One of the greatest challenges for early cancer detection is how to effectively manage patients who are at risk fordeveloping invasive cancer. As most at-risk patients will not develop cancer, frequent and invasive surveillance of atriskpatients carries financial, physical, and emotional burdens. But clinicians lack tools to accurately predict whichpatients will likely progress into malignancy. With our increased understanding of molecular changes in cancerdevelopment, it is now established that disrupted epigenome that can alter nuclear architecture occurs in all stages ofcancer development including in normal precursor cells. Therefore, assessment of nanoscale nuclear architecturerepresents a promising strategy for identifying pre-cancerous changes. Here we present the development of threedimensionalnuclear architecture mapping (3D-nanoNAM) to assess the depth-resolved properties of phase objects withslowly varying refractive index without a strong interface, based on a variant form of Fourier-domain optical coherencetomography (FD-OCT). By computing the Fourier phase of the FD-OCT signal resulting from the light back-scatteredby cell nuclei, 3D-nanoNAM quantifies, with nanoscale sensitivity, the depth-resolved alterations in mean nuclearoptical density, and localized heterogeneity in optical density of the cell nuclei. We demonstrate that 3D-nanoNAMdistinguishes high-risk patients with inflammatory bowel disease (IBD) colitis from those at low-risk via/throughimaging tissue sections that appear histologically normal according to pathologists. As 3D-nanoNAM uses clinicallyprepared formalin-fixed, paraffin-embedded tissue sections, it can be integrated into the clinical workflow.
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