Complete mediastinal lymph node dissection---does it make a difference?

PURPOSE: To review the evidence supporting a role for the beta (beta) isoform of protein kinase C (PKC) in the pathogenesis of diabetic retinopathy and the possible therapeutic benefit of inhibiting this enzyme. DESIGN: Brief literature review of research suggesting the potential use for systemic inhibitors of the beta isoform of PKC as a medical therapy to prevent the progression of diabetic retinopathy. Brief consideration is given to previous, primarily clinical, studies dealing with other therapies for this disease. RESULTS: Kinases transfer the terminal, "high energy," phosphate group of ATP to a site on a target protein, thereby activating the protein, which may be an enzyme, cell membrane receptor, or ion transport channel. The PKC family is a group of such enzymes that require specific activator molecules, including diacylglycerol, whose intracellular concentration is substantially increased during the hyperglycemia of diabetes. Protein kinase Cbeta is present at high levels in the retina. Increased activation of this enzyme, perhaps by producing tissue hypoxia, leads to increased expression of vascular endothelial growth factor, a mitogen that increases proliferation of vascular endothelial cells leading to neovascularization and enhances breakdown of the blood-retinal barrier, perhaps resulting in macular edema. CONCLUSIONS: By interfering with the above biochemical pathways, PKC inhibitors may retard or prevent the development and progression of diabetic retinopathy. Because members of the PKC family are found throughout the body, a generalized inhibitor is likely to be toxic. However, an inhibitor specific for PKCbeta may act effectively within the retina and have a favorable toxicity profile. Two phase III randomized controlled clinical trials of such an inhibitor are now in progress, attempting to evaluate the efficacy of this approach to preventing the progression, or inducing regression, of "nonclinically significant" diabetic macular edema and of severe nonproliferative diabetic retinopathy.

Clinical Trials, Phase III as Topic↗

PubMed2002

Statistical methodology of phase III cancer clinical trials: advances and future perspectives.

The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.

Clinical Trials, Phase III as Topic↗

PubMed2002

Health Economics Unit achievements.

This article describes the activities of the EORTC Health Economics Unit since its inception in early 1994. The aim of the unit is to carry out economic evaluations of competing treatment options in common cancers in order to provide health care decision makers with useful information about the relative benefits and costs of the therapies they have to choose between. These assessments are mainly carried out by integrating collection of economic data in selected phase III randomized controlled clinical trials conducted by the EORTC collaborative groups. Studies with an economic evaluation integrated are currently becoming mature enough for analysis and several publications have resulted or are in press. Some studies with data from other sources than EORTC trials have also been performed and published. In addition, the unit has actively followed and contributed to the continuous methodological development in the field of economic evaluation of health care interventions.

Clinical Trials, Phase III as Topic↗