The Pursuit of Television Broadcasting Activities in the European Community

In October 1989, the foreign ministers of the European Community (EC or Community) approved a Directive governing the pursuit of trans-European television broadcasting beginning in 1992. Controversial article 4 of the Directive requires Member States to devote a majority of their television air time to European-produced programs. Although the Community Council maintains that the quota is merely a political commitment intended to preserve Europe\u27s cultural heritage, the United States challenges the legality of the quota as economic protectionism under the General Agreement on Tariffs and Trade (GATT), and section 301 of the United States Trade Act, as amended by the Omnibus Trade and Competitiveness Act of 1988 (section 301). This Note examines the dispute between the United States and the EC concerning the implementation of the Directive\u27s majority quota on non-Community television programming. First, discussion focuses on the implementation of the Directive against the backdrop of the expanding United States presence in the European television market. This note then sets forth the United States challenge to the adoption of the Directive. Next, the possibilities for successful United States challenge to the Directive under the GATT or section 301 are analyzed. This analysis evaluates the applicability of GATT principles to television broadcasting and discusses recent attempts to adopt a far reaching General Agreement on Trade in Services (GATS) governed by GATT principles. In examining the applicability of section 301 to this dispute, the author assesses past United States responses under section 301. In conclusion, although the Directive raises legitimate concerns of the extent to which the EC will use quotas to achieve Community goals after 1992, the United States strong response to the Directive lacks credibility given past United States practice. Further, the Directive\u27s economic impact on United States suppliers of television programs is lessened by the increasing need for programming hours to fill the expanding EC television market and by the opportunity to circumvent the Directive\u27s suggested majority quota through European expansion by United States programming suppliers

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PURPOSE: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. EXPERIMENTAL DESIGN: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. RESULTS: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. CONCLUSIONS: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).This study was supported by Merck & Co., Inc. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research), the National Institute for Health Research (NIHR) Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), the NIHR Clinical Research Facility (to the Royal Marsden NHS Foundation Trust) and the Cancer Research UK and EPSRC Cancer Imaging Centre. T.A. Yap is the recipient of the 2011 Rebecca and Nathan Milikowsky – PCF Young Investigator Award and is supported by the NIHR. M.O. Leach is an NIHR Senior Investigator.This is the accepted manuscript. The final version is available from AACR at http://clincancerres.aacrjournals.org/content/early/2014/09/19/1078-0432.CCR-14-0868