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Theranostics 2018; 8(14):3991-4002. doi:10.7150/thno.23709 This issue Cite

Research Paper

[¹⁸F]fluoroethyltyrosine-induced Cerenkov Luminescence Improves Image-Guided Surgical Resection of Glioma

David Y. Lewis^1,4✉*, Richard Mair^1,2*, Alan Wright¹, Kieren Allinson³, Scott K. Lyons¹, Tom Booth¹, Julia Jones¹, Robert Bielik¹, Dmitry Soloviev^1,4, Kevin M. Brindle^1,2

1. Cancer Research UK - Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
2. Department of Biochemistry, University of Cambridge, Cambridge, UK
3. Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
4. Current address: Cancer Research UK - Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK
* These authors contributed equally to this work

✉ Corresponding author: David Lewis (Tel: +441413308161; Email: d.lewisgla.ac.uk)

Abstract

The extent of surgical resection is significantly correlated with outcome in glioma; however, current intraoperative navigational tools are useful only in a subset of patients. We show here that a new optical intraoperative technique, Cerenkov luminescence imaging (CLI) following intravenous injection of O‑(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET), can be used to accurately delineate glioma margins, performing better than the current standard of fluorescence imaging with 5-aminolevulinic acid (5-ALA).

Methods: Rats implanted orthotopically with U87, F98 and C6 glioblastoma cells were injected with FET and 5-aminolevulinic acid (5-ALA). Positive and negative tumor regions on histopathology were compared with CL and fluorescence images. The capability of FET CLI and 5-ALA fluorescence imaging to detect tumor was assessed using receptor operator characteristic curves and optimal thresholds (CLI_OptROC and 5-ALA_OptROC) separating tumor from healthy brain tissue were determined. These thresholds were used to guide prospective tumor resections, where the presence of tumor cells in the resected material and in the remaining brain were assessed by Ki-67 staining.

Results: FET CLI signal was correlated with signal in preoperative PET images (y = 1.06x - 0.01; p < 0.0001) and with expression of the amino acid transporter SLC7A5 (LAT1). FET CLI (AUC = 97%) discriminated between glioblastoma and normal brain in human and rat orthografts more accurately than 5-ALA fluorescence (AUC = 91%), with a sensitivity >92% and specificity >91%, and resulted in a more complete tumor resection.

Conclusion: FET CLI can be used to accurately delineate glioblastoma tumor margins, performing better than the current standard of fluorescence imaging following 5-ALA administration, and is therefore a promising technique for clinical translation.

Keywords: Cerenkov luminescence imaging, FET, glioblastoma, 5-ALA, intraoperative

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