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Cytotoxic Natural Killer Subpopulations as a Prognostic Factor of Malignant Pleural Effusion

  • Susana Herrera Lara
  • Estrella Fernández-Fabrellas
  • Gustavo Juan Samper
  • Josefa Marco Buades
  • Rafael Andreu Lapiedra
  • Amparo Pinilla Moreno
  • María Morales Suárez-Varela
PLEURAL DISEASE
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Abstract

Background

Malignant pleural effusion (MPE) is a sign of advanced disease of poor prognosis. As natural killer (NK) cells are involved in the first line of tumour defence, we aimed to validate a new diagnostic and prognostic indicator for MPE based on NK subpopulations of pleural fluid (PF) and peripheral blood (PB).

Methods

NK subpopulations were determined in PF and PB in 71 patients with malignant, paramalignant or benign pleural effusion. The receiver operating characteristic (ROC) curves, Kaplan–Meier, multivariable Cox model and decision trees created with the CHAID (Chi-square automatic interaction detector) methodology were employed.

Results

We demonstrated that the PF/PB ratios of the CD56 bright CD16− and CD56 dim CD16− NK subpopulations were higher (p = 0.013 and p = 0.003, respectively) in MPEs and paramalignant pleural effusions (PPEs) than in benign ones, with an AUC of 0.757 and 0.741, respectively. The PF/PB ratio of CD16+ NK and CD57+ NK obtained a higher hazard ratio (HR) in the crude Cox’s regression analysis. In the adjusted Cox’s regression analysis, the PF/PB ratio of CD16+ NK gave the highest HR (HR 6.1 [1.76–21.1]) (p = 0.004). In the decision tree created for the MPE prognosis, we observed that the main predictor variable among the studied clinical, radiological, and analytical variables was lung mass, and that 92.9% of the patients who survived had a PF/PB ratio of the CD56 dim CD16+ NK subpopulation ≤ 0.43.

Conclusions

Our data suggest that both the PF/PB ratios of cytotoxic subpopulations CD57+ NK and CD16+ NK are useful as a prognostic factor of MPE. Other subpopulations (CD56 bright CD16− and CD56 dim CD16− NK) could help to diagnose MPE.

Keywords

Biomarker Cancer Diagnosis Flow cytometry Natural killer cells Pleural effusion Prognosis 

Abbreviations

MPE

Malignant pleural effusion

NK

Natural killer

PF

Pleural fluid

PB

Peripheral blood

ROC

Receiver operating characteristic

CHAID

Chi-square automatic interaction detector

CT

Computed tomography

PPE

Paramalignant pleural effusion

CEIC

Committee of Ethics and Clinical Trials

PBS

Phosphate-buffered saline

SD

Standard deviation

AUC

ROC area under the curve

CI

Confidence intervals

BPE

Benign pleural effusion

HR

Hazard ratio

Notes

Acknowledgements

The authors would like to thank the Pulmonology Foundation of the Valencian Community for the grant that this work was awarded with, and with which the monoclonal antibodies employed were obtained. They also thank everyone who collaborated either directly or indirectly in this research.

Author Contributions

SHL designed and conducted the research, collected, analysed and interpreted data, and wrote the manuscript. EF-F designed and conducted the research, interpreted the data, wrote the manuscript and critically revised the article. GJS critically revised the article. JMB analysed and interpreted the data. RAL analysed and interpreted the data. APM provided technical assistance. MMS-V analysed and interpreted the data, performed the statistical analysis and critically revised the article.

Funding

Dr. Susana Herrera Lara has received research scholarship support from the Pulmonology Foundation of the Valencian Community.

Compliance with Ethical Standards

Conflict of interest

We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no financial support for this work that could have influenced its outcome.

Ethical Approval

We further confirm that any aspect of the work covered herein that has involved human patients has been conducted with the ethical approval of all the relevant bodies, and that such approvals are acknowledged in the manuscript.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Susana Herrera Lara
    • 1
  • Estrella Fernández-Fabrellas
    • 2
  • Gustavo Juan Samper
    • 2
  • Josefa Marco Buades
    • 3
  • Rafael Andreu Lapiedra
    • 4
  • Amparo Pinilla Moreno
    • 3
  • María Morales Suárez-Varela
    • 5
    • 6
  1. 1.Pulmonology DepartmentDr Peset University HospitalValenciaSpain
  2. 2.Pulmonology DepartmentGeneral University Consorci HospitalValenciaSpain
  3. 3.Hematology DepartmentDr Peset University HospitalValenciaSpain
  4. 4.Hematology DepartmentLa Fe University and Polytechnic HospitalValenciaSpain
  5. 5.Unit of Public Health and Environmental Care, Department of Preventive MedicineUniversity of ValenciaValenciaSpain
  6. 6.Biomedical Research Centre Network on Epidemiology and Public Health (CIBERESP)Institute of Health Carlos IIIMadridSpain

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