Citations

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

Ultrasound vibro-acoustography is a novel medical imaging modality that combines the high resolution of high-frequency ultrasound with the speckle-free images obtained using low-frequency methods. This imaging modality relies on the non-linear interaction of two high frequency beams at slightly different frequencies. We describe the physics of ultrasound vibro-acoustography and outline a strategy for its modeling, simulation, and optimal design.

MRI guided focused ultrasound (FUS) has been shown to create thermal lesions where tissue stiffness changes significantly. To assess the correlation between tissue stiffness change and tissue ablation, a pilot animal based study was conducted to treat LNCaP tumors in vivo and Hep3B tumors immediately post mortem. MR elastography was used to analyze tissue stiffness before and after ablation. Treated tissue was excised immediately after each experiment and processed by routine histological analysis. Four prostate cancer tumors and four liver cancer tumors showed, on average, a threefold increase in stiffness due to FUS thermal treatment. Histology showed complete (100%) coagulation necrosis in these cases. These data suggest that MRE may be an effective means to assess tissue ablation.

In paper, we report our recent results of using the air force ultrasound transducer to study the resonance of rubber tubes. Experiments were carried out on a rubber latex tube. Seven resonant frequencies were measured between 50 Hz and 200 Hz. Theoretical calculation of the resonant frequency on the tube was done with the wave propagation approach. The relative differences of the seven resonant frequencies between the experiment and the theory are less than 6 %. This research shows that the air force ultrasound transducer can be used for tube resonance measurement.

A custom computer-controlled rapid prototyping system was designed and developed in this research. This system for bio-manufacturing of polymer scaffolds included 3D motion control components, a nozzle, a pressure controller, and a temperature-controlled reservoir containing a biomaterial. Heating elements built into the reservoir melted the biomaterial. The pressure line attached to the reservoir provided a controllable force that extruded the polymer biomaterial through the nozzle and deposited the polymer biomaterial onto a platform to fabricate scaffolds. A low pressure (830 KPa) system was designed and fabricated to accommodate different temperatures, motion speeds, and viscosities of polymer biomaterials. The reservoir with the nozzle was mounted to servo motor-controlled linear x-y motion devices along with a third servo motor-controlled device that controlled the z-position of the platform. Poly(ε-caprolactone) [PCL] was used to fabricate scaffolds with designed structure that were used in cell and tissue regeneration studies. 3D computer-aided design (CAD) with Pro-Engineer and computational finite element analysis (FEA) programs with MSC_Patran and MSC_Marc were used to model scaffold designs with appropriate architecture and material selection. The CAD models were used in FEA to develop new methods for determining mechanical properties of tissue scaffolds of desired structure and geometry. FEA models were validated by mechanical testing and other published results. Technology developed in this research has potential for the advancement of bio-manufacturing, and design optimization of scaffolds for tissue engineering.

Purpose The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM. Patients and Methods In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov ( NCT00057564 ). Results A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%). Conclusion Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.