Conventional tissue sampling used in disease and cancer diagnosis can lead to misdiagnoses and repeated biopsies, and the tissue processed for histopathology suffers from poor nucleic acid quality/quantity for molecular profiling. Targeted micro-sampling of tissue can ensure accurate diagnosis and molecular profiling in the presence of spatial heterogeneity and complexity, especially in tumors, and facilitate acquisition of fresh tissue for molecular analysis. In this study, we explored the

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... ibility of a 1-mm precision biopsy approach guided by high-resolution reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) imaging, and reflective metallic grids for accurate spatial targeting and sampling in 7 skin cancers lesions in 6 patients. Accurate sampling was confirmed by histopathology or successful molecular profiling using next generation sequencing (NGS) approaches. Imaging guided 1-mm biopsy enabled spatial targeting and sampling for in vivo diagnosis, feature correlation and predicted depth as confirmed on histopathology. High DNA quantity (680 ng) and quality (DIN: 8) were obtained from imaging-guided high melanoma cell density areas. Subsequent mutational profiling on a 505-gene panel revealed a missense BRAF V600E oncogenic mutations at 0.02 allelic frequency for guiding therapy. Our findings demonstrate accurate sampling of regions of interest that enables downstream diagnosis, molecular analysis and research in both in vivo and ex vivo settings with broad diagnostic, therapeutic and research potential in dermatological and mucosal settings currently accessible to RCM-OCT imaging.