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Pulsed Saturation Transfer in Glioblastoma at 1.5T
Rachel W. Chan1, Sten Myrehaug2,3, Greg J. Stanisz1,4,5, Arjun Sahgal1,2,3, and Angus Z. Lau1,4

1Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada, 2Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 3Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada, 4Medical Biophysics, University of Toronto, Toronto, ON, Canada, 5Department of Neurosurgery and Pediatric Neurosurgery, Medical University, Lublin, Poland

Synopsis

The purpose of this study was to quantify the effects of saturation transfer (CEST and MT) measurements in glioblastoma (GBM) patients at 1.5T. Data from GBM patients (n=10), treated with intensity modulated radiation therapy with a dose of 2 Gy per session with concurrent temozolomide, were analyzed before and after 10 treatment fractions. MT data were fitted to the Bloch-McConnell (BM) equations using a two-pool model with extended phase graphs (EPG) incorporated into the model. Results showed differences between normal and tumor regions and demonstrated promise for the application of CEST at 1.5T.

Introduction

Glioblastoma multiforme (GBM) is the most aggressive and the most common form of brain tumor, accompanied by dismal patient outcomes despite standard treatment, which involves surgical resection followed by radiation therapy and chemotherapy1. Recently, saturation transfer MRI techniques including quantitative magnetization transfer (MT)2-3 and amide proton transfer (APT) chemical exchange saturation transfer (CEST)4 have been used to image human GBM tumours5-7 and also used in monitoring the response to treatment8-12. Previous GBM CEST studies were conducted at field strengths of 3T or higher. However, the clinical relevance of saturation transfer techniques would benefit from the application of the methodology at lower field strength. The aim of this study was to quantify the CEST and MT parameters in GBM patients at 1.5T.

Methods

GBM study:
The study was approved by the institutional research ethics board and informed consent was obtained from all patients. Data from 10 patients (treated with intensity modulated radiation therapy with a dose of 2 Gy per session with concurrent temozolomide) were analyzed before and after 10 treatment fractions.

MR protocol:
Data were acquired on a 1.5T Philips Ingenia system. MT and CEST imaging used a pulsed saturation scheme13-15 that consisted of short, block pulses designed to overcome the RF amplifier limitations on this scanner (10ms pulses for MT and 0.5ms pulses for CEST, both separated by short gaps in time). Figure 1 shows the MR parameters used for the pulsed saturation and B0/B1/T1/T2 mapping sequences.

Image pre-processing:
The Gd post-contrast T1 and T2 FLAIR volumes were first registered to the pre-contrast T1 volume using the “flirt” function from FSL (FSL, FMRIB, Oxford, UK; http://www.fmrib.ox.ac.uk/fsl). From each of the 3D volumes (pre- and post-contrast T1, and T2 FLAIR), 2D slices were extracted that corresponded to the scanned CEST/MT slice. For the CEST scans, motion correction was performed across the saturation frequencies using the FSL “mcflirt” function. Contours were drawn of the tumor and normal (i.e. white matter on the contralateral side or “cNAWM”, as in previous work8) brain regions.

Parameter quantification:
MT data were fitted to the Bloch-McConnell (BM) equations using a two-pool model3 (i.e., liquid and semi-solid pools) with extended phase graphs (EPG)16-17 incorporated into the model18. The CEST effect was quantified by computing the difference between the z-spectra and the quantitative MT-extrapolated curve19. The CEST asymmetry was quantified20 between 3 and 4ppm, after B0 correction and after removing the MT contribution. Parameter values were compared between normal and tumor regions. Results were quantified before and after 10 radiation treatment fractions.

Results and Discussion

Figure 2 shows standard (post-contrast T1-weighted and T2 FLAIR) scans and fitted MT parameter maps for an example case, before radiation treatment. In the tumor region, there is a decrease in the relative semisolid fraction, M0B, and an increase in the exchange rate between the two pools, R, compared to the cNAWM regions. There is an absence of gray and white brain structure in the M0B map at the location of the lesion. The model is well-fitted to the data points in both regions.

Figure 3a shows a difference map between the Nuclear Overhauser Effect (NOE) (quantified between -3 and -4 ppm) and amide (quantified between 3 and 4 ppm) areas. The CEST asymmetry map (Figure 3b) and corresponding plots for each region (Figure 3c) are shown to illustrate CEST asymmetry. Higher CEST asymmetry was seen at the tumor location compared to the normal region.

Figure 4 displays all MT/CEST maps for one patient, before radiation therapy and after 10 treatment fractions. The medians and interquartile ranges for all parameters are plotted in Figure 5, averaged over 10 GBM cases. For MT, the relative semi-solid fraction, M0B, was significantly lower in tumors than in normal regions (by the non-parametric Wilcoxon signed-rank test). Tumors also had significantly higher exchange rate, R, compared to normal regions. Higher CEST asymmetry was seen between tumor and normal regions. Overall, there were larger standard deviations in the tumor regions, likely reflecting tumor heterogeneity.

Conclusion

The present study shows that the APT CEST asymmetry can be detected and quantified in GBM patients at 1.5T. The tumor asymmetry values at 1.5T are more positive than those reported at 3T8, likely owing to differences in NOE effect between the two field strengths. Significant differences were found in the MT semi-solid fractions and exchange rates between tumor and normal regions. This shows promise for wider applicability of CEST imaging on scanners with lower field strengths.

Acknowledgements

The authors acknowledge funding from NSERC, Terry Fox and CIHR.

References

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Figures

Figure 1 – MR pulse sequence parameters: Sequences include the MT, CEST, WAter Shift And B1 (WASABI) sequence (used for B0 and B1 mapping), T1-weighted fast field echo (FFE) sequence (for T1 mapping) and T2-weighted multi-echo sequence (for T2 mapping). The B1 amplitudes represent the peak amplitudes, in μT. Square brackets around 100000 and the multiplicative factor N, for example “[100000]×N”, indicate that the frequency of 100000 Hz is repeated N times before subsequent saturation frequencies. The colon separates the start, step, and end frequencies.

Figure 2 – Quantitative magnetization transfer maps and model fits in glioblastoma at 1.5T: a) Standard scans (post-contrast T1-weighted, “T1C” and T2 FLAIR) are shown, with the tumor and “normal” (cNAWM) brain regions outlined, along with MT parameter maps (M0B, T2A, T2B, R). b) The fitted model (dotted lines) are shown with the acquired MT data (dots), for each region (tumor and cNAWM). Lines represent different combinations of saturation power and duration used in the MT scan.

Figure 3 – CEST asymmetry in glioblastoma at 1.5T: a) The difference map between the NOE and amide areas are shown for one patient, for the tumor and normal (cNAWM) brain regions. b) The CEST asymmetry map is shown. Maps have been interpolated to 2.5μT after B1 correction. c) Corresponding plots with the signal overlaid between the two sides of the CEST spectra illustrate differences in asymmetry (also indicated by arrows). The sign of the frequency corresponds to the black curves. The images are shown after 10 radiation treatment fractions.

Figure 4 – Example CEST and MT maps before and after radiation therapy: All CEST and MT maps are displayed for a single patient before and after 10 sessions of radiation therapy. The tumor and normal brain contours are also shown on the post-contrast T1-weighted images.

Figure 5 – Summary of saturation parameter values for 10 GBM patients: Boxplots are shown for all a) MT and b) CEST parameters, with the median and interquartile ranges over 10 patients. Parameters are plotted before and after radiation treatment (at D0 and D10, respectively) for each region (normal and tumor). CEST parameters are interpolated to 2.5μT after B1 correction.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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