Resistance to temozolomide and radiotherapy is a major problem for patients with glioblastoma but may be overcome using the poly(ADP-ribose) polymerase inhibitor ABT-888. Using two primary glioblastoma xenografts, the efficacy of ABT-888 combined with radiotherapy and/or temozolomide was evaluated. Treatment with ABT-888 combined with temozolomide resulted in significant survival prolongation (GBM12: 55.1%, P = 0.005; GBM22: 54.4%, P = 0.043). ABT-888 had no effect with radiotherapy alone but significantly enhanced survival in GBM12 when combined with concurrent radiotherapy/ temozolomide. With multicycle therapy, ABT-888 further extended the survival benefit of temozolomide in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for temozolomide resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with temozolomide, and a similar lack of efficacy was observed in two other temozolomide-resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that have not been previously exposed to temozolomide, and these results suggest that patients with newly diagnosed glioblastoma may be more likely to respond to combined temozolomide/poly(ADP-ribose) polymerase inhibitor therapy than patients with recurrent disease.

Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. Experimental Design: Nineteen patients were investigated on the 3-weekly phase Ia study and 11patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. Results: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m 2 (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m 2 . Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m 2 . Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m 2 in phase Ia and one in a patient with gastric carcinoma at 175 mg/m 2 in phase Ib. Conclusion: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.

No abstract

Interest has increased in the potential role of circulating tumour cells in cancer management. Most cell‐based studies have been designed to determine the number of circulating tumour cells in a given volume of blood. Ability to understand the biology of the cancer cells would increase the clinical potential. The purpose of this study was to develop and validate a novel, widely applicable method for detection and characterisation of circulating tumour cells. Cells were imaged with an ImageStreamX imaging flow cytometer which allows detection of expression of multiple biomarkers on each cell and produces high‐resolution images. Depletion of haematopoietic cells was by red cell lysis, leukocyte common antigen CD45 depletion and differential centrifugation. Expression of epithelial cell adhesion molecule, cytokeratins, tumour‐type‐specific biomarkers and CD45 was detected by immunofluorescence. Nuclei were identified with DAPI or DRAQ5 and brightfield images of cells were collected. The method is notable for the dearth of cell damage, recoveries greater than 50%, speed and absence of reliance on the expression of a single biomarker by the tumour cells. The high‐quality images obtained ensure confidence in the specificity of the method. Validation of the methodology on samples from patients with oesophageal, hepatocellular, thyroid and ovarian cancers confirms its utility and specificity. Importantly, this adaptable method is applicable to all tumour types including those of nonepithelial origin. The ability to measure simultaneously the expression of multiple biomarkers will facilitate analysis of the cancer cell biology of individual circulating tumour cells.