Clin Cancer Res
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Randomized Controlled Trial Clinical Trial
Phase I pharmacokinetic, food effect, and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors.
To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules. ⋯ For oral irinotecan, a dose of 70 mg/m(2)/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.
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The epidermal growth factor receptor (EGFR) is overexpressed in approximately 50% to 60% of glioblastoma multiforme tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24% to 67% of cases. We sought to determine whether glioblastoma multiforme expression of either overexpressed wild-type EGFR or the mutant EGFRvIII is an independent predictor of overall patient survival. ⋯ Neither the overexpressed wild-type EGFR nor EGFRvIII was an independent predictor of median overall survival in this selected cohort of patients who underwent extensive tumor resection. However, in patients surviving > or =1 year, the expression of EGFRvIII was an independent negative prognostic indicator.
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Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin. ⋯ This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.
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Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. ⋯ Analysis by flow cytometry in vitro revealed an apoptosis- and G(2)-M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment. Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoprotein-overexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.
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Allelic loss at 1p is seen in 70% to 85% of oligodendrogliomas (typically in association with 19q allelic loss) and 20-30% of astrocytomas. Because most 1p deletions in gliomas involve almost the entire chromosome arm, narrowing the region of the putative tumor suppressor gene has been difficult. To better define the histologic correlates of different patterns of 1p and 19q loss, we evaluated 1p/19q status in a large group of gliomas. This also allowed us to define a very small minimal deleted region (MDR) on 1p36. ⋯ Our data confirm the strong association of combined 1p/19q loss with classic oligodendroglioma histology and identify a very small segment of 1p36 located within CAMTA1 that was deleted in all oligodendroglial tumors with 1p LOH. This MDR also overlaps the neuroblastoma 1p36 MDR. CAMTA1 shows no evidence of inactivation by somatic mutations but its expression is reduced by half in cases with 1p LOH, suggesting that the functional effects of CAMTA1 haploinsufficiency warrant further investigation.