RESUMEN
Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Liposarcoma , Terapia Neoadyuvante , Neoplasias Retroperitoneales , Humanos , Liposarcoma/tratamiento farmacológico , Liposarcoma/inmunología , Terapia Neoadyuvante/métodos , Neoplasias Retroperitoneales/tratamiento farmacológico , Neoplasias Retroperitoneales/inmunología , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Anciano , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Sarcoma/terapia , Sarcoma/inmunología , Sarcoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacosRESUMEN
There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .
Asunto(s)
Neoplasias Pulmonares , Melanoma , Humanos , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melanoma/patología , Neoplasias Pulmonares/tratamiento farmacológico , Resultado del Tratamiento , IpilimumabRESUMEN
Exploitation of host components by microbes to promote their survival in the hostile host environment has been a recurring theme in recent years. Available data indicate that bacterial pathogens activate ectodomain shedding of host cell surface molecules to enhance their virulence. We reported previously that several major bacterial pathogens activate ectodomain shedding of syndecan-1, the major heparan sulfate proteoglycan of epithelial cells. Here we define the molecular basis of how Staphylococcus aureus activates syndecan-1 shedding. We screened mutant S. aureus strains devoid of various toxin and protease genes and found that only strains lacking both alpha-toxin and beta-toxin genes do not stimulate shedding. Mutations in the agr global regulatory locus, which positively regulates expression of alpha- and beta-toxins and other exoproteins, also abrogated the capacity to stimulate syndecan-1 shedding. Furthermore, purified S. aureus alpha- and beta-toxins, but not enterotoxin A and toxic shock syndrome toxin-1, rapidly potentiated shedding in a concentration-dependent manner. These results establish that S. aureus activates syndecan-1 ectodomain shedding via its two virulence factors, alpha- and beta-toxins. Toxin-activated shedding was also selectively inhibited by antagonists of the host cell shedding mechanism, indicating that alpha- and beta-toxins shed syndecan-1 ectodomains through stimulation of the host cell's shedding machinery. Interestingly, beta-toxin, but not alpha-toxin, also enhanced ectodomain shedding of syndecan-4 and heparin-binding epidermal growth factor. Because shedding of these ectodomains has been implicated in promoting bacterial pathogenesis, activation of ectodomain shedding by alpha-toxin and beta-toxin may be a previously unknown virulence mechanism of S. aureus.
Asunto(s)
Toxinas Bacterianas/farmacología , Proteínas Hemolisinas/farmacología , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Proteoglicanos/química , Proteoglicanos/metabolismo , Esfingomielina Fosfodiesterasa/farmacología , Staphylococcus aureus/genética , Animales , Toxinas Bacterianas/genética , Sitios de Unión , Células CHO , Cricetinae , Factor de Crecimiento Epidérmico/genética , Eliminación de Gen , Genotipo , Proteínas Hemolisinas/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina , Péptidos y Proteínas de Señalización Intercelular , Cinética , Proteínas Recombinantes/metabolismo , Esfingomielina Fosfodiesterasa/genética , SindecanosRESUMEN
OBJECTIVE: To assess the ability of clindamycin vaginal cream to reduce the incidence of preterm birth in women with abnormal genital tract flora in the second trimester of pregnancy. METHODS: This was a randomized, double-blind, placebo-controlled, tricenter study. A total of 409 women with abnormal genital tract flora on Gram stain of vaginal secretions at 13-20 weeks' gestation were randomized to receive a 3-day course of clindamycin vaginal cream or placebo. Those women who still had abnormal vaginal flora 3 weeks later received a 7-day course of the original study drug (ie, either clindamycin vaginal cream or placebo as per original randomization). The primary outcome measure was the incidence of preterm birth. RESULTS: There was a statistically significant reduction in the incidence of preterm birth in the clindamycin vaginal cream group (4%) compared with placebo (10%) (P <.03). Significantly more babies born preterm (63%) required admission to the neonatal intensive care unit compared with term infants (4%) (P <.001). CONCLUSION: A 2% clindamycin vaginal cream, when compared with placebo administered to women with abnormal genital tract flora before 20 weeks' gestation, can reduce the incidence of preterm birth by 60% and hence the need for neonatal intensive care.
Asunto(s)
Antibacterianos/uso terapéutico , Clindamicina/uso terapéutico , Trabajo de Parto Prematuro/prevención & control , Complicaciones Infecciosas del Embarazo/prevención & control , Administración Intravaginal , Adolescente , Adulto , Antibacterianos/administración & dosificación , Peso al Nacer , Clindamicina/administración & dosificación , Método Doble Ciego , Inglaterra , Femenino , Humanos , Embarazo , Resultado del Embarazo , Segundo Trimestre del Embarazo , Resultado del Tratamiento , Vagina/microbiologíaRESUMEN
The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 +/- 1.60 microg/ml [mean +/- standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 +/- 3.50 microg/ml) or ACs (2.61 +/- 5.01 microg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 microg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 microg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 microg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.