Jay P. Mohr - US grants

The aims of the Career Development Core of the NYCC-SPOTRIAS are to provide for the training of young investigators planning active research careers in academic neurology with a focus on translational acute stroke research. Careers in stroke research have been a strong goal of our 20-year training program. All of our prior trainees have actively participated in our ongoing research studies, some have successfully achieved independent NIH funding, and 7 of our more recent trainees have been supported by K awards. The growth of the program has depended on attracting able candidates, providing a supportive environment for career development, and relying on the senior faculty as mentors. Our proposal for the 1-year SPOTRIAS-sponsored fellowship program builds on the foundation of a strong clinical program for the new Vascular Neurology residency. The multi-disciplinary faculty includes neurologists with a specialized expertise in the care of patients with stroke, interventional neuroradiologists, neurointensivists, neuroradiologists, neurosurgeons, emergency room physicians, cardiologists, rehabilitation medicine physicians, ultrasonographers, epidemiologists, and statisticians. Clinical training is provided through hospital rotations on the Neurovascular Unit, Neurointensive Care Unit, Non-invasive ultrasound laboratory, outpatient consultation offices, didactic conferences, case conferences, and lecture courses. The additional year of funding through SPOTRIAS will provide for the fellow to get training in the methods of translational research through a combination of 4-6 didactic courses in our Mailman School of Public Health, active participation in an ongoing acute stroke translational research project, and fostering a supportive mentored relationship with our faculty translational stroke researchers.

Brain arteriovenous malformations (AVMs) have been the subject of a 15-year study at our institution. Our first efforts were to identify factors predictive of post-operative perfusion- breakthrough hemorrhage, then of cerebral 'steal', and more recently of risk factors predicting first and recurrent hemorrhage, single-center treatment study including quantitation of 'eloquence', and most recently a population-based prospective collection of AVM incidence hemorrhage and estimates of outcome and efforts to developed a world-wide study of this complex low- frequency illness. The current proposal is, in part, a continuation of work funded by prior RO1s, mainly NS-34747 relocated as of 1-Jan-2000 to Univ Calif San Francisco by the our long-term collaborator PI, WL Young, now a newly-chaired Professor of Research Anesthesia there, but also a change in focus and extension into new areas which we believe justifies our application for new funding. Dr Young's plans for an AVM project in San Francisco should lead to the development of another project which we hope can eventually lead to a bi-coastal effort. Three proposals are made. Specific aim 1 is a population-based acquisition of the incidence of AVM hemorrhage, its morbidity, and mortality drawn from the roughly 9,000,000 population in the `New York Islands' (Manhattan, Staten Island, and Long Island - including Queens, Brooklyn, and Nassau and Suffolk Counties), a study begun within the last year. The feasibility has been tested, the goals expanded, and data collection is well under way. The results are expected to provide useful assessments for AVM hemorrhage to permit better decisions for treatment versus conservative follow-up, and allow estimates of comparative costs of each of the current management plans. Specific aim 2 is to bring to fruition our worldwide web site for AVMs. The initial steps taken with colleagues from 19 countries to date has revealed the need for consensus on the interpretation of AVM imaging, planned for its first meeting in Feb-2000. Following consensus, centers whose population-based capabilities (i.e., Singapore, a population of 4,000,000 served by three hospitals some of whose staff members trained with us) will provide a means to test the risk factors for hemorrhage created from our referral-based Columbia center and identify possible other factors not represented in our data base. The findings will also test our current center-based data for the morphologic imaging characteristics of AVM in predicting hemorrhage. The two preceding aims should permit estimates for the formulation of a clinical trial, but we cannot promise the organization of a trial until more complete data available. Specific aim 3 is our proposal for a single-center treatment study, including more intensive studies of 'eloquence', a term in current use to decide suitability for treatment, but one based on largely-outmoded concepts of anatomical-clinical correlations. The methods employed are on-the-table assessments of cerebral function derived from Behavior Science principles and undertaken with local anesthesia challenges using agents with differential effects on brain white and gray matter. The results are improving the prediction for short- and long-term outcome for embolization and surgery.

[unreadable] DESCRIPTION (provided by applicant): Recent evidence has indicated an uncertainty of the best means of management for unruptured brain arteriovenous malformations (BAVMs), whether by medical management or invasive treatment. A Randomized trial of Unruptured Brain AVMs (ARUBA) is proposed in a re-application, conducted by two independent but highly coordinated units, ARUBA-CLIN and ARUBA-STAT. Patients will be randomized to medical management or to invasive treatment (endovascular, neurosurgical, or radiosurgery, alone or in combination) and followed for a minimum of 5 years. The primary hypothesis is that medical management improves long-term outcomes of patients with unruptured BAVMs compared to invasive treatment for the composite event of death from any cause or stroke (hemorrhage or infarction confirmed by imaging) and disability as measured by the Rankin Scale. The primary null hypothesis is that there is no difference between medical management or invasive treatment for these outcomes. The null hypothesis will be tested against the alternative hypothesis that there is a difference between treatments with a two-sided 0.05 level log-rank test. With a plan to enroll 800 patients at over 80 clinical sites, the test will have 87.5% power to detect a risk reduction of 40% (hazard ratio of 0.60), and 80% power to detect a risk reduction of 36.5% (hazard ratio of 0.635). These hazard ratios correspond to an absolute decrease in 5-year event rates of 7.5% and 6.7% respectively for medical management, from an assumed 5-year event rate of 20% for invasive treatment. ARUBA-CLIN, the clinical arm of the trial, will coordinate the day-to-day conduct of the trial and interface with a European arm. It will handle pre-randomization inquiries and respond to clinical queries and policy issues arising during the trial. An Executive Committee of ARUBA-CLIN and ARUBA-STAT investigators and senior coordinators will meet frequently under tightly specified and controlled communication protocols to implement the needs of the trial. The ARUBA-CLIN document outlines the background and preliminary work leading to the proposal, definitions, inclusion-exclusion criteria and the clinical sites which will participate in patient enrollment. The data management and statistical component is laid out in detail in the accompanying ARUBA-STAT proposal. An accompanying Manual of Protocol, including data collection forms, provides details for the implementation of the trial. [unreadable] [unreadable]

The stroke program at the Neurological Institute has provided clinical, research, and post-graduate opportunities in an eclectic style from its founding 1983. Over 50 trainees have had one or more years of such experiences, their number including both American and foreign clinicians. All but a handful now hold academic positions, many tenured, some are chaired professors, and at least 5 are now departmental chairs. SPOTRIAS provided qualitative and quantitative increases n opportunities for us. A more structured program could be put in place, one no longer controlled by the unpredictability in available funds for salary and planned committed time. The program now offers opportunities to take courses in epidemiology and clinical trial design at the Mailman School of Public Health, along with the time away from clinical duties to pursue them. The SPOTRIAS fellow also takes the lead in organizing and selecting the subjects and patients forthe weekly conferences, held midday on Fridays; joins or starts clinical research projects with one of more faculty, the success of which is reviewed twice yeariy with the SPOTRIAS faculty. The preparation and submission of abstracts for meetings are part of the responsibility, which is also reviewed by faculty. (S)he also participates in monthly SPOTRIAS meetings and in the collection of data and the analyses for publication. The range of cases is also reviewed monthly with a faculty supervisor to insure ample exposure to the disease states that comprise stroke. Weekly attendance in the Stroke Clinic adds to the experience.