Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma

Our plain-English summary of Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma, by K. Yoneda, T. Kuwata, Y. Chikaishi, et al (Cancer Science, 2019).

The study

• Authors: K. Yoneda, T. Kuwata, Y. Chikaishi, M. Mori, M. Kanayama, M. Takenaka, S. Oka, A. Hirai, N. Imanishi, K. Kuroda, Y. Ichiki, T. Ohnaga, F. Tanaka
• Journal: Cancer Science
• Published: 2019;110(2):726-733
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Detection of rare tumor cells circulating in the blood (CTCs) presents technical challenges. CellSearch, the only approved system for clinical use, fails to capture epithelial cell adhesion molecule-negative CTCs such as malignant pleural mesothelioma (MPM). We have developed a novel microfluidic device (CTC-chip) in which any Ab to capture CTCs is conjugated. The CTC-chip was coated with an Ab against podoplanin that is abundantly expressed on MPM. Circulating tumor cell-detection performance was evaluated in experimental models in which MPM cells were spiked in blood sampled from a healthy volunteer and in clinical samples drawn from MPM patients. The CTC-chip showed superior CTC-detection performance over CellSearch in experimental models (sensitivity, 63.3%-64.5% vs 0%-1.1%; P < .001) and in clinical samples (CTC-positivity, 68.8% vs 6.3%; P < .001). A receiver operating characteristic (ROC) analysis showed that the CTC test provided a significant diagnostic performance in discrimination of unresectable disease from resectable disease (area under the ROC curve, 0.851; P = .003). The higher CTC count (≥2 cells/mL) was significantly associated with a poor prognosis (P = .030). The novel CTC-chip enabled sensitive detection of CTCs, which provided significant diagnostic and prognostic information in MPM.

© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This laboratory and clinical study from Japan tested a new device, the CTC-chip, for finding tumor cells circulating in the blood of people with malignant pleural mesothelioma. The chip was coated with an antibody against podoplanin, a protein on mesothelioma cells. Asbestos exposure was not studied. After antibody amounts were adjusted, the chip captured an average 84.1% of cells from one mesothelioma cell line added to healthy volunteer blood, but few cells from two lines with low podoplanin. With 10 or 50 tumor cells added to 1 mL of blood, the chip detected 64.5% and 63.3%, versus 0% and 1.1% for CellSearch, the approved system. In patient blood, the chip found tumor cells in 11 of 16 samples and CellSearch in 1. Among 25 patients, the chip found them in 16, more often at later stages. Cell counts helped distinguish unresectable from resectable disease, and 2 or more cells per mL was associated with poorer survival. The authors concluded the chip gave diagnostic and prognostic information that future prospective studies should validate.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiments with mesothelioma cell lines added to blood, plus a clinical evaluation of blood samples from mesothelioma patients comparing a new podoplanin-coated microfluidic device (CTC-chip) with CellSearch
• Who was studied: Four human mesothelioma cell lines (ACC-MESO-4, H226, H28, MSTO-211H) added to blood from a healthy volunteer. For the device comparison, 16 blood samples from 15 patients with malignant pleural mesothelioma. For the clinical analysis, 25 patients with malignant pleural mesothelioma (21 men, 4 women; median age 72). The study was at the University of Occupational and Environmental Health, Kitakyushu, Japan. Study dates are not given.
• Exposure: Asbestos exposure was not examined. What was tested was a detection method: a CTC-chip coated with an antibody against podoplanin, compared with the CellSearch system.
• Main results:
  • With ACC-MESO-4 mesothelioma cells added to healthy volunteer blood, average capture efficiency was 38.5% under the earlier conditions. It rose to 84.1% when the base antibody concentration was increased to 200 μg/mL.
  • H226 cells (podoplanin positive) were captured at an average 76.3%. H28 and MSTO-211H cells, which had low podoplanin expression, were captured at an average 4.4% and 9.0%, respectively.
  • When 10 or 50 tumor cells were added to 1 mL of blood, average detection sensitivity was 64.5% and 63.3% with the CTC-chip, versus 0% and 1.1% with CellSearch.
  • In 16 patient blood samples, the CTC-chip detected circulating tumor cells in 11 samples and CellSearch in 1. The results section gives this as 68.5% vs 6.3% (P < .001).
  • Among 25 patients, circulating tumor cells were detected with the CTC-chip in 16 (sensitivity, 64.0%).
  • Detection did not differ significantly by subtype among the 25 patients: 58.8% (10/17) epithelioid, 75.0% (3/4) biphasic and 75.0% (3/4) sarcomatoid (P = .734).
  • Detection was higher in advanced stages (P = .003). As printed: 0.0% (0/4) in stage IA, 42.9% (3/7) in stage IB, 56.3% (9/10) in stage IIIB, and 100.0% (4/4) in stage IV.
  • The tumor cell count distinguished 'unresectable' disease (stage IIIB or IV) from 'resectable' disease (stage IIIA or earlier). The area under the ROC curve was 0.851 (95% confidence interval, 0.667 to 1.000; P = .003).
  • At a cut-off of 2 cells, the test had a specificity of 90.9% and a sensitivity of 64.3% for unresectable disease. At a cut-off of 1, sensitivity was 92.3% and specificity 72.7%.
  • Patients with a count of 2 or more cells per mL had significantly poorer survival than those with 0 or 1. The article's abstract gives P = .030.
  • Counts were tracked during treatment in 2 patients. In both, the count decreased after effective treatment.
• The authors' conclusion: The authors concluded that the CTC-chip detected circulating tumor cells sensitively in mesothelioma patients without relying on EpCAM. In their view, it gave significant diagnostic performance in identifying 'unresectable' patients and significant prognostic value. They stated that future prospective studies are needed to validate the results.
• Limitations the authors state:
  • The podoplanin-coated chip cannot capture mesothelioma cells that lack podoplanin. Cell lines with no or low podoplanin were not captured.
  • Blood was applied to the chip immediately. Storage and shipping conditions needed for routine clinical use have not been worked out.
  • The comparisons between subtypes were based on small numbers of cases.
  • Molecular profiling of the captured cells, needed for further clinical use, has not yet been done.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Podoplanin (D2-40), Unresectable, Prognosis.

Related studies

• EpCAM-independent capture of circulating tumor cells with a 'universal CTC-chip' — Y. Chikaishi, K. Yoneda, et al. (2017)
• Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM) — K. Yoneda, F. Tanaka, et al. (2014)
• Detection of circulating tumour cells in peripheral blood of patients with malignant pleural mesothelioma — J. Raphael, C. Massard, et al. (2015)
• Circulating endothelial cell (CEC) as a diagnostic and prognostic marker in malignant pleural mesothelioma (MPM) — K. Yoneda, F. Tanaka, et al. (2012)
• Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma — H. Sato, J. Soh, et al. (2019)
• A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma — B.T.V. Duong, L. Wu, et al. (2020)

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