Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

A discussion of “Estimating the historical and future probabilities of large terrorist events'' by Aaron Clauset and Ryan Woodard

The terrorist attacks in the United States on September 11, 2001 appeared to be a harbinger of increased terrorism and violence in the 21st century, bringing terrorism and political violence to the forefront of public discussion. Questions about these events abound, and “Estimating the Historical and Future Probabilities of Large Scale Terrorist Event” [Clauset and Woodard (2013)] asks specifically, “how rare are large scale terrorist events?” and, in general, encourages discussion on the role of quantitative methods in terrorism research and policy and decision-making. Answering the primary question raises two challenges. The first is identify- ing terrorist events. The second is finding a simple yet robust model for rare events that has good explanatory and predictive capabilities. The challenges of identifying terrorist events is acknowledged and addressed by reviewing and using data from two well-known and reputable sources: the Memorial Institute for the Prevention of Terrorism-RAND database (MIPT-RAND) [Memorial Institute for the Prevention of Terrorism] and the Global Terror- ism Database (GTD) [National Consortium for the Study of Terrorism and Responses to Terrorism (START) (2012), LaFree and Dugan (2007)]. Clauset and Woodard (2013) provide a detailed discussion of the limitations of the data and the models used, in the context of the larger issues surrounding terrorism and policy.