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      Label-free high-throughput photoacoustic tomography of suspected circulating melanoma tumor cells in patients in vivo

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          Abstract.

          Significance: Detection and characterization of circulating tumor cells (CTCs), a key determinant of metastasis, are critical for determining risk of disease progression, understanding metastatic pathways, and facilitating early clinical intervention.

          Aim: We aim to demonstrate label-free imaging of suspected melanoma CTCs.

          Approach: We use a linear-array-based photoacoustic tomography system (LA-PAT) to detect melanoma CTCs, quantify their contrast-to-noise ratios (CNRs), and measure their flow velocities in most of the superficial veins in humans.

          Results: With LA-PAT, we successfully imaged suspected melanoma CTCs in patients in vivo, with a CNR > 9 . CTCs were detected in 3 of 16 patients with stage III or IV melanoma. Among the three CTC-positive patients, two had disease progression; among the 13 CTC-negative patients, 4 showed disease progression.

          Conclusions: We suggest that LA-PAT can detect suspected melanoma CTCs in patients in vivo and has potential clinical applications for disease monitoring in melanoma.

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          Most cited references37

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          Contrast agents for molecular photoacoustic imaging.

          Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ∼100 μm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI.
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            Real-time imaging reveals the single steps of brain metastasis formation.

            Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.
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              Detection, clinical relevance and specific biological properties of disseminating tumour cells.

              Most cancer deaths are caused by haematogenous metastatic spread and subsequent growth of tumour cells at distant organs. Disseminating tumour cells present in the peripheral blood and bone marrow can now be detected and characterized at the single-cell level. These cells are highly relevant to the study of the biology of early metastatic spread and provide a diagnostic source in patients with overt metastases. Here we review the evidence that disseminating tumour cells have a variety of uses for understanding tumour biology and improving cancer treatment.
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                Author and article information

                Contributors
                Journal
                J Biomed Opt
                J Biomed Opt
                JBOPFO
                JBO
                Journal of Biomedical Optics
                Society of Photo-Optical Instrumentation Engineers
                1083-3668
                1560-2281
                13 March 2020
                March 2020
                13 March 2020
                : 25
                : 3
                : 036002
                Affiliations
                [a ]Washington University in St. Louis , Department of Biomedical Engineering, St. Louis, Missouri, United States
                [b ]California Institute of Technology , Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Department of Medical Engineering, Pasadena, California, United States
                [c ]Washington University School of Medicine , Division of Dermatology, St. Louis, Missouri, United States
                [d ]California Institute of Technology , Caltech Optical Imaging Laboratory, Department of Electrical Engineering, Pasadena, California, United States
                Author notes
                [* ]Address all correspondence to Lynn A. Cornelius, E-mail: cornelil@ 123456wustl.edu ; Lihong V. Wang, E-mail: lvw@ 123456caltech.edu
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-6670-296X
                https://orcid.org/0000-0001-7498-133X
                https://orcid.org/0000-0003-3387-1913
                https://orcid.org/0000-0002-6338-9338
                https://orcid.org/0000-0001-9783-4383
                Article
                JBO-190413R 190413R
                10.1117/1.JBO.25.3.036002
                7069252
                32170857
                37e2a15c-db86-4a1f-96ae-ea8fb3aa8f72
                © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
                History
                : 29 November 2019
                : 27 February 2020
                Page count
                Figures: 8, Tables: 0, References: 50, Pages: 17
                Funding
                Funded by: National Institutes of Health https://doi.org/10.13039/100000002
                Award ID: DP1 EB016986
                Award ID: R01 CA186567
                Award ID: R01 EB016963
                Award ID: U01 NS090579
                Award ID: U01 NS099717
                Categories
                Imaging
                Paper
                Custom metadata
                Hai et al.: Label-free high-throughput photoacoustic tomography of suspected circulating melanoma…

                Biomedical engineering
                photoacoustic imaging,melanoma,circulating tumor cell
                Biomedical engineering
                photoacoustic imaging, melanoma, circulating tumor cell

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