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Pharmacokinetic analysis of [68Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

DOTA-D-Phe1-Tyr3-octreotide with gallium-68 ([68Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [68Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [68Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation.

Methods

Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [68Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (VB). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR.

Results

Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [68Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBRmean) (r = 0.757, P = 0.001) and SUVmean (r = 0.714, P = 0.003). Significant positive correlations were also found between [68Ga]Ga-DOTA-TOC PET metrics, and VEGFA and VB. SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [68Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation.

Conclusion

[68Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBRmean being the best PET metric for assessing SSTR2.

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Abbreviations

B2M:

Beta-2-microglobulin

BBB:

Blood-brain barrier

Ct:

Cycle threshold

DOTA:

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

DOTA-TATE:

DOTA-D-Phe1-Tyr3-octreotate

DOTA-TOC:

DOTA-D-Phe1-Tyr3-octreotide

DOTA-NOC:

DOTA-1-Nal3-ocreotide

IDIF:

Image-derived input function

HPFs:

High-power fields

HPRT:

Hypoxanthine phosphoribosyltransferase 1

IL18:

Cytokine interleukin-18

PET:

Positron emission tomography

phh3:

Phosphohistone-H3

PRRT:

Peptide receptor radionuclide therapy

PVE:

Partial volume effect

qPCR:

Quantitative polymerase chain reaction

ROI:

Region of interest

SSTR:

Somatostatin receptor

SUV:

Standardized uptake value

TAC:

Time-activity curve

TBR:

Tumour-to-blood ratio

TNMR:

Tumour-to-neck muscle ratio

TPR:

Tumour-to-plasma ratio

TWBR:

Tumour-to-whole-blood ratio

V B :

Fractional blood volume

VOI:

Volume of interest

V T :

Total distribution volume

VEGFA:

Vascular endothelial growth factor A

NETs:

Neuroendocrine tumours

WHO:

World Health Organization

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Acknowledgments

We are grateful to all study participants and their relatives for their patience and willingness to contribute to the research. We would like to thank our technical staff, Sakeena Elkington and Loida Eunice Saxtoft, for the support with patient care, preparation of radiopharmaceuticals and acquisition of scans. In addition, the authors would like to thank the nuclear medicine specialist, Oriol Puig Calvo, for helping with kinetic modelling images for the study.

Funding

The work was financially 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.

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Authors and Affiliations

  1. Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Asma Bashir, Mark Bitsch Vestergaard, Tina Binderup, Lisbeth Marner, Andreas Kjær & Ian Law

  2. Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Asma Bashir

  3. Cluster for Molecular Imaging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Tina Binderup & Andreas Kjær

  4. Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Helle Broholm

  5. Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark

    Lisbeth Marner

  6. Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Morten Ziebell, Kåre Fugleholm & Tiit Mathiesen

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  1. Asma Bashir
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Contributions

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 histopathological examinations. Asma Bashir conducted the statistical analysis with the guidance from a senior statistician, Professor Lene Theil Skovgaard. Asma Bashir drafted the first and subsequent manuscripts. Asma Bashir, Mark B. Vestergaard, Helle Broholm, Tina Binderup, Lisbeth Marner, Morten Ziebell, Kåre Fugleholm, Tiit Mathiesen, Andreas Kjær and Ian Law contributed to the data interpretation, the increase in the intellectual content, provided input to revision of the manuscript and approved the final version.

Corresponding author

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 were 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., Vestergaard, M.B., Binderup, T. et al. Pharmacokinetic analysis of [68Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2. Eur J Nucl Med Mol Imaging 47, 2577–2588 (2020). https://doi.org/10.1007/s00259-020-04759-1

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