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In vivo imaging of cell proliferation in meningioma using 3′-deoxy-3′-[18F]fluorothymidine PET/MRI

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Abstract

Purpose

Positron emission tomography (PET) with 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [18F]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis.

Methods

Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [18F]FLT PET following surgery. Maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET40–60) and ~ 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (VB) was performed to determine the total distribution volume (VT). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction.

Results

Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUVmax and SUVmean normalized to blood radioactivity from PET40–60 and blood sampling, and VT were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94–95%, accuracy 99%; P = 0.003). Static [18F]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or VB. Using Ki-67 index with a threshold > 4%, the majority of [18F]FLT metrics showed a high ability to identify aggressive meningiomas with SUVmean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024).

Conclusion

[18F]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas.

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Abbreviations

BBB:

Blood-brain barrier

CI:

Confidence interval

CT:

Computed tomography

CT :

Cycle threshold

EANO:

European Association of Neuro-Oncology

EGFR:

Epidermal growth factor receptor

[18F]FDG:

2-[18F]fluoro-2-deoxy-D-glucose

[18F]FET:

O-(2-[18F]fluoroethyl)-L-tyrosine

[18F]FLT:

3′-deoxy-3′-[18F]fluorothymidine

IDIF:

Image-derived input function

GOI:

Genes of interest

IQR:

Interquartile range

KRAS:

Kirsten RAt Sarcoma viral oncogene homologue

[11C]MET:

[Methyl-11C]-L-methionine

MGAT5:

N-Acetylglucosaminyltransferase V

MMP2/9:

Matrix metallopeptidases 2 and 9

MRI:

Magnetic resonance imaging

PCNA:

Proliferating cell nuclear antigen

PET:

Positron emission tomography

PF:

Parent fraction

phh3:

Phosphohistone-H3

qPCR:

Quantitative polymerase chain reaction

ROC:

Receiver operating characteristic

ROI:

Region of interest

SSTR2:

Somatostatin receptor subtype 2

SUV:

Standardized uptake value

TAC:

Time-activity curve

TBR:

Tumour-to-blood ratio

TGR:

Tumour-to-grey ratio

TIMP3/4:

TIMP metallopeptidase inhibitors 3 and 4

TK1:

Thymidine kinase 1

TPFR:

Tumour-to-parent fraction ratio

TPR:

Tumour-to-plasma ratio

TWBR:

Tumour-to-whole-blood ratio

TWR:

Tumour-to-white matter ratio

V B :

Blood volume fraction

VEGFA:

Vascular endothelial growth factor A

VOI:

Volume of interest

WHO:

World Health Organization

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Acknowledgements

The authors would like to thank the technical staff Nadia Azizi, Marianne Federspiel, Jakup Martin Poulsen, and Karin Stahr and chemists at Clinic of Clinical Physiology, Nuclear Medicine & PET, for help with PET scanning and patient care. The authors would also like to thank the nuclear medicine specialist, Oriol Puig, for helping with kinetic modelling images for the study. Finally, a special thanks to the statistician, Lasse Anderberg, for helping with ROC analyses.

Funding

The work was supported by a grant from the Danish Cancer Society (R146-A9508–16-S2). The Siemens mMR hybrid PET/MR system at Copenhagen University Hospital Rigshospitalet was donated by the John and Birthe Meyer Foundation.

Author information

Asma Bashir, Ian Law, Morten Ziebell, and Kåre Fugleholm conceived the study design. Asma Bashir was responsible for patient recruitment. Asma Bashir and Ian Law contributed to the acquisition, analysis, and interpretation of the PET/MRI data. Asma Bashir, Mark B. Vestergaard, and Lisbeth Marner conducted full kinetic modelling using an image-derived input function. Tina Binderup performed quantitative polymerase chain reaction. Helle Broholm performed the neuropathological examination. Asma Bashir conducted the statistical analysis with the guidance from senior statisticians, Thomas Sheike (Professor) and Lasse Anderberg (MSc). Asma Bashir drafted the first and subsequent manuscripts. Asma Bashir, Mark B. Vestergaard, Helle Broholm, Tina Binderup, Lisbeth Marner, Morten Ziebell, Kåre Fugleholm, Andreas Kjær, and Ian Law contributed to the data interpretation, the increase in the intellectual content, and approved the final version.

Correspondence to Asma Bashir.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Scientific Health Ethics Committee of the Capital region, Copenhagen, Denmark (reference number: H-15006091) and was based on the Declaration of Helsinki II (2013) and the principles of “good clinical practices”.

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

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Bashir, A., Binderup, T., Vestergaard, M.B. et al. In vivo imaging of cell proliferation in meningioma using 3′-deoxy-3′-[18F]fluorothymidine PET/MRI. Eur J Nucl Med Mol Imaging (2020). https://doi.org/10.1007/s00259-020-04704-2

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Keywords

  • Meningioma
  • [18F]FLT
  • Thymidine kinase 1
  • Ki-67 index