One of the major challenges in subsaharan Africa is the high prevalence of AIDS related cancers (the second wave of AIDS). This includes aggressive lymphomas such as diffuse large B-cell and Burkitt's, a considerable proportion of which are not worked up or are misclassified. This is because of bottlenecks in pathology services, restricted access to proper tissue specimen, limited availability of specialists, lack of adequate instrumentation in rural settings, among other factors. Considering that a good proportion of cases are curable even in low and middle income countries (LMICs), windows of therapeutic opportunities are commonly missed. As a result, there is a need for low-cost, fast and accurate detection technology to correctly diagnose aggressive lymphomas (and other prevalent cancers). Innovation. We have developed a low-cost, simple holography-based molecular detection strategy that has been implemented on smartphones. In essence, freshly harvested fine needle aspirates (FNA) are added to a disposable array chamber with lyophilized antibody coated beads of unique sizes and absorbance/holographic signatures. Bead binding to cells is holographically measured using the smartphone's built-in camera. Captured images are transferred to a server where reconstruction algorithms deconvolute image content to provide quantitative measures of malignant cell numbers and molecular subtypes. This approach bypasses large core or surgical biopsies, the need for embedding, sectioning and staining, and expert immunopathologist interpretation. Indeed, the entire procedure can be carried out by nurses, a major advantage in Africa. We have integrated these innovative features into a working smartphone prototype and have tested the device in lymphoma and cervical cancer. In these preliminary feasibility experiments, we have achieved single cell detection sensitivities as well as phenotyping capabilities. The goal of this application is to advance this cutting-edge point-of-care platform and apply it to address the diagnostic lymphoma challenges in Africa. We propose two major aims. In the UH2 phase we will expand the existing prototype to multiplexed sensing essential for lymphoma diagnostics. In The UH3 phase we will conduct two clinical trials in Botswana. In a first trial (HALT-1 trial) we will enroll 200 patients in Gaborone and Francistown with a high clinical suspicion for lymphoma to compare smartphone diagnostics to conventional immunohistochemistry. To extend the utility to rural settings we will partner with a recently established Botswana initiative that supports 30 rural communities and perform a `real world' study on 200 patients who will have FNA for lymphadenopathy of unknown etiology (HALT-2 trial). The cooperative proposal brings together a new collaborative team of world class clinicians, oncologists, innovators, engineers, global health experts and entrepreneurs to test the system through the existing Botswana-Harvard partnership. We propose the following aims in the two phases of this proposal.

Public Health Relevance

We propose to use a low cost, simple, holography-based molecular smartphone system to allow molecular detection and phenotyping of cancers in low and middle income countries. We anticipate that the technology will be broadly applicable to not only lymphoma diagnostics but also other highly prevalent malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
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Special Emphasis Panel (ZCA1-TCRB-6 (A1))
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Liddell Huppi, Rebecca
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Massachusetts General Hospital
United States
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Im, Hyungsoon; Pathania, Divya; McFarland, Philip J et al. (2018) Design and clinical validation of a point-of-care device for the diagnosis of lymphoma via contrast-enhanced microholography and machine learning. Nat Biomed Eng 2:666-674
Im, Hyungsoon; Park, Yong Il; Pathania, Divya et al. (2016) Digital diffraction detection of protein markers for avian influenza. Lab Chip 16:1340-5
Pathania, Divya; Im, Hyungsoon; Kilcoyne, Aoife et al. (2016) Holographic Assessment of Lymphoma Tissue (HALT) for Global Oncology Field Applications. Theranostics 6:1603-10
Song, Jun; Leon Swisher, Christine; Im, Hyungsoon et al. (2016) Sparsity-Based Pixel Super Resolution for Lens-Free Digital In-line Holography. Sci Rep 6:24681
Park, Yong Il; Im, Hyungsoon; Weissleder, Ralph et al. (2015) Nanostar Clustering Improves the Sensitivity of Plasmonic Assays. Bioconjug Chem 26:1470-4
Im, Hyungsoon; Castro, Cesar M; Shao, Huilin et al. (2015) Digital diffraction analysis enables low-cost molecular diagnostics on a smartphone. Proc Natl Acad Sci U S A 112:5613-8