Joseph Ransohoff, MD - US grants

The primary requisite of programs designed to improve treatment modalities in malignant brain tumor is that an adequate number of patients be available to performs prospective randomly organized trials. Only by such trials can effective improvements in therapy be substantiated. The history of the treatment of this disease includes a number of instances in which the promise of an effective advance in treatment held out in a Phase II trial has failed to materialize in a Phase III trial. It is likely that the major reason for this failure is that an inadequate number of patients was entered. Brain Tumor Study Group data indicate that there are multiple disease characteristics which influence survival and that these prognostic variables differ from one patient to another. Thus, enough patients must be entered into a trial to distinguish between the effects of therapy and those produced by prognostic variables. Furthermore we believe that randomized prospective trials that include a control group are better than those using historical controls. The major reason for this is the occurrence during the course of trials of a change in the ability to diagnose the disease. For example, the computerized tomographic scanner (CT) produced a quantum change in the ability to diagnose brain tumor in some patients. How could it be shown that the improvement in survival that occurred over the years that the CT scan came into use was not merely a function of earlier diagnosis. Because the BTSG has always included a "control" arm consisting of surgery, radiation therapy and BCNU, we could show that despite the introduction of the CT scan the combination of surgery, radiation therapy and BCNU produced essentially the same overall effect.

This is a request for funding of a feasibility study for head injury, to provide for programmatic development leading to the creation of a head injury clinical research center. Four research projects and a core facility are proposed. Project 1: Will establish and develop animal models of traumatic brain injury. The aim is to utilize these models to study the role of ion dynamics, particularly their role in secondary injury. The relevance of ionic shifts to the development of management strategies will be emphasized. These studies will fill a major gap in this field and the characterization of the models developed serve as a basis for the development of new and hopefully clinically relevant therapeutic interventions. Project 2: Will develop methods and measures of cognitive and behavioral interventions. The long term goal will be to establish a program of neurobehavioral interventions leading to improvement in the major causes of long term disability in the head injured population. Project 3: Will assess the role of early administration of high dose methylprednisolone on the outcome of patients with moderate and severe traumatic brain injury. Outcome will be assessed by quantitative measures of cognitive and behavioral function developed by investigators in the Core Facility of this program. Project 4: Will test the feasibility of electrical stimulation of deep brain structures to modify the neurobehavioral status of patients with post-traumatic coma - persistent vegetative state. Electrophysiologic, behavioral and cognitive methods will be developed and tested as measures of outcome in this project. The Core Facility will support all projects in this proposal. This facility will be responsible for the establishment of methods of tracking patients admitted to the Institution with traumatic brain injury. The long term goals are to characterize the patient population served by the institution; to define the neurologic, cognitive and behavioral outcome of this population; and to develop biostatistical methods to address the effects of acute, subacute and chronic interventions on the long term functional status of the traumatic brain injured patient population.