RESUMEN
BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).
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Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Desarrollo Infantil/efectos de los fármacos , Herpes Simple/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Aciclovir/efectos adversos , Antivirales/efectos adversos , Enfermedades del Sistema Nervioso Central/prevención & control , Enfermedades del Sistema Nervioso Central/virología , Método Doble Ciego , Femenino , Herpes Simple/prevención & control , Humanos , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Prevención SecundariaRESUMEN
We have previously shown that expanded/activated γδ T cells from healthy donors are cytotoxic to GBM cell lines and primary GBM explants. In this report, we examined the therapeutic effect of intracranial infusion of expanded/activated γδ T cells on human minimal and established U251 tumor xenografts in athymic nude mice. Immunohistochemistry was used to determine the presence of NKG2D ligands on cell lines and tumors, and blocking studies were used to determine the effect of these ligands on γδ T cell recognition. Expanded/activated γδ T cells were prepared by 18-day culture in RPMI, human serum (HS), anti-CD2, IL-12, IFN-γ, and OKT-3. Anti-GBM activity of the cell product was assessed using in vitro cytotoxicity assays against the GBM cell line U251MG in suspension and in adherent culture. Ex vivo expanded/activated γδ T cells were of the effector/memory phenotype, expressed Th1 cytokines, and effectively killed U251 cells in vitro. Xenografts were prepared using a U251 cell line following transfection with a firefly luciferase gene to monitor tumor progression. Mice treated with γδ T cells showed slower progression of both new and established GBM xenografts versus mice that received vehicle only as determined by photon emission over time. Median survival was improved in all γδ T cell treated groups between 32 and 50 days by Kaplan-Meier analysis. U251 cells expressed ULBP-2 and ULBP-3, although blocking of these reduced in vitro cytotoxicity of γδ T cells to U251MG by only 33 and 25%, respectively. These studies show that expanded/activated γδ T cells can mediate killing of new or established GBM xenografts, reduce tumor progression, and constitute a potentially effective novel immunotherapeutic strategy against GBM.
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Glioblastoma/inmunología , Glioblastoma/terapia , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antígenos CD/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Citometría de Flujo/métodos , Proteínas Ligadas a GPI/metabolismo , Glioblastoma/mortalidad , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Desnudos , Análisis de Supervivencia , Linfocitos T/clasificación , Linfocitos T/citología , Factores de Tiempo , Transfección/métodos , Factor de Necrosis Tumoral alfaRESUMEN
PURPOSE: To ascertain predictors of distant brain failure (DBF) in patients treated initially with stereotactic radiosurgery alone for newly diagnosed brain metastases. We hypothesize that these factors may be used to group patients according to risk of DBF. METHODS AND MATERIALS: We retrospectively analyzed 100 patients with newly diagnosed brain metastases treated from 2003 to 2005 at our Gamma Knife radiosurgery facility. The primary endpoint was DBF. Potential predictors included number of metastases, tumor volume, histologic characteristics, extracranial disease, and use of temozolomide. RESULTS: One-year actuarial risk of DBF was 61% for all patients. Significant predictors of DBF included more than three metastases (hazard ratio, 3.30; p = 0.004), stable or poorly controlled extracranial disease (hazard ratio, 2.16; p = 0.04), and melanoma histologic characteristics (hazard ratio, 2.14; p = 0.02). These were confirmed in multivariate analysis. Those with three or fewer metastases, no extracranial disease, and nonmelanoma histologic characteristics (N = 18) had a median time to DBF of 89 weeks vs. 33 weeks for all others. One-year actuarial freedom from DBF for this group was 83% vs. 26% for all others. CONCLUSIONS: Independent significant predictors of DBF in our series included number of metastases (more than three), present or uncontrolled extracranial disease, and melanoma histologic characteristics. These factors were combined to identify a lower risk subgroup with significantly longer time to DBF. These patients may be candidates for initial localized treatment, reserving whole-brain radiation therapy for salvage. Patients in the higher risk group may be candidates for initial whole-brain radiation therapy or should be considered for clinical trials.
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Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Radiocirugia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Femenino , Humanos , Neoplasias Pulmonares , Masculino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Melanoma/cirugía , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , TemozolomidaRESUMEN
BACKGROUND: Coccidioidomycosis can be difficult to treat with available therapies, particularly in patients with progressive or disseminated disease. Posaconazole is a new azole antifungal with potent activity against Coccidioides species, the causative agent of coccidioidomycosis. METHODS: Twenty patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis were enrolled in a multicenter trial to study the safety and tolerability of posaconazole therapy, with efficacy as a secondary end point. Patients received posaconazole (400 mg/day) in capsule formulation for up to 6 months. Safety was evaluated on the basis of the occurrence of adverse events. A satisfactory efficacy response was defined as a >or=50% reduction in the Mycoses Study Group score from baseline. RESULTS: Seventeen (85%) of 20 patients had a satisfactory response to treatment. The median duration of treatment was 173 days. Paired baseline and end-of-treatment culture results for Coccidioides species were available for 4 patients, all of whom converted from being positive to being negative for Coccidioides species. Relapse was experienced by 3 of 9 patients who did not receive antifungal therapy during the follow-up period. In general, posaconazole therapy was well tolerated, with 12 of 20 patients reporting adverse events that were possibly or probably related to treatment. The most common adverse events were dry mouth (in 5 patients [25%]) and headache (in 3 patients [15%]). CONCLUSIONS: Courses of posaconazole therapy that were up to 6 months in duration were well tolerated in patients with coccidioidomycosis. Although this study was limited by the number of patients enrolled, it clearly demonstrates that posaconazole shows promise in the treatment of patients with coccidioidomycosis and warrants additional investigation in a full-scale clinical trial.
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Antifúngicos/uso terapéutico , Coccidioidomicosis/tratamiento farmacológico , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Triazoles/uso terapéutico , Adulto , Anciano , Antifúngicos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Triazoles/efectos adversosRESUMEN
BACKGROUND: Health care expenditures for persons infected with human immunodeficiency virus (HIV) in the United State determined on the basis of actual health care use have not been reported in the era of highly active antiretroviral therapy. METHODS: Patients receiving primary care at the University of Alabama at Birmingham HIV clinic were included in the study. All encounters (except emergency room visits) that occurred within the University of Alabama at Birmingham Hospital System from 1 March 2000 to 1 March 2001 were analyzed. Medication expenditures were determined on the basis of 2001 average wholesale price. Hospitalization expenditures were determined on the basis of 2001 Medicare diagnostic related group reimbursement rates. Clinic expenditures were determined on the basis of 2001 Medicare current procedural terminology reimbursement rates. RESULTS: Among the 635 patients, total annual expenditures for patients with CD4+ cell counts <50 cells/microL (36,533 dollars per patient) were 2.6-times greater than total annual expenditures for patients with CD4+ cell counts > or =350 cells/microL (13,885 dollars per patient), primarily because of increased expenditures for nonantiretroviral medication and hospitalization. Expenditures for highly active antiretroviral therapy were relatively constant at approximately 10,500 dollars per patient per year across CD4+ cell count strata. Outpatient expenditures were 1558 dollars per patient per year; however, the clinic and physician component of these expenditures represented only 359 dollars per patient per year, or 2% of annual expenses. Health care expenditures for patients with HIV infection increased substantially for those with more-advanced disease and were driven predominantly by medication costs (which accounted for 71%-84% of annual expenses). CONCLUSIONS: Physician reimbursements, even with 100% billing and collections, are inadequate to support the activities of most clinics providing HIV care. These findings have important implications for the continued support of HIV treatment programs in the United States.
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Infecciones por VIH/economía , Gastos en Salud , Adolescente , Adulto , Anciano , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Carga ViralRESUMEN
We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor.
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Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Herpesvirus Humano 1/genética , Interleucina-12/genética , Neuroblastoma/genética , Neuroblastoma/inmunología , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/administración & dosificación , Línea Celular Tumoral , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Vectores Genéticos/genética , Inmunidad Celular/inmunología , Inmunofenotipificación , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Clasificación del Tumor , Neuroblastoma/patología , Neuroblastoma/terapia , Virus Oncolíticos/genética , Fenotipo , Análisis de Supervivencia , Resultado del Tratamiento , VacunaciónRESUMEN
BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections. METHODS: We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the "continuous fluconazole arm") with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the "episodic fluconazole arm") in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC. The primary study end point was the time to development of fluconazole-refractory OPC or EC, which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days, respectively. RESULTS: A total of 413 subjects were randomized to receive continuous fluconazole, and 416 were randomized to receive episodic fluconazole. After 42 months, 17 subjects (4.1%) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections, compared with 18 subjects (4.3%) in the episodic fluconazole arm, with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months (P=.88, by log-rank test) or before the end of the study (P=.97, by the log-rank test). Continuous fluconazole therapy was associated with fewer cases of OPC or EC (0.29 vs. 1.08 episodes per patient-year; P<.0001) and fewer invasive fungal infections (15 vs. 28 episodes; P=.04, by chi2 test), but not with improved survival, compared with episodic fluconazole therapy. CONCLUSION: Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC, compared with episodic fluconazole therapy, in HIV-infected patients with access to active antiretroviral therapy.
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Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Candidiasis Bucal/complicaciones , Candidiasis Bucal/tratamiento farmacológico , Fluconazol/administración & dosificación , Fluconazol/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Adulto , Anciano , Recuento de Linfocito CD4 , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Orofaringe/microbiologíaRESUMEN
BACKGROUND: In patients with moderate to severe histoplasmosis associated with AIDS, the preferred treatment has been the deoxycholate formulation of amphotericin B. However, serious side effects are associated with use of amphotericin B. OBJECTIVE: To compare amphotericin B with liposomal amphotericin B for induction therapy of moderate to severe disseminated histoplasmosis in patients with AIDS. DESIGN: Randomized, double-blind, multicenter clinical trial. SETTING: 21 sites of the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. PATIENTS: 81 patients with AIDS and moderate to severe disseminated histoplasmosis. MEASUREMENTS: Clinical success, conversion of baseline blood cultures to negative, and acute toxicities that necessitated discontinuation of treatment. RESULTS: Clinical success was achieved in 14 of 22 patients (64%) treated with amphotericin B compared with 45 of 51 patients (88%) receiving liposomal amphotericin B (difference, 24 percentage points [95% CI, 1 to 52 percentage points]). Culture conversion rates were similar. Three patients treated with amphotericin B and one treated with liposomal amphotericin B died during induction (P = 0.04). Infusion-related side effects were greater with amphotericin B (63%) than with liposomal amphotericin B (25%) (P = 0.002). Nephrotoxicity occurred in 37% of patients treated with amphotericin B and 9% of patients treated with liposomal amphotericin B (P = 0.003). CONCLUSION: Liposomal amphotericin B seems to be a less toxic alternative to amphotericin B and is associated with improved survival.
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Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Histoplasmosis/tratamiento farmacológico , Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Método Doble Ciego , Humanos , Liposomas , SeguridadRESUMEN
Human γδ T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 mice and measured circulating γδ T cell count, phenotype, Vγ/Vδ repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10-12 post-injection and at end stage. Circulating γδ T cells transiently increased and upregulated Annexin V expression at post-tumor day 10-12 followed by a dramatic decline in γδ T cell count at end stage. T cell receptor repertoire showed no changes in Vγ1, Vγ4, Vγ7 or Vδ1 subsets from controls at post-tumor day 10-12 or at end stage except for an end-stage increase in the Vδ4 population. Approximately 12% of γδ T cells produced IFN-γ. IL-17 and IL-4 producing γδ T cells were not detected. Tumor progression was the same in TCRδ-/- C57BL/6 mice as that observed in WT mice, suggesting that γδ T cells exerted neither a regulatory nor a sustainable cytotoxic effect on the tumor. WT mice that received an intracranial injection of γδ T cells 15m following tumor placement showed evidence of local tumor growth inhibition but this was insufficient to confer a survival advantage over untreated controls. Taken together, our findings suggest that an early nonspecific proliferation of γδ T cells followed by their depletion occurs in mice implanted with syngeneic GL261 gliomas. The mechanism by which γδ T cell expansion occurs remains a subject for further investigation of the mechanisms responsible for this immune response in the setting of high-grade glioma.
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Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Encéfalo/metabolismo , Glioma/inmunología , Glioma/patología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Encéfalo/inmunología , Neoplasias Encefálicas/sangre , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glioma/sangre , Humanos , Interleucina-17/inmunología , Interleucina-4/inmunología , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Receptores de Antígenos de Linfocitos T gamma-delta/sangre , Subgrupos de Linfocitos T/patologíaRESUMEN
The median duration of highly active antiretroviral therapy (HAART) regimens was reported to be 11.8 months in one US study, but that study included both treatment-experienced and treatment-naive patients. The duration of initial HAART regimens for treatment-naive patients alone has not been reported. We selected 405 antiretroviral-naive patients who were seen at the University of Alabama at Birmingham HIV Outpatient Clinic from 1 January 1996 through 9 October 2001, and we assessed the duration of initial and successive HAART regimens in this group. Any antiretroviral medication change, excluding dosage changes, that lasted >or=14 days was considered to indicate the start of a new regimen. The median duration of regimens was determined by Kaplan-Meier analysis, and proportional hazards regression was used to identify factors associated with shorter duration of initial regimen. The median duration of initial regimens was 1.6 years, and medication toxicity-associated events were the cause of one-half of discontinuations. Only a history of opportunistic infection and injection drug use were significantly associated with shorter regimen duration.
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Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Adolescente , Adulto , Anciano , Terapia Antirretroviral Altamente Activa/estadística & datos numéricos , Estudios de Cohortes , Esquema de Medicación , Femenino , VIH/efectos de los fármacos , VIH/aislamiento & purificación , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/tratamiento farmacológico , Pacientes Ambulatorios/estadística & datos numéricos , Estudios Prospectivos , Abuso de Sustancias por Vía Intravenosa/tratamiento farmacológico , Privación de Tratamiento/estadística & datos numéricosRESUMEN
To determine the long-term immunologic and virologic effects of antiretroviral treatment interruptions, a retrospective analysis of an ongoing observational database was performed at a university HIV clinic. All patients who began highly active antiretroviral therapy (HAART) after January 1, 1996 and (1) were HAART experienced for >/=90 days, (2) had a treatment interruption (TI) for >/=30 days, (3) resumed HAART for >/=30 days, and (4) had CD4(+) cell counts performed pre- and post-TI were included. Main outcome measures included the following: Immunologic success was defined as a post-TI CD4(+) cell count >90% of the pre-TI CD4(+) cell count (post-TI/pre-TI, >90%). Virologic success was defined as a post-TI viral load (VL) less or equal to twice the pre-TI VL (post-TI/pre-TI, =2) or a post-TI VL of <1000 copies/ml. The pre-TI (baseline) value was the value at the start of the TI (range, -20 to +7 days); the post-TI value was the highest CD4(+) cell count and lowest VL copy achieved during the follow-up window (270 days). One thousand and eight patients were included in the analysis and 75 met the inclusion criteria. Forty-four of 75 patients (58.6%) achieved a successful immunologic outcome and 52 of 68 patients (76.5%; 7 patients did not have a VL determined within the specified periods) achieved a successful virologic outcome. No factors predicting success were identified. The median CD4(+) cell counts pre- and post-TI were 233 and 231 cells/microl, respectively; the median VLs pre- and post-TI were 11,456 and 404 copies/ml, respectively. We conclude that the majority of our patients in virologic failure who underwent a temporary TI recovered 90% of their baseline CD4(+) cell counts and returned to within 2-fold of their baseline VL when HAART was resumed.
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Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/fisiología , Carga Viral , Adulto , Recuento de Linfocito CD4 , Esquema de Medicación , Femenino , Infecciones por VIH/virología , Humanos , MasculinoRESUMEN
Vδ2(neg) γδ T cells, of which Vδ1+ γδ T cells are by far the largest subset, are important effectors against CMV infection. Malignant gliomas often contain CMV genetic material and proteins, and evidence exists that CMV infection may be associated with initiation and/or progression of glioblastoma multiforme (GBM). We sought to determine if Vδ1+ γδ T cells were cytotoxic to GBM and the extent to which their cytotoxicity was CMV dependent. We examined the cytotoxic effect of ex vivo expanded/activated Vδ1+ γδ T cells from healthy CMV seropositive and CMV seronegative donors on unmanipulated and CMV-infected established GBM cell lines and cell lines developed from short- term culture of primary tumors. Expanded/activated Vδ1+ T cells killed CMV-negative U251, U87, and U373 GBM cell lines and two primary tumor explants regardless of the serologic status of the donor. Experimental CMV infection did not increase Vδ1+ T cell--mediated cytotoxicity and in some cases the cell lines were more resistant to lysis when infected with CMV. Flow cytometry analysis of CMV-infected cell lines revealed down-regulation of the NKG2D ligands ULBP-2, and ULBP-3 as well as MICA/B in CMV-infected cells. These studies show that ex vivo expanded/activated Vδ1+ γδ T cells readily recognize and kill established GBM cell lines and primary tumor-derived GBM cells regardless of whether CMV infection is present, however, CMV may enhance the resistance GBM cell lines to innate recognition possibly contributing to the poor immunogenicity of GBM.
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Citotoxicidad Inmunológica/inmunología , Glioblastoma/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Línea Celular , Línea Celular Tumoral , Citomegalovirus/clasificación , Citomegalovirus/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/virología , Citometría de Flujo , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Glioblastoma/patología , Glioblastoma/virología , Humanos , Hibridación in Situ , Péptidos y Proteínas de Señalización Intercelular/inmunología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/metabolismo , Linfocitos T/virología , Células Tumorales CultivadasRESUMEN
BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.
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Adamantano/efectos adversos , Antivirales/efectos adversos , Gripe Humana/tratamiento farmacológico , Oseltamivir/efectos adversos , Rimantadina/efectos adversos , Adamantano/uso terapéutico , Antivirales/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades del Sistema Nervioso/inducido químicamente , Oseltamivir/uso terapéutico , Estudios Retrospectivos , Rimantadina/uso terapéuticoRESUMEN
BACKGROUND: Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS). OBJECTIVES: To assess the neurodevelopmental impact of ganciclovir therapy in this population. STUDY DESIGN: 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment. Denver developmental tests were performed at 6 weeks, 6 months, and 12 months. For each age, developmental milestones that > or =90% of normal children would be expected to have achieved were identified. The numbers of milestones not met ("delays") were determined for each subject. The average number of delays per subject was compared for each treatment group. RESULTS: At 6 months, the average number of delays was 4.46 and 7.51, respectively, for ganciclovir recipients and "no treatment" subjects (p=0.02). At 12 months, the average number of delays was 10.06 and 17.14, respectively (p=0.007). In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 months (p=0.007). CONCLUSIONS: Infants with symptomatic congenital CMV involving the CNS receiving intravenous ganciclovir therapy have fewer developmental delays at 6 and 12 months compared with untreated infants. Based on these data as well as the previously published data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy can be considered in the management of babies with symptomatic congenital CMV disease involving the CNS. If treatment is initiated, it should be started within the first month of life and patients should be monitored closely for toxicity, especially neutropenia. Since existing data only address the treatment of symptomatic congenital CMV disease involving the CNS, these data cannot be extrapolated to neonates with other manifestations of CMV disease, including asymptomatic babies and symptomatic babies who do not have CNS involvement.
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Antivirales/uso terapéutico , Sistema Nervioso Central/virología , Infecciones por Citomegalovirus/tratamiento farmacológico , Discapacidades del Desarrollo/prevención & control , Ganciclovir/uso terapéutico , Antivirales/administración & dosificación , Sistema Nervioso Central/fisiopatología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/congénito , Discapacidades del Desarrollo/virología , Femenino , Ganciclovir/administración & dosificación , Humanos , Lactante , Recién Nacido , Inyecciones Intravenosas , Masculino , Análisis Multivariante , Análisis de Regresión , Resultado del TratamientoRESUMEN
In contrast to Ag-specific alphabeta T cells, gammadelta T cells can kill malignantly transformed cells in a manner that does not require the recognition of tumor-specific Ags. Although such observations have contributed to the emerging view that gammadelta T cells provide protective innate immunosurveillance against certain malignancies, particularly those of epithelial origin, they also provide a rationale for developing novel clinical approaches to exploit the innate antitumor properties of gammadelta T cells for the treatment of cancer. Using TRAMP, a transgenic mouse model of prostate cancer, proof-of-concept studies were performed to first establish that gammadelta T cells can indeed provide protective immunosurveillance against spontaneously arising mouse prostate cancer. TRAMP mice, which predictably develop prostate adenocarcinoma, were backcrossed with gammadelta T cell-deficient mice (TCRdelta(-/-) mice) yielding TRAMP x TCRdelta(-/-) mice, a proportion of which developed more extensive disease compared with control TRAMP mice. By extension, these findings were then used as a rationale for developing an adoptive immunotherapy model for treating prostate cancer. Using TRAMP-C2 cells derived from TRAMP mice (C57BL/6 genetic background), disease was first established in otherwise healthy wild-type C57BL/6 mice. In models of localized and disseminated disease, tumor-bearing mice treated i.v. with supraphysiological numbers of syngeneic gammadelta T cells (C57BL/6-derived) developed measurably less disease compared with untreated mice. Disease-bearing mice treated i.v. with gammadelta T cells also displayed superior survival compared with untreated mice. These findings provide a biological rationale for clinical trials designed to adoptively transfer ex vivo expanded autologous gammadelta T cells for the treatment of prostate cancer.
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Adenocarcinoma/inmunología , Vigilancia Inmunológica , Neoplasias de la Próstata/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Traslado Adoptivo , Animales , Línea Celular Tumoral , Humanos , Transfusión de Linfocitos , Masculino , Ratones , Ratones Transgénicos , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/patología , Linfocitos T/trasplante , Trasplante IsogénicoRESUMEN
BACKGROUND: Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. METHODS: Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration of valganciclovir oral solution and of intravenous ganciclovir. RESULTS: On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC12 (area under the concentration-time curve over a 12-h period) of 27 mg x h/L was defined. The median dose of oral valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC12 of 27.4 mg x h/L. The bioavailability of valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had > or =4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. CONCLUSIONS: In neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganciclovir.
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Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/aislamiento & purificación , Ganciclovir/análogos & derivados , Administración Oral , Área Bajo la Curva , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/virología , Esquema de Medicación , Femenino , Ganciclovir/efectos adversos , Ganciclovir/sangre , Ganciclovir/farmacocinética , Ganciclovir/farmacología , Humanos , Recién Nacido , Masculino , Valganciclovir , Carga ViralRESUMEN
PURPOSE: This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. PATIENTS AND METHODS: Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. RESULTS: A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. CONCLUSION: Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Venenos de Serpiente/uso terapéutico , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/patología , Estudios de Cohortes , Glioma/patología , Humanos , Imagen por Resonancia Magnética , Dosis Máxima Tolerada , Recurrencia , Venenos de Serpiente/efectos adversosRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) infections have become common among both hospitalized and nonhospitalized patients. Optimal outpatient therapy for MRSA infections has yet to be determined, but this matter is complicated by the possibility of inducible macrolide-lincosamide-streptogramin B resistance (MLSBi). We studied the prevalence of MLSBi in community- and hospital-associated S. aureus isolates and the prevalence of community-associated MRSA (CA-MRSA) and identified clinical predictors of CA-MRSA and MLSBi. Among 402 S. aureus isolates, the overall prevalence of MLSBi was 52%, with 50% of MRSA and 60% of methicillin-susceptible S. aureus isolates exhibiting MLSBi. CA-MRSA represented 14% of all isolates and had a lower prevalence of MLSBi than hospital-associated MRSA (33% versus 55%). The presence of skin or soft-tissue infection was predictive for CA-MRSA, and the presence of a comorbidity was predictive for MLSBi. Due to the low prevalence of MLSBi among CA-MRSA isolates, clindamycin remains a useful option for outpatient therapy.
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Antibacterianos/farmacología , Clindamicina/farmacología , Infecciones Comunitarias Adquiridas/microbiología , Infección Hospitalaria/microbiología , Farmacorresistencia Bacteriana , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Femenino , Humanos , Lincosamidas , Macrólidos/farmacología , Masculino , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/aislamiento & purificación , Estreptogramina B/farmacologíaRESUMEN
A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.
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Anticuerpos Antifúngicos/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Cryptococcus neoformans/inmunología , Inmunización Pasiva , Meningitis Criptocócica/terapia , Animales , Anticuerpos Antifúngicos/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Antígenos Fúngicos/sangre , Área Bajo la Curva , Infecciones por VIH/complicaciones , Humanos , RatonesRESUMEN
PURPOSE: To determine thresholds of quality for a T2*-weighted perfusion magnetic resonance imaging (MRI) study and evaluate the effects of an angiogenesis inhibitor on relative blood flow and volume changes in brain tumor patients in a multi-institution setting. MATERIALS AND METHODS: A total of 36 volunteers from four participating institutions with clinically diagnosed malignant gliomas were studied using perfusion MRI protocols. These included a baseline study and follow-up studies every eight weeks to evaluate the effect of an anti-angiogenic agent on tumor perfusion. Quality tests were performed on the perfusion imaging data by defining statistical thresholds of acceptance. Region of interest (ROI) analysis was performed on tumors and kinetic parameters were normalized with respect to normal tissue. RESULTS: Statistical thresholds for goodness of the gamma variate fit, T2* recovery, and mean signal full-width half-minimum (FWHMin) were computed for our data sets with a 99% one-sided confidence interval; these were 6.91%, 79.48%, and 23.35 seconds, respectively. Decreases in-blood volume and flow measurements were observed in patients with documented clinical response. CONCLUSION: Malignant brain tumors have altered perfusion parameters that may be used to understand and monitor neovascularization. This permits non-invasive assessment of the efficacy of angiogenesis inhibiting drugs.