RESUMEN
Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Ipilimumab/administración & dosificación , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Ipilimumab/efectos adversos , Masculino , Dosis Máxima Tolerada , Melanoma/parasitología , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Nivolumab , Seguridad del Paciente , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Análisis de SupervivenciaAsunto(s)
Enfermedades del Pie/patología , Melanoma/parasitología , Neoplasias Cutáneas/patología , Estrés Mecánico , Anciano , Femenino , Pie/patología , Enfermedades del Pie/fisiopatología , Humanos , Masculino , Melanoma/patología , Melanoma/fisiopatología , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Cutáneas/fisiopatologíaRESUMEN
OBJECTIVE: To explore the anti-tumor effect of 17XL strains of Plasmodium yoelii (P.y) infection on melanoma in mice. METHODS: B16F10 tumor cells were axillarilly injected into the right flank of 20 C57BL/6 mice to establish tumor-bearing mouse models. The next day, the mice were randomly divided into a P.y infection group and control group, 10 mice each group. Each mouse of the P.y infection group was intraperitoneally injected with 1×106 red blood cells including 20% P.y infection red blood cells, and each one of the control group were intraperitoneally injected with 1×106 normal red blood cells of C57BL/6 mice. The time of tumor formation of the mice in the two groups was observed and the tumor volumes were measured. RESULTS: The time of tumor formation in the P.y infection groupï¼» (11.30 ± 0.21) dï¼½was significantly later than that in the control group ï¼» (10.40 ± 0.22) dï¼½ (P < 0.05). From the tumors could be accurately measured to the study end point, both the tumors of mice in the two groups were growing, and the tumor volumes of mice in the P.y infection group were significantly less than those in the control group at each time point (all P < 0.05). The growth rate of tumors in the P.y infection group ï¼» (71.10 ± 6.29) mm3/dï¼½ was significantly slower than that in the control group ï¼» (302.80 ± 49.94) mm3/dï¼½ (P < 0.05), and the growth rates of tumors everyday in the P.y infection group were significantly slower than those in the control group (all P < 0.05). CONCLUSIONS: The P.y infection can delay the occurrence of tumor and inhibit the growth of melanoma.
Asunto(s)
Eritrocitos/parasitología , Malaria , Melanoma/parasitología , Plasmodium yoelii , Animales , Ratones , Ratones Endogámicos C57BLRESUMEN
Protozoan parasites belonging to genera Leishmania and Trypanosoma are the etiological agents of severe neglected tropical diseases (NTDs) that cause enormous social and economic impact in many countries of tropical and sub-tropical areas of the world. In our screening program for new drug leads from natural sources, we found that the crude extract of the endophytic fungus Cochliobolus sp. (UFMGCB-555) could kill 90% of the amastigote-like forms of Leishmania amazonensis and inhibit by 100% Ellman's reagent reduction in the trypanothione reductase (TryR) assay, when tested at 20 microg mL(-1). UFMGCB-555 was isolated from the plant Piptadenia adiantoides J.F. Macbr (Fabaceae) and identified based on the sequence of the internally transcribed spacer (ITS) regions of its ribosomal DNA. The chromatographic fractionation of the extract was guided by the TryR assay and resulted in the isolation of cochlioquinone A and isocochlioquinone A. Both compounds were active in the assay with L. amazonensis, disclosing EC(50) values (effective concentrations required to kill 50% of the parasite) of 1.7 microM (95% confidence interval = 1.6 to 1.9 microM) and 4.1 microM (95% confidence interval = 3.6 to 4.7 microM), respectively. These compounds were not active against three human cancer cell lines (MCF-7, TK-10, and UACC-62), indicating some degree of selectivity towards the parasites. These results suggest that cochlioquinones are attractive lead compounds that deserve further investigation aiming at developing new drugs to treat leishmaniasis. The findings also reinforce the role of endophytic fungi as an important source of compounds with potential to enter the pipeline for drug development against NTDs.
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Ascomicetos , Fabaceae/microbiología , Fabaceae/parasitología , Leishmania mexicana/aislamiento & purificación , Trypanosoma/aislamiento & purificación , África del Sur del Sahara , Animales , Ascomicetos/genética , Benzoquinonas/aislamiento & purificación , Neoplasias de la Mama/parasitología , Línea Celular Tumoral , América Central , Cartilla de ADN , ADN de Hongos/genética , ADN Ribosómico/genética , Femenino , Humanos , Neoplasias Renales/parasitología , Melanoma/parasitología , NADH NADPH Oxidorreductasas/metabolismo , Proteínas Recombinantes/metabolismo , América del Sur , Esterol O-Aciltransferasa/antagonistas & inhibidores , Clima Tropical , Trypanosoma cruzi/enzimología , Trypanosoma cruzi/aislamiento & purificación , Organización Mundial de la SaludRESUMEN
BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy in patients with advanced and metastatic melanoma confined to a limb. It is essentially a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1993 and 2007 were identified. In all patients a cytotoxic drug combination of melphalan and actinomycin-D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C). RESULTS: The majority of patients (62%) were female. Their average age was 74 years (range 29-93 years). Most patients had MD Anderson stage III disease (134/185). The overall response rate was 84% [complete response (CR) rate 38%, partial response rate 46%]. Median response duration was 13 months (22 months for patients with CR; P = 0.01). Median follow-up was 20 months and median survival was 38 months. In those patients with a CR, the median survival was 53 months (P = 0.005). CR rate and survival time decreased with increasing stage of disease. On multivariate analysis significant factors for a favorable outcome were achievement of CR, stage of disease, thickness of primary melanoma, the CO(2 )level in the isolated circuit, and a Wieberdink limb toxicity score of III (considerable erythema and edema). CONCLUSION: The response rates and duration of response after ILI are comparable to those achieved by conventional ILP. ILI is a minimally invasive alternative to the much more complex and morbid conventional ILP technique for patients with advanced metastatic melanoma confined to a limb.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia del Cáncer por Perfusión Regional , Melanoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Dactinomicina/administración & dosificación , Extremidades , Femenino , Humanos , Masculino , Melanoma/parasitología , Melfalán/administración & dosificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Prospectivos , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Several comparative genomic hybridization studies provide evidence for overrepresentation of the long arm of chromosome 20 in malignant melanoma. These studies also suggest that chromosome 20q contains genes that may contribute to melanoma pathogenesis. To refine the region of 20q amplification and to identify potential candidate genes involved in melanoma or even in melanoma progression from these regions, we combined fluorescence in-situ hybridization with MYBL2, ZNF217, CYP24 and STK6 specific probes (chromosomal region 20q13.1-q13.2) with high-throughput tissue microarray consisting of 280 primary melanomas and melanoma metastases. Low-level amplification ranging from 0.5 to 2.0% was detected for the tumor-related genes of interest. Higher frequencies of gain when compared with amplification were detected for MYBL2, ZNF217, CYP24 and STK6. Aneusomy of centromere 20 was observed in 29.9% of the analyzed tumors. A significantly higher frequency of ZNF217, CYP24 and STK6 total copy-number increase, as well as aneusomy of centromere 20, was found in the group of metastases when compared with the group of primary melanomas. Despite the technological advantage of fluorescence in-situ hybridization on tissue microarray, which allows refining regions of amplification, we were not able to recognize any of the MYBL2, ZNF217, CYP24 and STK6 genes as a particular relevant gene for melanoma tumorigenesis.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 20 , Melanoma/genética , Centrómero/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Melanoma/parasitología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
We investigated the cytoadherence of Plasmodium falciparum infected erythrocytes to target cells that express CD36 by soft x-ray microscopy. Using immunogold beads enhanced with silver, we localized CD36 on the surface of intact melanoma cells and throughout Triton extracted melanoma cells. We examined the orientation of parasites within erythrocytes that bound to target cells, and the interactions between the red cell membrane and the target cell, and we confirmed that fibrillar structures on the surface of melanoma and endothelial cells can be involved in the association between infected erythrocytes and melanoma cells or endothelial cells.
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Antígenos CD36/análisis , Eritrocitos/parasitología , Plasmodium falciparum/fisiología , Animales , Antígenos CD36/inmunología , Adhesión Celular , Microanálisis por Sonda Electrónica , Endotelio Vascular/inmunología , Endotelio Vascular/parasitología , Eritrocitos/fisiología , Eritrocitos/ultraestructura , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Melanoma/inmunología , Melanoma/parasitología , Melanoma/ultraestructura , Plasmodium falciparum/ultraestructura , Células Tumorales CultivadasRESUMEN
This study examined the mechanism of the cytopathic effect (CPE) of Acanthamoeba castellanii on human target cells. Pathogenic Acanthamoeba trophozoites were incubated with human ocular melanoma (OCM1) cells for 30 min, 1 hr, and 3 hr. The amoebae were treated with a calcium ionophore (A23187), phorbol myristate ester (PMA), calcium channel blocker (Bepridil), cytochalasin D, and L-leucyl-L-leucine methyl ester (leu-leu-OMe). Cytolysis was quantified using a spectrophotometric assay. Cocultures of amoeba and cells were also observed by transmission electron microscopy at 1, 2, and 3 hr. Results show that trophozoites formed pseudopodia that made intimate contact with the target cell membrane. Neither amebostomes nor phagocytosis was seen. The calcium ionophore A23187 increased the cytopathic effect of the trophozoites on the cultured OCM1. In contrast, cytochalasin D, Bepridil, and PMA reduced the cytopathic effect. Leu-leu-OMe did not result in killing of Acanthamoeba trophozoites. The results suggest that the cytopathic effect of Acanthamoeba trophozoites involves calcium channels and cytoskeletal elements. There was no evidence of trogocytosis or phagocytosis as sometimes occurs in cytolysis by other free-living amoeba. Although Acanthamoeba-mediated CPE in some ways resembles CPE produced by cytotoxic lymphocytes, the mechanisms are not identical.
Asunto(s)
Acanthamoeba/fisiología , Melanoma/parasitología , Neoplasias de la Úvea/parasitología , Acanthamoeba/efectos de los fármacos , Acanthamoeba/ultraestructura , Animales , Bepridil/farmacología , Calcimicina/farmacología , Canales de Calcio/efectos de los fármacos , Canales de Calcio/fisiología , Catepsina C , Supervivencia Celular , Citocalasina D/farmacología , Citoesqueleto/efectos de los fármacos , Citoesqueleto/fisiología , Citotoxicidad Inmunológica/efectos de los fármacos , Dipéptidos/farmacología , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Humanos , Inmunosupresores/farmacología , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Microscopía Electrónica , Proteína Quinasa C/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Células Tumorales CultivadasRESUMEN
We observed considerable diversity in the cytoadherence of Plasmodium falciparum isolates from Malawi to melanoma cells, U937 cells and human peripheral monocytes. Each isolate exhibited a unique cytoadherence profile for the three human cell types. These isolates generally adhered well to U937 cells and fresh monocytes, moderately to melanoma cells and poorly to TE 671, MIA-Pa-Ca, WI 38, PLC/PRF/5 and HeLa cells. An antimalarial immunoglobulin pool inhibited binding to melanoma cells by 50% or more and to U937 cells by 25% or less. There was no correlation between in vitro cytoadherence to the three cells and clinical disease. These results suggest that malarial adherence ligands exposed on the surface of infected erythrocytes vary from one isolate to another.
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Melanoma/parasitología , Monocitos/parasitología , Plasmodium falciparum/fisiología , Adolescente , Animales , Células Cultivadas/citología , Células Cultivadas/microbiología , Niño , Preescolar , Eritrocitos/parasitología , Eritrocitos/patología , Eritrocitos/fisiología , Células HeLa , Humanos , Linfoma de Células B Grandes Difuso/parasitología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/fisiopatología , Malaria Falciparum/sangre , Malaria Falciparum/epidemiología , Malaria Falciparum/patología , Malaui/epidemiología , Melanoma/patología , Melanoma/fisiopatología , Monocitos/patología , Monocitos/fisiología , Plasmodium falciparum/aislamiento & purificación , Células Tumorales Cultivadas/parasitología , Células Tumorales Cultivadas/patologíaRESUMEN
Mycoplasmal infection of cell cultures remains a significant threat to diagnostic and research procedures. In certain defined situations, curing of mycoplasmal infected cultures is a reasonable exercise. Four methods of curing were compared: treatment with BM-cycline, 5 bromouracil, use of specific antisera and treatment of infected cells suspended in soft agar with antibiotics. Antisera treatments were of low efficiency of curing: 50%. None of nine infected cell lines treated with 5-bromouracil were consistently cured of mycoplasmas. The use of BM-cycline was effective for some, but not all lines and required long periods of treatment, 12-21 days. 35 naturally or deliberately infected cultures were treated in soft agar a total of 119 times. This procedure which consisted of suspending infected cultures in soft agar containing appropriate antibiotics resulted in successful mycoplasmal elimination 118/119 times. This soft agar technique took 1-3 days. In separate studies, it was shown that certain Mycoplasma fermentans strains were resisted to this and other curing methods. This may be due to their intracellular location. Such strains may be more amenable to antibiotics that penetrate mammalian cells. It is concluded that the soft agar technique is a rapid, efficient and reliable method to eliminate cell culture mycoplasmas.
Asunto(s)
Bromouracilo/farmacología , Mycoplasma/citología , Agar , Animales , Células Cultivadas , Fibroblastos/citología , Fibroblastos/parasitología , Humanos , Linfocitos/citología , Linfocitos/parasitología , Linfoma/parasitología , Linfoma/patología , Melanoma/parasitología , Melanoma/patología , Métodos , Ratones , Monocitos/citología , Monocitos/parasitología , Mycoplasma/efectos de los fármacos , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/parasitología , Células Tumorales Cultivadas/patologíaRESUMEN
Erythrocytes infected with Plasmodium falciparum bind specifically to cultured endothelial cells and to a line of amelanotic melanoma cells. We have fixed endothelial cells and amelanotic melanoma cells in various ways and determined whether the fixed cells were still able to bind infected erythrocytes. Only cells fixed with 1.0-2.5% formalin in phosphate-buffered saline continued to bind infected erythrocytes as well as unfixed cells. The mechanism of binding to fixed and unfixed cells appeared to be identical for the following reasons. First, erythrocytes infected by parasite strains that bound to unfixed cells also bound to fixed cells while those that did not bind to unfixed cells did not bind to fixed cells. Second, immune serum that inhibited binding to unfixed cells also inhibited binding to fixed cells. Third, electron microscopy showed that knobs were the points of attachment between infected erythrocytes and both fixed and unfixed melanoma cells. Fixed cells gave reproducible results over at least 2 months. Thus, we have developed a simplified, reproducible assay for measuring binding of P. falciparum-infected erythrocytes to target cells.