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Sci Transl Med. 2019 Jun 12;11(496). pii: eaat5857. doi: 10.1126/scitranslmed.aat5857.

In vivo liquid biopsy using Cytophone platform for photoacoustic detection of circulating tumor cells in patients with melanoma.

Author information

1
Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
2
Laboratory of Biomedical Photoacoustics, Saratov State University, 83 Astrakhanskaya Street, Saratov, 410012, Russia.
3
Department of Applied Science (Physics), University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA.
4
Department of General and Visceral Surgery, University Hospital of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
5
Institute of Aging, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
6
Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
7
Department of Biostatistics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
8
Division of Hematology Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
9
Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
10
Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. zharovvladimirp@uams.edu.

Abstract

Most cancer deaths arise from metastases as a result of circulating tumor cells (CTCs) spreading from the primary tumor to vital organs. Despite progress in cancer prognosis, the role of CTCs in early disease diagnosis is unclear because of the low sensitivity of CTC assays. We demonstrate the high sensitivity of the Cytophone technology using an in vivo photoacoustic flow cytometry platform with a high pulse rate laser and focused ultrasound transducers for label-free detection of melanin-bearing CTCs in patients with melanoma. The transcutaneous delivery of laser pulses via intact skin to a blood vessel results in the generation of acoustic waves from CTCs, which are amplified by vapor nanobubbles around intrinsic melanin nanoclusters. The time-resolved detection of acoustic waves using fast signal processing algorithms makes photoacoustic data tolerant to skin pigmentation and motion. No CTC-associated signals within established thresholds were identified in 19 healthy volunteers, but 27 of 28 patients with melanoma displayed signals consistent with single, clustered, and likely rolling CTCs. The detection limit ranged down to 1 CTC/liter of blood, which is ~1000 times better than in preexisting assays. The Cytophone could detect individual CTCs at a concentration of ≥1 CTC/ml in 20 s and could also identify clots and CTC-clot emboli. The in vivo results were verified with six ex vivo methods. These data suggest the potential of in vivo blood testing with the Cytophone for early melanoma screening, assessment of disease recurrence, and monitoring of the physical destruction of CTCs through real-time CTC counting.

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