0956

Magnetic Resonance Spectroscopy markers of survival in paediatric brain tumours: A 3T Multi-Centre investigation
Ben Babourina-Brooks1,2, Lesley MacPherson2, Laurence J Abernethy3, Theodoros N Arvanitis2,4, Simon Bailey5, Nigel P Davies1,2,6, Daniel Rodriguez Gutierrez 7,8,9, Tim Jaspan 7,10, Dipayan Mitra11, Paul S Morgan7,9,10, Barry Pizer 12, Richard G. Grundy 7, Dorothee P Auer7,8,10, and Andrew C Peet1,2

1University of Birmingham, Birmingham, United Kingdom, 2Birmingham children's hospital, Birmingham, United Kingdom, 3Department of Radiology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom, 4Institute of Digital Healthcare, WMG, University of Warwick, Coventry, United Kingdom, 5Paediatric Oncology Department, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom, 6Department of Imaging and Medical Physics, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom, 7The Children‘s Brain Tumour Research Centre, University of Nottingham, Nottingham, United Kingdom, 8Radiological Sciences, Department of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom, 9Medical Physics, Nottingham University Hospital, Queen’s Medical Centre, Nottingham, United Kingdom, 10Neuroradiology, Nottingham University Hospital, Queen’s Medical Centre, Nottingham, United Kingdom, 11Neuroradiology Department, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, United Kingdom, 12Department of Paediatric Oncology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom

Synopsis

Brain tumours have a high mortality rate and are the most common solid tumour of childhood. The non-invasive imaging technique, MRS, measures tumour metabolites which can provide additional prognostic information to aid in clinical management. MRS metabolites Glycine, Scyllo-Inositol, NAA and Lipids have been associated with prognosis for pediatric brain tumour patients in a single centre 1.5T study. This study aimed to validate these MRS survival markers in a 3T multicentre setting. In this preliminary study Lipids were validated as a survival marker across childhood brain tumours.

PURPOSE:

Brain tumours have a high mortality rate and are the most common solid tumour of childhood [1]. Identification of high risk patients may allow for better treatment stratification and more effective disease management, increasing survival and reducing treatment related damage. Magnetic Resonance Spectroscopy (MRS) provides a non-invasive measure of brain tumour metabolism[2], which has been previously used to identify diagnostic and prognostic metabolite markers in adult and paediatric brain tumours[3]. Metabolites such as high lipids, scyllo-inositol (SI), and glycine (Gly) have been shown to reflect poor survival, whilst N-Acetylaspartic acid (NAA) is a marker of good outcome in paediatric brain tumours[4, 5, 6]. However, studies have focussed on 1.5T spectroscopy and are based on single centre studies. A study at higher field strengths would increase spectral resolution and SNR therefore distinguish more metabolites. To date, metabolites measured by MRS have not been investigated as a potential survival marker in a multi-centre study for paediatric brain tumours. The aim of this preliminary study were to investigate if the established 1.5T single centre survival markers hold true in a 3T multi-centre setting.

METHODS:

Ninety one children with newly diagnosed brain tumours were examined with MRS on a 3T system prior to treatment from four hospitals between 2012-2016, with follow up until September 2017. Multicentre ethical and parental approval consent was obtained. Clinical data was obtained including gender, age at diagnosis, and dates of death. Tumour diagnosis was confirmed by a multidisciplinary team using histopathology, clinical and radiological information. Most patients were treated with surgical resection, followed by fractionated radiotherapy and chemotherapy with the protocol based on diagnosis and clinical risk factors. MR imaging and MRS were acquired pre-treatment using single voxel spectroscopy PRESS from different scanner systems (Phillips Acheiva, Siemens Verio) using the following parameters TR =2000ms and TE=30-46ms. The MRS voxel was placed within the solid component of the primary tumour. Unprocessed data was pushed from the scanner to a local database, anonymised and uploaded, by individual centres, to the CCLG database for retrospective analysis. Unprocessed MRS signals were analyzed using TARQUIN[7] software (version 4.3.6). Spectra were excluded based on displaced voxel location, unstable spectral baseline, artefacts present, signal to noise ratio (SNR) < 4, overall metabolite linewidths exceeded 0.15ppm and water linewidth >10Hz. Survival analysis was performed on individual metabolites using univariate Cox regression and Kaplan-Meier analysis based on median metabolite concentration cut-off values. For significant metabolite markers of prognosis and the 1.5T established markers of survival (NAA, Gly, Lipids and SI) the cut off was optimised iteratively based on p value. Statistical tests were performed in the R software package using the survival library with P<0.05 chosen for significance.

RESULTS and DISCUSSION:

The final cohort consisted of 71 patients after quality control, with a median follow up of 1182±583 days. All 6 patient deaths were a direct result of their disease. The mean age of the patient cohort was 7.45±4.5 years and 67% were male, neither were found to influence survival. Lipids at 0.9ppm and total lipids and macromolecules (TLM) at 1.3ppm, were found to be biomarkers of poor prognosis (p<0.01), Figure 1, Table 1. In both cases the optimised cut off identified all the patient deaths in the cohort, providing high hazard ratios (Table 1). Given the limited events in this cohort this result indicates that lipids are a strong marker of poor prognosis. NAA, SI and Gly, have been previously reported as biomarkers [4,6]. However, in this preliminary study they were not found to be significant survival markers, which could be due to the limited number of events in this cohort. Mean spectral profiles were created for the patients that survived and died during the follow up period (Figure 2). There is a clear difference in the peak height of lipids at 1.3ppm. Patients that died have a lower NAA peak height even though it was not found to be a significant survival marker. Lipids are well documented as being associated with poor prognosis in both paediatric and adult brain tumour patients being associated with apoptosis, necrosis and cytoplasmic lipid droplets [8-11]. This is the first study in paediatric brain tumours to validate lipids as survival markers using MRS in a multicentre setting. Further work includes building up this cohort to assess if with more numbers and events the other metabolites of survival can be validated.

Conclusion:

Lipids have been found to be a predictor of survival for childhood brain tumours in a multicentre setting, adding confidence to using MRS for predicting prognosis in different centres.

Acknowledgements

We would like to thank Dr Paul Davies for advice on the statistical methodology and analysis.

References

[1] Bleyer W et al. 8 drugs in 1 day chemotherapy for brain tumors: a new approach and rationale for preradiation chemotherapy. Med Pediat Oncol: 1983 11: 213

[2] Peet AC, Arvanitis TN, Auer DP, Davies NP, Hargrave D, and F. Howe, The value of magnetic resonance spectroscopy in tumour imaging. Arch Dis Child, 2008. 93: p. 725-727.

[3] Verma A, Kumar I, Verma N, Aggarwal P, and R. Ojha, Magnetic resonance spectroscopy — Revisiting the biochemical and molecular milieu of brain tumours. BBA Clinical, 2016. 5: p. 170-178.

[4] Wilson M, Cummins CL, and MacPherson LM et al, Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours. Eur. J. Cancer, 2013. 49: p. 457-464.

[5] Wilson M, Gill SK, Macpherson L, English M, Arvanitis TN, and A. Peet, Noninvasive detection of glutamate predicts survival in paediatric medulloblastoma. Clin Cancer Res, 2014. 20(17): p. 4532-4539.

[6] B.Babourina-Brooks, S.Kohe, Gill SK, Wilson M, MacPherson L, N.P.Davies, A.C.Peet. Glycine a non-invasive marker of survival in paediatric brain tumours. International Society for Magnetic Resonance in Medicine (ISMRM), Honolulu,USA, 2017. Abstract1102

[7] Wilson M. et al. A constrained least-squares approach to the automated quantitation of in vivo ¹H magnetic resonance spectroscopy data. Mag Reson Med 2011;65:1-12

[8] Murphy PS, Rowland IJ, Viviers L, Brada M, Leach MO, and Dzik-Juras AS, Could assessment of glioma methylene lipid resonance by in vivo (1)H-MRS be of clinical value? Br J Radiol, 2003. 76(907): p. 459-463.

[9] Negendank W, Li CW, Padavic-Shaller K, Murphy-Boesch J, and Brown TR, Phospholipid metabolies in 1H-decoupled 31P MRS in vivo in human cancer: implications for experimental models and clinical studies. Anticancer Res, 1996. 16(3B): p. 1539-1544.

[10] Kaminogo M, Ishimaru H, and Morikawa M et al, Diagnostic potential of short echo time MR spectroscopy of gliomas with single-voxel and point-resolved spatially localised proton spectroscopy of brain. Neuroradiology, 2001. 43(5): p. 353-363.

[11] Opstad KS, Bell BA, Griffiths JR, and Howe FA, An investigation of human brain tumour lipids by high-resolution magic angle spinning 1H MRS and histological analysis. NMR Biomed, 2008. 21(7): p. 677-685.

Figures

Table 1: Hazard ratios (mean), log rank and associated likelihood test values for the potential multicentre survival markers, Glycine, NAA, Scyllo-Inositol, lipids at 0.9ppm and TLM 1.3ppm

Figure 1: Kaplan-Meier survival curves for the patient cohort. High concentrations of both lipids at 0.9ppm and total lipids and macromolecules at 1.3ppm indicated poor prognosis.

Figure 2: Example mean spectra of patients who died (n=6) and survived (n=65) in this cohort. Lipid peaks and NAA are highlighted in the profile.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)
0956