Title: Improving diagnostic US specificity on breast biopsies using US-guided Diffuse Optical Tomography Abstract In current clinical practice, while the characteristics of malignant and benign breast lesions are well established by conventional imaging techniques, the overlapping appearances of malignant and benign lesions have prompted radiologists to recommend biopsy for most low and moderate risk breast lesions. As a result, in the United States, approximately one million image-guided breast biopsies are performed each year, with the majority of the lesions yielding benign results. Many attempts to improve this situation have not been successful. This application will explore the potential impact of Ultrasound (US)-guided diffuse optical tomography (DOT) as an adjunct to US in a diagnostic setting, with the goal of reducing benign biopsies without compromising cancer detection sensitivity. US-guided DOT provides hemoglobin concentration values and distributions which in turn map out lesion vascularity or angiogenesis. Recently, we retrospectively evaluated 288 patients to assess the potential clinical impact of our technique in characterizing low and moderate risk breast lesions, which might not need to be biopsied if the US-guided DOT technology were used in the biopsy decision making process. In this patient cohort, the total hemoglobin level combined with two radiologists’ diagnosis achieved high sensitivity of 96.6-100% on cancer detection and negative predictive value of 99-100%. Using a conservative threshold for the total hemoglobin (tHb) data to differentiate lesions based on the amount of vascularity, we found the number of lesions that would be referred to biopsy decreased by approximately 45% on average, while maintaining high detection sensitivity. Our hypotheses are: 1) The first hypothesis is that the measured tHb values and distribution can be potentially used as an adjunct for radiologists to reduce unnecessary biopsies in low risk patients with benign pathological results; and 2) The second hypothesis is that while reducing unnecessary benign biopsies, the addition of adjunct information from US-guided DOT still maintains a high sensitivity of capturing nearly all malignant tumors. In this application, we propose three aims: 1) Optimization and validation of a new non-iterative imaging reconstruction algorithm and new statistical methods for automated data processing, robust data selection, with the goal of near real-time imaging for onsite diagnosis by physicians. This is a significant step forward to bring this technology into clinics; 2) To prospectively assess the impact of adjunctive US-guided DOT to conventional breast imaging on accurate breast cancer diagnosis and reduction of benign biopsy. Approximate 300 patients will be recruited at the Radiology Department of Washington University to validate the early retrospective results; and 3) Perform statistical analysis to validate the reduction of benign biopsy while main...