18F-methylcholine PET/CT and magnetic resonance spectroscopy imaging and tissue biomarkers of cell membrane turnover in primary brain gliomas – a pilot study
Matthew Grech-Sollars1,2, Katherine Ordidge1,2, Babar Vaqas3, Lesley Honeyfield2, Sameer Khan2, Sophie Camp3, David Towey2, David Peterson3, Federico Roncaroli4, Kevin S O'Neill3, Tara Barwick2,5, and Adam D Waldman1,2

1Division of Brain Sciences, Imperial College London, London, United Kingdom, 2Department of Imaging, Imperial College NHS Healthcare Trust, London, United Kingdom, 3Department of Neurosurgery, Imperial College NHS Healthcare Trust, London, United Kingdom, 4Department of Neuropathology, Imperial College NHS Healthcare Trust, London, United Kingdom, 5Department of Surgery and Cancer, Imperial College London, London, United Kingdom

Synopsis

Choline elevation has been reported as a marker of aggressive glioma phenotype in numerous in vivo MRS studies, and more recently 18F-methylcholine-PET has been applied to glioma characterisation. This study examines the relationship between MRS and PET choline measures in defined tumour regions, in order to validate these against tissue biomarkers of choline metabolism and proliferation. Our initial results raise the possibility that imaging markers of choline metabolism are influenced by inflammatory and reactive processes for low grade tumours.

Background

Choline containing compounds (cho) are key components of cell membranes; their metabolism important in membrane turnover, and therefore cellular proliferation. Cho elevation has been reported as a marker of aggressive glioma phenotype in numerous in vivo magnetic resonance spectroscopy (MRS) studies, and more recently 18F-methylcholine-PET has been applied to glioma characterisation. This preliminary study aims to examine the relationship between MRS and PET imaging cho measures in defined tumour regions, and validate these against tissue biomarkers of cho metabolism and proliferation.

Methods

12 patients (7 male, 5 female; aged 23-73 years, mean 41 years), with suspected primary supratentorial glioma suitable for biopsy/resection were recruited to this pilot study. An MRI protocol, including multivoxel MRS (TE=30ms; TR=1500ms), was acquired at 3T using a 32 channel head coil; PET/CT was performed with 285MBq of 18F-methylcholine, with a dedicated 45 minute brain dynamic list mode acquisition. Stereotactic biopsies were obtained using an ultrasound based neuro-navigational system from low and high cho areas identified on MRS and PET, and fused with high resolution structural images (Figure 1).

Results

Preliminary data from patients with low- and mid-grade tumours suggests spatial concordance between high cho uptake on PET and elevated MRS cho/cr ratios. In higher grade tumours, areas of high cho PET uptake correlated with the contrast-enhancing tumour. Higher grade tumours had increased uptake on PET compared to lower grade tumours and contra-lateral white matter (Figures 2 and 3). Maximum Cho/Cr ratios on MRS did not show a significant statistical difference between tumour grades (Figure 3). Tissue from 5 patients (3 WHO grade-II, 2 grade-III) showed high cho areas on imaging correlate with reactive gliosis and macrophage infiltrates, but not mitotic activity or denser cellularity. In one predominantly grade II astrocytoma, areas of elevated uptake on PET showed denser cellularity and mitoses, in keeping with early malignant progression.

Conclusions

Preliminary findings suggest cho PET and MRS may detect regions of inflammatory infiltrate, rather than showing a simple relationship with high tumour cellular proliferation. In one case, elevated cho markers corresponded to early focal malignant transformation. Whilst these imaging methods show continued promise for glioma characterisation, further validation against tissue enzymatic and genetic biomarkers, and clinical outcomes is essential for their rational translation into wider clinical practice.

Acknowledgements

This work was funded by the NIHR Imperial Biomedical Research Centre. MGS is partly funded by The Brain Tumour Charity and Brain Tumour Research Campaign. We would also like to thank Mr. Daniel Darian for his help in this study. MRI and PET imaging was carried out at the Imperial College Clinical Imaging Facility.

References

No reference found.

Figures

Figure 1: MRS and Surgery Planning. A: In vivo MRS shows the concentration of choline in a defined region of the brain. B: Samples of low and high choline areas are taken during surgery using an ultra-sound based neuro-navigation system. C: Screenshots for the biopsy site are taken which show near real-time ultrasound imaging overlaid on the pre-operative MRI together with the intended areas to biopsy marked as 3D colour coded hollow spheres.

Figure 2: Time Activity Curves. The average time activity curves from 18F-methylcholine PET imaging in 10 patients grouped into low and high grade tumours are shown together with that in the contralateral white matter. The time activity curves show prompt tracer uptake in tumours followed by a steady state plateau within 5 minutes post-injection. All tumours showed increased uptake relative to contralateral white matter.

Figure 3: Box plots for PET and MRS data by tumour grade. (A) SUVmax in tumour and in contralateral white matter in 10 patients showed a significant difference in uptake between contralateral white matter and each of the grade II, III and IV tumours (p<0.02). However, there was no significant difference observed between grade II and grade III tumours. (B) Maximum choline to creatine ratio in 12 patients showed no significant difference between tumour grades.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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