Ben Babourina-Brooks1, Sarah Kohe1, Andrew Peet1, and Nigel Davies2
1University of Birmingham, Birmingham, United Kingdom, 2University Hospitals Birmingham, Birmingham, United Kingdom
Synopsis
The rate of improvement in survival, among children with
brain tumours, has decreased in recent years and novel prognostic markers that
may contribute to treatment stratification and improved outcomes are required. Medulloblastoma tumours have a high rate of mortality due to their aggressive nature, however some do not. MRS can measure absolute
water proton resonance frequency (PRF), which is sensitive to temperature and
other features of the tumour microenvironment. This could be utilized as a potential prognosis marker, however has not been explored. This
study assessed the water PRF as a predictor of survival in a medulloblastoma
patients, using MRS at diagnosis. Introduction
The rate of improvement in survival, among children
with brain tumours, has decreased in recent years and novel prognostic markers
that may contribute to treatment stratification and improved outcomes are
required. Medulloblastomas have the highest rate of mortality due to their
aggressive nature, WHO grade IV, compared to other common paediatric tumour
types. However not all medulloblastomas have a high risk of mortality and
establishing the non-invasive markers of prognosis in this group of tumours is
of particular interest
1. In addition to providing characteristic metabolite
levels
2, MRS can measure absolute water proton resonance frequency (PRF).
Water PRF is sensitive to temperature and other features of the tumour microenvironment
and has been shown to be useful for characterisation of common childhood brain
tumour types
3. However, the potential for variations in water PRF within
tumour types to non-invasively predict prognosis has not been explored. The aim of this retrospective study was to investigate
water PRF as a predictor of survival in a cohort of medulloblastoma
patients using MRS at diagnosis.
Methods
Single-voxel MRS data were acquired using a 1.5T
Siemens system (PRESS, TR 1500ms, TE 30ms) in 45 histology confirmed medulloblastoma
brain tumour patients. The accrual period
was between September 2003 and December 2012 and
patients were followed up until August 2015.
In this time span a number of treatment protocols
were used. The general principles were that a maximal surgical resection of the
primary tumour was followed by adjutant treatment: chemotherapy and craniospinal
radiotherapy for older children, focal radiotherapy for younger ones. Spectra were analysed using jMRUI and the AMARES
tool
4. The weakly suppressed water (H
2O, 4.68ppm) and total
choline (tCho, 3.22ppm) peaks were fitted with Lorentzian lineshapes and the
water PRF calculated relative to tCho (δH2O
(tCho)).
The Cho reference was chosen since it was prominent in all tumour spectra and
not highly affected by macromolecules. The median δH2O(tCho) value was used
as the cut-off for a Kaplan-Maier survival analysis. A log-rank test was used to
investigate the significance of the difference in survival between the groups. Histopathological
subtypes and clinical features related to survival, including Chang M staging,
sex and age, were compared between the high and low δH2O
(tCho) groups and regression
analysis was performed to investigate correlations.p<0.05 was used as the threshold
for significance in all tests.
Results and Discussion
A total of 40 patients with medulloblastoma were
eligible for the study and 18 had died by the end of the study period. Kaplan-Maier
analysis (Figure 3) shows good separation of the high and low δH2O
(tCho) groups throughout
the five year time span with significantly poorer survival in the low δH2O
(tCho) group (chi
square 8.4, p <0.01). Based on previous studies this could indicate
that more aggressive medulloblastomas have a higher temperature or lower
protein concentration or a contribution from both
3,5. Table 1 shows a comparison of patient characteristics that may affect
survival between high and low δH2O
(tCho)
groups. There was no significant difference in median age between the
groups and a subsequent analysis showed there was no survival difference based
on age in this cohort.Sex of the patient was also not found to be a significant
survival factor in this study, p= 0.625.The Chang M staging values did not
correlate with the water PRF shift and the mean M stage value was not
significantly different between the deceased and alive patient groups in this
cohort. Histological subtypes of medulloblastoma are known to provide
indicators of survival
6, specifically the desmoplastic nodular and large
cell anaplastic tumour sub-types, indicating good and poor prognosis,
respectively. Seven out of the eight desmoplastic nodular tumours survived and
all were in the high water PRF group. All three of the large cell tumour
patients died, and two of these had low water PRF potentially predicting poor
prognosis. The third patient was close to the cut off value, 4.694ppm. All reported myc status’ for the cohort were
negative in this study.The possible effect of differences in treatment regime on
survival in this cohort and any other potential bias on the survival analysis
based on water PRF will be investigated.
Conclusion
This
study suggests that absolute water PRF may be a useful non-invasive
marker of prognosis in medulloblastoma. This novel biomarker, related to the
tumour microenvironment, can be measured using common MRS methods independently
of and complementary to metabolite profile measurements. A More detailed
investigation of the added-value of the water PRF measure compared with known
prognostic factors and its potential to improve treatment stratification are
warranted.
Acknowledgements
No acknowledgement found.References
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