prolonged daily subcutaneous administration of ultra low dose IL-2 could influence the constitutive endogenous production of a type 1 (IFN-gamma) cytokine in patients with AIDS or AIDS-associated malignancies. Using a quantitative reverse transcription PCR assay, we demonstrate that daily administration of one type 1 cytokine, IL-2, for 3 mo increases significantly the constitutive endogenous gene expression of another type 1 cytokine, IFN-gamma, in vivo. The predominant source of IFN-gamma appears to be IL-2-expanded natural killer cells and CD8(+) T cells. Moreover, PBMC obtained from these patients during IL-2 therapy showed normalization of a profound deficit in IFN-gamma protein production after stimulation with extracts from infectious agents in vitro. Our data suggest that prolonged exogenous administration of a type 1 cytokine in a nontoxic fashion to patients with AIDS and AIDS-associated malignancies can enhance significantly the endogenous type 1 cytokine profile in vivo. Consequently, ultra low dose IL-2 therapy has the potential to improve the immunodeficient hosts' immune response to infectious pathogens that require IFN-gamma for clearance.
Assuntos
Síndrome da Imunodeficiência Adquirida/terapia , Interferon gama/metabolismo , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Linfoma Relacionado a AIDS/terapia , Sarcoma de Kaposi/terapia , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/metabolismo , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citometria de Fluxo , Expressão Gênica , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido/efeitos dos fármacos , Hospedeiro Imunocomprometido/imunologia , Imunoterapia/métodos , Interferon gama/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/imunologia , Contagem de Linfócitos , Linfoma Relacionado a AIDS/imunologia , Linfoma Relacionado a AIDS/metabolismo , Reação em Cadeia da Polimerase , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/metabolismo , Subpopulações de Linfócitos T/imunologiaRESUMO
BACKGROUND: The objective of this study was to develop and test a combined therapeutic approach for patients with AIDS-related lymphoma (ARL), employing agents with independent mechanisms of action and nonoverlapping toxicity. This study was designed to test the feasibility and tolerance of combining low dose chemotherapy with infusional immunotoxin in the treatment of ARL patients. METHODS: Previously untreated patients received low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, and vincristine (m-BACOD) on a 21- to 28-day schedule. Patients who did not have progressive disease by Cycle 3 received anti-B4-blocked ricin (anti-B4bR), a murine monoclonal antibody linked to modified ricin, 20 microg/kg/day for 7 days administered by continuous infusion on an outpatient basis. A repeat cycle of anti-B4-bR was administered during Cycle 4 of chemotherapy based on tolerance. Patients received two cycles of chemotherapy beyond complete remission up to eight cycles. Study endpoints were toxicity, development of human antimurine antibody (HAMA) and human antiricin (HARA), tumor response, and survival. RESULTS: Twenty-six of 44 patients received the immunotoxin therapy. Anti-B4-bR infusion was associated with transaminase elevation (Grade 3) in 14 of 26 patients (58%), and flulike symptoms were common. HAMA or HARA was observed in 8 patients (31%). The overall response rate was 57% (13 complete responses and 12 partial responses). The median survival for all patients was 8.9 months. CONCLUSIONS: This study demonstrates the safety and feasibility of using chemotherapy and immunotoxin therapies in combination and supports their further evaluation to improve the outcomes of patients with ARL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunotoxinas/uso terapêutico , Linfoma Relacionado a AIDS/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imunotoxinas/efeitos adversos , Leucovorina/administração & dosagem , Linfoma Relacionado a AIDS/mortalidade , Masculino , Metotrexato/administração & dosagem , Ricina/imunologia , Vincristina/administração & dosagemRESUMO
The poor prognosis associated with patients afflicted with the acquired immunodeficiency syndrome and primary central nervous system lymphoma (AIDS-PCNSL) is due in part to the intrinsic resistance of this Epstein-Barr virus (EBV)-associated tumor to conventional antineoplastic therapy. Fas (CD95) is a transmembrane protein receptor that transmits an intracellular signal leading to rapid programmed cell death following ligation with its natural ligand or anti-Fas antibodies. Fas expression and function were assessed in AIDS-PCNSL biopsy samples and in EBV+ human B-cell tumors that spontaneously developed in severe combined immune deficient (SCID) mice engrafted with human lymphocytes (hu-PBL-SCID mice). All tumors samples showed high-density surface expression of Fas by flow cytometry or immunohistochemical staining. Cells from two AIDS-PCNSL biopsy samples that did not express pan B-cell markers did not express Fas antigen. All tumors examined were susceptible to Fas-mediated apoptosis, as measured by standard assays for endonucleolytic cleavage of DNA. The response to Fas-mediated apoptosis was dependent on log-fold increases in the concentration of immobilized anti-Fas antibody, but could also be induced with a mobilized anti-Fas antibody. No evidence for intrinsic resistance to Fas-mediated apoptosis (ie, secreted or truncated forms of Fas) could be shown. Radiation-induced apoptosis of neoplastic EBV+ B cells was enhanced by activation of Fas, and prolonged exposure to interleukin-2 increased both Fas expression and Fas-induced apoptosis. As the normal brain parenchyma appears to have either low-density or absent expression of Fas, and antineoplastic therapy can be selectively delivered to the CNS with little systemic toxicity, local delivery of Fas-activating molecules could prove to be a useful component in the multimodal treatment of AIDS-PCNSL.
Assuntos
Neoplasias Encefálicas/imunologia , Linfoma Relacionado a AIDS/imunologia , Receptor fas/análise , Animais , Neoplasias Encefálicas/patologia , Citometria de Fluxo , Humanos , Linfoma Relacionado a AIDS/patologia , Camundongos , Camundongos SCID , Receptor fas/imunologiaRESUMO
We have earlier reported that patients suffering from acquired immuno-deficiency syndrome (AIDS), systemic lupus erythematosus (SLE) with vasculitis, Wegner granulomatosis and certain types of late stage cancer have interferon inhibitory activity in their serum. The purpose of this study was to identify the factor(s) involved in this interferon inhibitory activity. Twenty patients with advanced AIDS, twenty patients with SLE and vasculitis and twenty normal healthy controls between ages 25-40 years were studied. In contrast to normal, healthy controls, significant interferon inhibitory activity was found in AIDS and SLE patients. This appears to be largely due to: (a) increased soluble circulating interferon alpha/beta receptors, (b) increased prostaglandin E2 levels which inhibits interferon and (c) a interferon inhibitory protein. Further understaging of the nature of interferon inhibitory activity in the patient's sera and development of anti-interferon inhibitory agents would greatly enhance interferons potential as a treatment modality.
Assuntos
Síndrome da Imunodeficiência Adquirida/sangue , Interferons/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/sangue , Vasculite/sangue , 3',5'-AMP Cíclico Fosfodiesterases/sangue , Adulto , Anticorpos/sangue , Anticorpos/fisiologia , Dinoprostona/sangue , Feminino , Humanos , Interferons/imunologia , Lúpus Eritematoso Sistêmico/complicações , Masculino , Receptores de Interferon/sangue , Vasculite/complicaçõesRESUMO
PURPOSE: Congenital, acquired, and some iatrogenically induced immune deficiencies are characterized by an increased incidence of viral-associated cancers. Preclinical and clinical studies were conducted to understand the pathogenesis of immune-deficiency-associated cancer and its response to low-dose recombinant interleukin-2 (rIL-2) therapy, with the ultimate goal of applying this or other immune therapy in the treatment or prevention of immune-deficiency-associated lymphoma. METHODS: We have used the severe combined immune-deficient (SCID) mouse engrafted with human peripheral blood lymphocytes (PBL) from healthy Epstein-Barr virus seropositive donors to study the pathogenesis of malignant B-cell lymphoproliferative disease that commonly occurs in some immune-deficient patients. In this chimeric human (hu)-PBL-SCID mouse model, administration of daily low-dose rIL-2 interacts with murine natural killer cells and human CD8+ T cells to prevent the outgrowth of human Epstein-Barr virus lymphoproliferative disease. We have utilized the information gained from this chimeric mouse model to perform a phase I study of daily, subcutaneous, low-dose rIL-2 therapy in patients with both acquired immune deficiency syndrome (AIDS) and cancer. RESULTS: Plasma concentrations of rIL-2 were achieved in vivo comparable to those seen in our hu-PBL-SCID model, in the absence of significant (grade 3) clinical toxicity or an increase in the plasma human immune deficiency virus (HIV) RNA level. Significant expansion in human cells, particularly the CD3-CD56bright natural killer cell subset, resulted after 6 weeks of therapy. Results of the hu-PBL-SCID mouse model and the phase I study have led to a national trial of low-dose rIL-2 therapy in AIDS-associated lymphoma. CONCLUSION: Daily low-dose rIL-2 therapy may be effective in treating or preventing AIDS-associated lymphoma without amplifying HIV replication.
Assuntos
Imunoterapia/métodos , Interleucina-2/uso terapêutico , Linfoma Relacionado a AIDS/terapia , Transtornos Linfoproliferativos/fisiopatologia , Síndrome da Imunodeficiência Adquirida/complicações , Animais , Citocinas/fisiologia , Modelos Animais de Doenças , Herpesvirus Humano 4/efeitos dos fármacos , Humanos , Interleucina-10/fisiologia , Interleucina-2/administração & dosagem , Interleucina-2/sangue , Interleucina-2/fisiologia , Interleucina-6/fisiologia , Transfusão de Linfócitos , Transtornos Linfoproliferativos/mortalidade , Camundongos , Camundongos SCID , Taxa de SobrevidaAssuntos
Abscesso Abdominal/etiologia , Antineoplásicos/efeitos adversos , Coriocarcinoma/tratamento farmacológico , Infecções por Escherichia coli/etiologia , Fístula/etiologia , Enteropatias/etiologia , Neoplasias Testiculares/tratamento farmacológico , Abscesso Abdominal/cirurgia , Adulto , Coriocarcinoma/patologia , Infecções por Escherichia coli/terapia , Fístula/cirurgia , Humanos , Enteropatias/cirurgia , Masculino , Orquiectomia , Neoplasias Testiculares/patologia , Tomografia Computadorizada por Raios XRESUMO
Factor VIII replacement therapy for patients with hemophilia A is conventionally monitored using a plasma-based factor VIII:C assay (a modified activated partial thromboplastin time [APTT] test). The plasma factor VIII assay requires the preparation of plasma from citrated whole blood and measurement of the clotting times of mixtures of patient plasma, factor VIII-deficient substrate, and APTT reagent. Results are not routinely available in less than 1.5 hr, reducing the clinical value of the laboratory data regarding the ability to immediately adjust patient therapy. Results from the whole blood factor VIII assay, performed on a portable coagulation analyzer and using test tubes prefilled with the necessary APTT and factor VIII-deficient reagents, are available within 5-7 min. This immediate determination of the factor VIII:C level from citrated whole blood provides the opportunity to greatly reduce turnaround time and improve the efficacy of factor VIII replacement therapy. Based on clotting time, factor VIII:C activity is read from a standard curve. A clinical evaluation of this whole blood test was performed in two hemophilia centers. A high degree of correlation was seen (r=0.813, n=220) between the whole blood values obtained and conventional laboratory results. This level of correlation was superior to that obtained when comparing two different plasma-based systems(r=0.753, n=23). Factor VIII:C activity levels measured using the whole blood assay system were similar,irrespective of the test operator (laboratory technologist, nurse clinician, or patient). This study indicates that the whole blood factor VIII assay provides results comparable to those of conventional plasma-based assays, but in a more rapid and efficient manner. It provides an opportunity to reduce unnecessary patient consumption of replacement preparations, hence reducing the cost of hemophilia A maintenance and prophylaxis regimens, and to reduce overall patient exposure to human blood products.