Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Comparison of permeability in high-grade and low-grade brain tumors using dynamic susceptibility contrast MR imaging.

OBJECTIVE: The purpose of this study was to compare permeability measurements in high-grade and low-grade glial neoplasms using a T2(*)-weighted method. Our hypothesis was that permeability measurements using a T2(*)-weighted technique would show permeability in high-grade neoplasms to be higher than that in low-grade neoplasms. MATERIALS AND METHODS: Twelve patients with biopsy-proven high-grade neoplasms and 10 patients with biopsy-proven low-grade neoplasms underwent dynamic susceptibility contrast MR perfusion imaging (TR/TE, 1500/80) after bolus infusion of 0.2 mmol/kg of MR contrast material. Color-coded permeability-weighted maps were created using a model that weights relative contributions to signal intensity from intravascular T2(*) effects and extravascular T1 effects from blood-brain barrier permeability. Two measures of permeability were performed: mean value of highest permeability found on three images through the tumor (mean regional value) and highest value found at any region of interest in the tumor (single area of maximum permeability). Depending on the normality of the data sets, we used the Wilcoxon's rank sum test or the two-tailed Student's t test for statistical analysis. RESULTS: For low-grade tumors, the range was 0.006-0.041, and the median of the mean regional value for each image was 0.017. For high-grade tumors, the range was 0.005-0.092, and the median of the mean regional value was 0.035 (p = 0.025). For low-grade tumors, the range was 0.008-0.045, and the mean of the single area of maximum values was 0.02. For high-grade tumors, the range was 0.007-0.136, and the mean of the single area of maximum values was 0.054 (p = 0.018). CONCLUSION: Permeability values for high-grade tumors obtained using a T2(*)-weighted method were significantly greater than those for low-grade tumors and are consistent with previous studies reporting results using T1-weighted methods.