Imatinib Mesylate: Past Successes and Future Challenges in the Treatment of Gastrointestinal Stromal Tumors

Just over a decade ago, gastrointestinal tumours were a poorly understood mesenchymal neoplasm unsuccessfully treated with chemotherapy. Cytotoxic therapy for advanced disease yielded response rates of 10% and median survival of just 18 months. However, the discovery of KIT and platelet derived growth factor receptor alpha (PDGFRA) mutations as oncogenic drivers of most gastrointestinal tumours, paved the way for targeted therapy. Imatinib mesylate, a tyrosine kinase inhibitor, produces a clinical benefit rate (complete response, partial response, and stable disease) of more than 80% in metastatic setting and a median survival of 57 months. Imatinib is now also approved in adult patients following resection of KIT-positive GIST. Major insights into the mechanism of action of imatinib, unique pharmacokinetics, drug resistance, and management of low grade but chronic adverse effects continue to be made

The extremal index for GARCH(1,1) processes with t-distributed innovations

Economics Department Working Papers, University of Parm

Regular variation and extremal dependence of GARCH residuals with application to market risk measures

Stock returns exhibit heavy tails and volatility clustering. These features, motivating the use of GARCH models, make it difficult to predict times and sizes of losses that might occur. Estimation of losses, like the Value-at-Risk, often assume that returns, normalized by the level of volatility, are Gaussian. Often under ARMA-GARCH modeling, such scaled returns are heavy tailed and show extremal dependence, whose strength reduces when increasing extreme levels. We model heavy tails of scaled returns with generalized Pareto distributions, while extremal dependence can be reduced by declustering data

Does ownership affect the variability of the production process? Evidence from international courier services

A firm often must ensure that products or services it produces match customer expectations. We define variability as any deviation in a production process yielding products or services whose attributes differ from the firm's stated target specifications. Firms pursuing products marked by low variability are more subject to maladaptation costs if production processes are not adjusted to avoid nonconformities. Furthermore, such adjustments often require idiosyncratic investments (e.g., dedicated information technology systems), thereby creating contractual hazards and potential underinvestment. We hypothesize that ownership of sequential activities in the value chain helps mitigate problems associated with maladaptation as well as suboptimalities in transaction-specific investment, thereby resulting in lower variability. Using data on delivery times from the Japanese international courier and small package services industry, we assess the variability-reducing role of ownership in two complementary ways. The first approach is parametric, allowing us to assess the impact of ownership on the variance associated with delivery time; here we focus on shipments that frequently fail to arrive precisely within the time period initially expected by customers. The second approach is more consistent with the notion of reliability, or the likelihood that shipments will not arrive later than expected: we nonparametrically estimate the distribution of deviations between actual and expected delivery time, and verify how distinct organizational choices change the distribution. Ownership of multiple segments yields a particularly pronounced effect on both variance and reliability. Ownership bestows variability-reducing benefits of ownership, especially when ownership is observed in multiple stages of the value chain