Ions formed by a single laser desorption event can be remeasured more than 500 times in a Fourier transform ion cyclotron resonance spectrometer. Quadrupolar excitation and collisional axialization are used to move ions located in any region of the ICR cell to the center of the cell, where they can be effectively detected. With this method, the signal from ions formed by a single laser desorption event is averaged for 200 remeasurement cycles with an efficiency in excess of 99.5% per cycle. Collisions of ions with helium are found to give higher remeasurement efficiencies than collisions with methane, due to reduced scattering losses by the lighter collision gas. With this method, ions that are stored in the analyzer cell for more than 1 hour can be detected. This technique is shown to be compatible with high-resolution data acquisition. Ions formed by one laser desorption event are remeasured at eight bandwidths, demonstrating low-resolution, wide-mass-range analysis and high-resolution, narrow-mass-range analysis of the same group of ions.
Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non–voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine–DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.
classified as both chemical (preferential sputtering) and physical (surface roughness) effects.
ACKNOWLEDGMENTWe gratefully acknowledge both Pat Sullivan and Frank Dalton for helpful discussions.Registry No. Fe(vbpy)2(CN)2 (homopolymer), 119058-92-3; vbpy (homopolymer), 82441-96-1; silver nitrate, 7783-99-5.
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