RESUMEN
OBJECTIVE: This study was designed to analyze porcine plasma and peritoneal fluid for concentration differences of angiogenic molecular mediators and to determine local peritoneal sites of production of these molecules. BACKGROUND: The peritoneum is now recognized as a dynamic cellular membrane with important functions, including antigen presentation; transport and movement of fluid, solutes, and particulate matter across serosal cavities; and secretion of glycosaminoglycans, extracellular matrix proteins, proinflammatory cytokines, and growth factors. The mechanisms of the peritoneal response to injury and the factors that determine the outcome of the reactive or reparative processes of the peritoneum remain poorly defined. METHODS: Domestic swine (n = 12) underwent percutaneous diagnostic peritoneal lavage to obtain preincision peritoneal fluid for biochemical analysis. Open biopsy samples of parietal peritoneum and omentum were obtained for immunochemical and molecular analysis. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels were quantitated by enzyme-linked immunosorbent assay, and nitrite/nitrate (NOx) measured by nonenzymatic assay. Sections of formalin-fixed tissue were stained for immunoreactivity to VEGF, bFGF, and nitric oxide synthase (NOS). Frozen homogenized peritoneum and omentum were prepared for isolation of protein and RNA. An endothelial growth assay was created using human umbilical vein endothelial cells cultured with peritoneal fluid with or without anti-VEGF or anti-bFGF antibodies. RESULTS: The mean plasma concentrations of VEGF, bFGF, and NOx were 20 +/- 5 pg/mL, 35 +/- 9 pg/mL, and 4.5 +/- 1.3 microm, compared with mean peritoneal fluid concentrations of 395 +/- 75 pg/mL, 486 +/- 72 pg/mL, and 35.0 +/- 8.8 mum respectively (P < 0.05 for each molecule). Immunochemistry demonstrated VEGF, bFGF, and NOS protein in mesothelium, submesothelium, and omentum. The use of Western blotting and reverse transcription polymerase chain reaction confirmed peritoneal and omental presence of VEGF and NOS-2. The use of endothelial bioassay documented peritoneal fluid angiogenic activity, which was inhibited by addition of neutralizing antibody to VEGF or bFGF. CONCLUSION: Peritoneal compartmentalization of angiogenic mediators important in wound healing, inflammation, and tumor growth suggests that the plasma concentrations of these mediators do not reflect their tissue concentrations or local biological activity.
Asunto(s)
Líquido Ascítico/química , Factor 2 de Crecimiento de Fibroblastos/análisis , Óxido Nítrico/análisis , Factor A de Crecimiento Endotelial Vascular/análisis , Animales , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Inmunohistoquímica , Óxido Nítrico/sangre , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/sangre , Porcinos , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Poor performance status patients with advanced non-small cell lung cancer (NSCLC) have frequently been excluded from clinical trials due to the perception that they would have excessive treatment-related toxicity and a limited life expectancy. METHODS: A retrospective review of two multicenter trials centered at the University of North Carolina of patients who were treated with platinum-based chemotherapy for advanced NSCLC was conducted. Patients were divided into two subgroups based on Karnofsky performance status (KPS). Patients with a KPS = 70 were considered to have poor performance status, while patients with a KPS > or =80 were considered to have good performance status. RESULTS: Of the 387 patients, 19% (n = 73) had a poor performance status. The response rate (complete and partial responses) was similar between the two sub-groups (26% versus 28%); however, there was a difference in survival (p = 0.0004, log-rank test) between the groups. The median survival and 1-year survival rate for the poor performance status patients was 4.9 months and 21%, while the good performance status patients had a median survival of 8.4 months and a 1-year survival rate of 31%. The rate of National Cancer Institute (NCI) Common Toxicity Criteria (CTC) toxicities was similar between the two groups (p = 0.33). The percentage of patients receiving <4 cycles of therapy in the poor and good performance status was 55 and 39%, respectively (p = 0.012). CONCLUSIONS: Patients with poor performance status treated with platinum based chemotherapy have a similar rate of toxicity compared to good performance status patients. Their overall survival was lower despite a similar response to chemotherapy.