2. Advances in cryoablation

Clinically-based cryoablation, grounded on well-recognized scientific principles along with the use of multiprobe devices and advanced imaging techniques, has experienced a rebirth in physician-managed destruction of diverse cancers. Cryoablative techniques have beneficially evolved over the past forty years with the development of successive generations of devices including cryoneedles, cryoballoons, intraoperative ultrasound and an expanded knowledge of the mechanisms by which cancer cells are challenged by low temperatures. A key discovery in 1998 identified the putative role of gene regulated cell death (apoptosis) in the management of the freeze zone. We now recognize three modes of cell death following a freezing insult: ice-dependent cell rupture in the tumor core, necrosis (primary and secondary) throughout the tumor and apoptosis. The AUA 2008 Best Practice Policy Statement on Cryosurgery for the Treatment of Localized Prostate Cancer recognizes that “prostate cancer cells experiencing multiple molecular-targeted stressors (cytotoxic agents) succumb more readily to low temperature exposure and that with the adoption of appropriately paired combinations, even freezing at −1°C can be totally lethal.” This presentation will focus on the evolution of recent developments supportive of the use of combinatorial cryoablative strategies that may raise the ablative temperature to near −1°C. Data will demonstrate the existence of an “apoptotic continuum” whereby the more severe cryogenic stress activates the extrinsic (membrane mediated) apoptotic pathway while less severe freezing activates the intrinsic (mitochondrial mediated) path. Ultimately, it is our aim to decipher the events and signaling pathways that are specifically involved in triggering these diverse cryo-induced mechanisms of cell death. Once known, cryosurgical procedures might be modified such that rapid-onset and delayed programmed cell death pathways would be selectively and preferentially induced in an effort to improve the overall efficacy of cryoablation. Early evidence suggesting that select cryo-sensitizers offer the potential to improve freeze sensitivity will be presented.