Project Summary/Abstract The primary goal of this research project is to develop and translate to clinical use a novel optical imaging technology based on combined Optical Coherence Tomography (OCT) and Confocal Microscopy (CM) for non- invasive real-time diagnosis of non-melanoma skin cancers (NMSCs), tumor subtyping and margin mapping that will assist physician-patient decision in treatment planning (biopsy vs. no biopsy, surgery vs. non-surgical), as well as on performing the therapy. The increasing incidence and prevalence in skin cancer, especially among the aging population, combined with the high costs of surgery and subsequent reconstruction, and the physical and psychological trauma that patient endures with surgical intervention, has led to an increasing adoption and implementation of alternative non-surgical treatments that can be highly effective and less invasive. Laser ablation and radiotherapy have been proven to be effective therapies for common skin cancers and have the additional benefits that are easily tolerable and not associated with less scarring or disfigurement. Therefore, their clinical use has substantially increased within the recent years to treat skin cancers. However, the primary challenge in delivering effective laser fluence or radiotherapy dose for skin cancer is accurate delineation of the cancer target, both in depth and laterally. Fortunately, the unique capability of OCT/CM to visualize tissue morphology with micron-scale resolution can be used in real-time in the clinics to aid therapy target delineation and enable more precise delivery of therapy without need to ?estimate? the subclinical extent of spread, thereby minimizing side effects. In addition, CM/OCT can be used to confirm eradication of skin cancer, which is currently limited to visual inspection, a highly insensitive and subjective method. The preliminary evaluation of the feasibility of this technology for aiding accurate target delineation will be performed during the Phase I program. Based on Phase I conclusions, the technology will be refined in Phase II and evaluated clinically on a large pool of patient population. Both therapy decision aiding and therapy guidance capabilities will be evaluated.