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BackgroundEsophageal cancer management lacks reliable response predictors to chemotherapy. In this study we evaluated the feasibility and accuracy of Biodynamic Imaging (BDI), a technology that employs digital holography as a rapid predictor of chemotherapy sensitivity in locoregional esophageal adenocarcinoma. MethodsPre-treatment endoscopic pinch biopsies were collected from patients with esophageal adenocarcinoma during standard staging procedures. BDI analyzed the tumor samples and assessedin vitrochemotherapy sensitivity. BDI sensitivity predictions were compared to patients’ pathological responses, the gold standard for determining clinical response, in the surgically treated subset (n=18). ResultBDI was feasible with timely tissue acquisition, collection, and processing in all 30 enrolled patients and successful BDI analysis in 28/29 (96%) eligible. BDI accurately predicted chemotherapy response in 13/18 (72.2%) patients using a classifier for complete, marked, and partial/no-response. BDI technology had 100% negative predictive value for complete pathological response hence identifying patients unlikely to respond to treatment. ConclusionBDI technology can potentially predict patients’ response to platinum chemotherapy. Additionally, this technology represents a promising step towards optimizing treatment strategies for esophageal adenocarcinoma patients by pre-emptively identifying non-responders to conventional platinum-based chemotherapy. 

Abstract Nearly half of cancer patients who receive standard-of-care treatments fail to respond to their first-line chemotherapy, demonstrating the pressing need for improved methods to select personalized cancer therapies. Low-coherence digital holography has the potential to fill this need by performing dynamic contrast OCT on living cancer biopsies treated ex vivo with anti-cancer therapeutics. Fluctuation spectroscopy of dynamic light scattering under conditions of holographic phase stability captures ultra-low Doppler frequency shifts down to 10 mHz caused by light scattering from intracellular motions. In the comparative preclinical/clinical trials presented here, a two-species (human and canine) and two-cancer (esophageal carcinoma and B-cell lymphoma) analysis of spectral phenotypes identifies a set of drug response characteristics that span species and cancer type. Spatial heterogeneity across a centimeter-scale patient biopsy sample is assessed by measuring multiple millimeter-scale sub-samples. Improved predictive performance is achieved for chemoresistance profiling by identifying red-shifted sub-samples that may indicate impaired metabolism and removing them from the prediction analysis. These results show potential for using biodynamic imaging for personalized selection of cancer therapy. 

Abstract This review examines the biological physics of intracellular transport probed by the coherent optics of dynamic light scattering from optically thick living tissues. Cells and their constituents are in constant motion, composed of a broad range of speeds spanning many orders of magnitude that reflect the wide array of functions and mechanisms that maintain cellular health. From the organelle scale of tens of nanometers and upward in size, the motion inside living tissue is actively driven rather than thermal, propelled by the hydrolysis of bioenergetic molecules and the forces of molecular motors. Active transport can mimic the random walks of thermal Brownian motion, but mean-squared displacements are far from thermal equilibrium and can display anomalous diffusion through Lévy or fractional Brownian walks. Despite the average isotropic three-dimensional environment of cells and tissues, active cellular or intracellular transport of single light-scattering objects is often pseudo-one-dimensional, for instance as organelle displacement persists along cytoskeletal tracks or as membranes displace along the normal to cell surfaces, albeit isotropically oriented in three dimensions. Coherent light scattering is a natural tool to characterize such tissue dynamics because persistent directed transport induces Doppler shifts in the scattered light. The many frequency-shifted partial waves from the complex and dynamic media interfere to produce dynamic speckle that reveals tissue-scale processes through speckle contrast imaging and fluctuation spectroscopy. Low-coherence interferometry, dynamic optical coherence tomography, diffusing-wave spectroscopy, diffuse-correlation spectroscopy, differential dynamic microscopy and digital holography offer coherent detection methods that shed light on intracellular processes. In health-care applications, altered states of cellular health and disease display altered cellular motions that imprint on the statistical fluctuations of the scattered light. For instance, the efficacy of medical therapeutics can be monitored by measuring the changes they induce in the Doppler spectra of livingex vivocancer biopsies. 

Doppler frequency shifts associated with the motions in cells range from mHz to Hz, requiring ultra-stable interferometry to capture frequency offsets at several parts in 10¹⁸. Common-path interferometers minimize the influence of mechanical disturbances when the signal and reference share common optical elements. In this paper, multi-mode speckle self-referencing via a Fresnel biprism demonstrates frequency stability down to 1 mHz. A low-coherence NIR source creates an OCT-like pseudo-coherence-gate in Fourier-domain holography without phase stepping, and the Fourier reconstruction of the self-referencing speckle fields produces an image-domain autocorrelation of the target. Fluctuation spectroscopy of dynamic speckle is performed on a semi-solid lipid emulsion that captures Brownian thermal signatures and on feline tissue culture that measures active intracellular transport. The extension of biodynamic imaging to lower frequencies opens the opportunity for studies of cell crawling in macroscopic living tissues.