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[18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis

European Journal of Nuclear Medicine and Molecular Imaging volume 44, pages 1383–1392 (2017)Cite this article

Abstract

Purpose

Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival.

Patients and methods

In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens.

Results

[18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005).

Conclusions

Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance.

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Acknowledgements

We thank neurosurgeons S. Khoury, B. Gadan, A. Borha. We also thank S. de Bouard, J. Pierre, S. Lecot-Cotigny and N. Elie. We thank V. Constans and S. Kabani for editing the manuscript.

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Affiliations

  1. Department of Neurology, CHU de Caen, Caen, France

    Lien Bekaert, Pierre Branger & Jean-Sébastien Guillamo

  2. Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France

    Lien Bekaert, Samuel Valable, Emmanuèle Lechapt-Zalcman, Keven Ponte, Solène Collet, Jean-Marc Constans, Karim Bordji, Edwige Petit, Myriam Bernaudin & Jean-Sébastien Guillamo

  3. Department of Neurosurgery, CHU de Caen, Caen, France

    Lien Bekaert, Keven Ponte & Evelyne Emery

  4. Service de Neurochirurgie, CHU de Caen, Avenue de la Côte de Nacre, 14000, Caen, France

    Lien Bekaert

  5. Department of Pathology, CHU de Caen, Caen, France

    Emmanuèle Lechapt-Zalcman & Guénaëlle Levallet

  6. Department of Neuroradiology, CHU de Caen, Caen, France

    Jean-Marc Constans

  7. Department of Nuclear Medicine, CHU de Caen, Caen, France

    Alain Manrique

  8. Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP group, 14000, Caen, France

    Louisa Barré

  9. Department of Neurology, CHU de Nimes, Place du Professeur Robert Debre, 30029, Nimes cedex 9, France

    Jean-Sébastien Guillamo

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  1. Lien Bekaert
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  2. Samuel Valable
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  14. Myriam Bernaudin
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  15. Jean-Sébastien Guillamo
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Corresponding authors

Correspondence to Lien Bekaert or Jean-Sébastien Guillamo.

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Funding

This study was funded by Centre National de la Recherche Scientifique (CNRS), Université de Caen Normandie (UCN), Conseil Régional de Basse-Normandie (CRBN) and Institut National du Cancer (INCa).

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None of the authors have a conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Bekaert, L., Valable, S., Lechapt-Zalcman, E. et al. [18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis. Eur J Nucl Med Mol Imaging 44, 1383–1392 (2017). https://doi.org/10.1007/s00259-017-3677-5

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Keywords

  • Hypoxia
  • [18F]-FMISO PET
  • Glioma
  • Glioblastoma
  • Angiogenesis