Structured Illumination Microscopy and a Quantitative Image Analysis for the Detection of Positive Margins in a Pre-Clinical Genetically Engineered Mouse Model of Sarcoma.
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2016
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Abstract
Intraoperative assessment of surgical margins is critical to ensuring residual tumor does not remain in a patient. Previously, we developed a fluorescence structured illumination microscope (SIM) system with a single-shot field of view (FOV) of 2.1 × 1.6 mm (3.4 mm2) and sub-cellular resolution (4.4 μm). The goal of this study was to test the utility of this technology for the detection of residual disease in a genetically engineered mouse model of sarcoma. Primary soft tissue sarcomas were generated in the hindlimb and after the tumor was surgically removed, the relevant margin was stained with acridine orange (AO), a vital stain that brightly stains cell nuclei and fibrous tissues. The tissues were imaged with the SIM system with the primary goal of visualizing fluorescent features from tumor nuclei. Given the heterogeneity of the background tissue (presence of adipose tissue and muscle), an algorithm known as maximally stable extremal regions (MSER) was optimized and applied to the images to specifically segment nuclear features. A logistic regression model was used to classify a tissue site as positive or negative by calculating area fraction and shape of the segmented features that were present and the resulting receiver operator curve (ROC) was generated by varying the probability threshold. Based on the ROC curves, the model was able to classify tumor and normal tissue with 77% sensitivity and 81% specificity (Youden's index). For an unbiased measure of the model performance, it was applied to a separate validation dataset that resulted in 73% sensitivity and 80% specificity. When this approach was applied to representative whole margins, for a tumor probability threshold of 50%, only 1.2% of all regions from the negative margin exceeded this threshold, while over 14.8% of all regions from the positive margin exceeded this threshold.
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Scholars@Duke
Melodi Javid Whitley
Melodi Javid Whitley, MD, PhD
Assistant Professor of Dermatology
Assistant Program Director for Trainee Research
Director of Transplant Dermatology
I am a physician scientist focused on the dermatologic care of solid organ transplant recipients. Clinically, I manage the the complex dermatologic side effects of immunosuppression with a focus on high-risk skin cancer. My research focuses on understanding the drivers of cutaneous malignancy in this population using translational approaches.
Diana Marcella Cardona
I am active in translational research involving gastrointestinal/hepatobiliary pathology [specifically transplant related pathology (GVHD and rejection) and carcinogenesis of the pancreas] and bone and soft tissue malignancies [imaging techniques for intraoperative margin assessment].
Nimmi Ramanujam
Nirmala (Nimmi) Ramanujam is the Robert W. Carr Professor of Biomedical Engineering, Professor of Cancer Pharmacology and Cancer Biology, and Global Health at Duke University. She founded the Center for Global Women’s Health Technologies (GWHT) in 2013 to reshape women’s health through technology innovation. Her translation program in cervical and breast cancer has brought together multiple partners across U.S. and international academic institutions, hospitals, companies, non-governmental organizations, and ministries of health.
Prof. Ramanujam creates technological solutions to detect cancer at its earliest stages, improve the effectiveness of current treatments and refine them to be more effective and less toxic. Prof. Ramanujam has developed point of care imaging technologies (Pocket colposcope and Callascope) and deep learning algorithms for the global prevention of cervical cancer. She has implemented these technologies in global health care settings where access to cancer prevention and treatment is sparse or non-existent. Towards cancer treatment, Prof. Ramanujam has developed a drug releasing immunomodulating polymer that simultaneously disrupts tumor cells and elicits an immune boost. This injectable therapeutic can be deployed in settings where treatment is unavailable owing to its simple and low-cost formulation, and it can also provide an immune boost to checkpoint inhibitors. To understand why some tumors are resistant to therapy, she has created tools to image basic cellular processes that provide insight into tumor resistance. She has shown that metabolic plasticity in human residual disease can serve as a cue for treatment optimization and patient management.
Prof. Ramanujam has created a global consortium, Women Inspired strategies for health or WISH to establish technology-enabled community clinics for cervical cancer detection in Peru and Kenya. The MacArthur Foundation recognized WISH in 2019 as one of the top 100 most transformative and impactful global solutions. She founded Calla Health in 2019 to commercialize women’s health technologies developed by her group. Through WISH and Calla Health, her femtech innovations have been disseminated in 11 countries and has reached more than 8,000 women globally. She has also co-developed the (In)visible Organ documentary on reshaping the future of women’s health through femtech. Her documentary was officially selected for the Women at the Center Film Festival at the International Papillomavirus Conference in 2020. Prof. Ramanujam has seen the value of co-creating solutions with those that are at the level of the problem. This has led to the creation of a global education program IGNITE that intersects engineering design thinking, STEM concepts, and the U.N. Sustainable Development Goals. This peer mentoring model between undergraduate students and high school and middle students has been deployed in 5 locations globally, reaching more than 2,500 students and the online curriculum has more than 1000 users.
Prof. Ramanujam has received numerous awards, several of which are highlighted here. She received the prestigious DOD Breast Cancer Innovator award in 2024 given to gifted individuals who have a history of visionary scholarship, leadership, and creativity. She received the IEEE Biomedical Engineering Award Technical Field Award in 2023 given annually for outstanding contributions to the field of Biomedical engineering. She is a fellow of and has received several awards from professional societies in the field of biomedical optics. She is a Fulbright scholar, a fellow of the National Academy of Inventors, and the American Institute of Biomedical and Biomedical Engineering (AIMBE). She has been invited as a speaker at the United Nations and at TEDx events. Her textbook, Biomedical Engineering for Global Health (2024), examines the intersection of health systems, point of care technologies, and data analytics / artificial intelligence and how these technological capabilities can broaden access to care in the 21st century.
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