Fernando Vinuela - US grants

Despite an expanding role of stereotactic radiosurgery, a number of key questions remain unanswered regarding the fundamental radiobiological and histopathological mechanisms contributing to radiosurgical obliteration of brain arteriovenous malformations (AVMs). Radiosurgical dose selection remains largely empirical, and AVM characteristics (volume, hemodynamics, vessel caliber) that may dictate dose dependent radiosurgical occlusion have not been studied adequately. The long-term objective of this project is to improve the overall clinical management of patients harboring brain AVMs by increasing the efficacy and safety of stereotactic radiosurgery. This may be achieved by a more thorough understanding of the underlying radiobiological principles, obtained through investigations in an appropriate experimental model. The immediate objective of this project is to use a reliable in vivo model of experimental AVM developed in our laboratories for radiosurgical research: 1) To study characteristics of AVM that may affect its response to radiosurgey. In particular we will investigate the role of AVM hemodynamics as a variable in altering the response of the lesion to radiosurgery. 2) To perform detailed histopathological studies of radiosurgical effects and investigate how this leads to vessel occlusion. 3) To elucidate the molecular factors responsible for the morphological changes observed in an AVM following radiosurgery. In particular immunohistochemical analysis of irradiated tissue will be performed looking for the presence of cytokines that may have a role in this process. Through these efforts, we hope to enhance the success and safety of stereotactic radiosurgery for patients with brain AVMs.

DESCRIPTION (provided by applicant): Guglielmi detachable coils (GDCs) are the gold standard for endovascular treatment of brain aneurysms. However, GDCs appear to be less effective in wide-necked aneurysms (> 4mm). We propose to develop a new, bio-active, bio-absorbable polymeric material (BPM) coil that improves aneurysm healing by accelerating clot maturation and organization within the aneurysm. We hypothesize that aneurysm healing can be controlled by using BPMs. LONG-TERM OBJECTIVE: To improve clinical management of brain aneurysms by overcoming the present limitations of GDC system. The knowledge of the bio-molecular cascade eliciting aneurysm healing will allow its manipulation and development of better embolic agents. IMMEDIATE OBJECTIVE: 1) Bio-molecular and histological evaluations of natural thrombus formation in surgically created aneurysm. Special attention will be paid on cytokine expression related to clot maturation. 2) In-vitro evaluation of physical, chemical and degradation properties of commercially available Polymers for potential application in brain aneurysm therapy. 3) Utilization of a lateral aneurysm model in swine to evaluate anatomical and histological effects of different bioabsorption properties of commercially available Polymers and their impact in aneurysm healing. 4) Transform current GDC technology to bioactive surface GDC (Hybrid BPM/GDC) and evaluation of angiographic and histological effectiveness of a Hybrid BPWGDC coil. 5) Development of a 100 percent bio-absorbablehio-active intravascular coil for endovascular embolization of intracranial aneurysms

DESCRIPTION (provided by applicant): Intracranial aneurysms (ICAs) are an increasingly common finding, both from incidental discovery on imaging studies and on autopsy;it is estimated that anywhere from 1-6% of the American population will develop this problem. Unfortunately, while our ability to detect ICAs has grown, our fundamental understanding of this disease entity remains lacking and significant debate continues in regards to its treatment. Given the high degree of mortality and comorbidity associated with ruptured intracranial aneurysms, it is imperative that new insights and approaches be developed to inform medical decision making involving ICAs. Thus, the objective of this proposal is the creation of an informatics infrastructure to help elucidate the genesis, progression, and treatment of intracranial aneurysms. Building from our efforts from the previous R01, a set of technical developments is outlined to transform the array of information routinely collected from clinical as- sessment of ICA patients into a Bayesian belief network (BBN) that models the disease. First, we evolve the concept of a phenomenon-centric data model (PCDM) as the basis for (temporally) organizing clinically-derived observations, enabling the model to be associated with processing pipelines that can identify and transform targeted variables from the content of clinical data sources. Through these pipelines, specific values in free- text reports (radiology, surgery, pathology, discharge summaries) and imaging studies will be automatically extracted into a scientific-quality database. Second, the PCDM schema for ICAs is mapped to a Bayesian belief network: the linkage between the PCDM and BBN allows automatic updating of the network and its progressive refinement from a growing dataset. The BBN's topology will be determined by clinical experts and conditional probabilities computed from the extracted clinical data. A basic graphical user interface (GUI) will permit users to interact with the BBN, aiding in medical decision making tasks. The GUI will allow a clinician to pose questions from either a set of common clinical queries or to create new queries: loading a patient's medical record into this application will automatically populate BBN variables with extracted information (i.e., from the pipelines). Each technical component of this proposal will be evaluated in a laboratory setting. In addition, the BBN will be tested for its predictive capabilities and compared to other statistical models to assess its potential in guiding ICA treatment. This proposal leverages a clinical collaboration with the UCLA Division of Interventional Neuroradiology, a leader in ICA research and treatment. A combined dataset of 2,000 retrospective and prospective subjects will be used to create the ICA database and BBN. Data collection will encompass a comprehensive set of variables including clinical presentation, imaging assessment (morphology, hemodynamics), histopathology, gene expression, treatment, and outcomes. We will additionally leverage the NIH/NINDS Human Genetic DNA and Cell Line Repository for additional ICA-related data. PUBLIC HEALTH RELEVANCE: Intracranial aneurysms (ICAs) are an increasingly common finding on routine computed tomography (CT) and magnetic resonance (MR) neuro-imaging studies. The associated mortality rate and comorbidity resultant from ruptured ICAs are extreme: subarachnoid hemorrhage causes 50% of individuals to die within one month of rupture, and more than one third of survivors develop major neurological deficits. Hence, the focus of this re- search is the creation of a comprehensive research database for ICA patients, using the spectrum of data routinely acquired in the diagnosis and treatment of the problem;from this database, a new probabilistic model of ICAs will be created, providing new insights into the disease and its optimal treatment for a given individual.