The management of soft tissue sarcoma remains problematic despite advances in surgery, radiotherapy, and chemotherapy. Fifty percent of patients still develop distant metastasis and will eventually die from this disease. Presently, the grade and size of the sarcoma are the most important factors used to estimate risk of relapse and overall survival. Assigning a pathologic grade to an individual sarcoma as a means of predicting clinical behavior is often difficult with a 40% discordance rate even between expert sarcoma pathologists. In addition, within each grade it remains difficult to identify those patients at highest risk for distant relapse. Although neoadjuvant chemotherapy is now given for large, high grade extremity and truncal sarcoma it remains difficult to identify those patients unlikely to respond to such therapy at an early enough time point in their treatment course to avoid the toxicity of such therapy. There is mounting evidence that the composition of membrane phospholipid in tumor tissue is an important indicator of a tumor's cellularity and proliferative capacity as well as an important early marker for tumor cell death. However, there is a lack of information on the biochemical determinants of sarcoma proliferation, metastasis and response to therapy. To address these problems novel quantitative ex-vivo NMR methods will be utilized to determine the biochemical changes in tissue lipid and cholesterol for soft tissue sarcoma and therefore predict sarcoma cellularity, necrosis, growth rate, differentiation, metastasis and response to therapy. The specific objectives are: (1) Improve lipid analysis of ex-vivo human sarcoma tissue. (2) Provide an objective measure of human sarcoma tissue cellularity and the percentage of cells in synthesis phase of the cell cycle. (3) Provide an objective measure of human sarcoma microscopic necrosis. (4) Provide an objective measure of sarcoma apoptotic and non-apoptotic cell death in transformed fibroblasts in-vitro. (5) Predict the response to neoadjuvant chemotherapy in human soft tissue sarcoma. (6) Create a novel objective biochemical NMR grading system that is more reproducible and prognostic for survival than the conventional FNCLCC histologic grading system. The results of the proposed investigation will permit the development of a clinically relevant biochemical system of prognostic determinants for soft tissue sarcoma which is currently unavailable. Utilizing this system the treating physician would have a more accurate assessment of prognosis and an improved ability to select patients for adjuvant therapy that are at highest risk of relapse and are most likely to respond to such therapy.
