ESTABLISHMENT 0F MECHANISMS OF CRYODESTRUCTION

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DESCRIPTION (Adapted from Applicant's Abstract): Prostate cancer is expected to be diagnosed in more that 300,000 new patients this year. There is debate as to the optimal treatment of the disease of which cryosurgery is one. Based on what is currently known about cellular level mechanisms of injury less than one half of the volume of tissue frozen in a typical cryosurgical iceball would be destroyed. Nonquantitative studies in vivo, however, suggest that the volume of tissue destroyed in vivo is closer to the total volume of the tissue frozen in the cryosurgical iceball. In order to firmly establish cryosurgery as a treatment of prostate cancer, the relationship between the iceball formed during the surgery and the ultimate damage it creates after thawing must be both controllable and reproducible. Therefore this work aims to develop a precise understanding of the mechanism of damage induced by the formation and thawing of the cryosurgical iceball at the cellular, vascular, and whole tissue (in vitro and in vivo) level. The following hypotheses and specific aims have been developed. Hypotheses: 1. Given that cryosurgery produces tissue death, the injury during cryosurgery depends on predominantly cellular mechanisms in the center of the cryosurgery iceball and predominately vascular injury at the periphery of the iceball. 2. The thermal history imposed on tissue during the cryosurgery can be used to predict the amount of tissue death by cellular and vascular mechanisms. Specific Aims: In order to test these hypotheses, the following specific aims will be accomplished: 1. Establish the thermal history during formation and thawing of a cryosurgical iceball in vitro and in vivo. 2. Quantify the relationship between biophysical and thermal changes during the formation of an iceball in vitro. 3. Establish thermally and biophysically mediated cellular injury after thawing of the iceball in vitro. 4. Establish cellular biophysical changes during the formation, and vascular injury after thawing, of the cryosurgical iceball in vivo. 5. Correlate total tissue destruction by all mechanisms to thermal history during the formation, and after thawing, of a cryosurgical iceball in vivo.