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Amide proton transfer (APT) MRI is a predictor of survival and progression in high-grade glioma patients
Daniel Paech1, Constantin Dreher1, Sebastian Regnery1, Jan-Eric Meissner2, Steffen Goerke2, Johannes Windschuh2, Katerina Deike-Hofmann1, Sebastian Bickelhaupt1, Alexander Radbruch3, Moritz Zaiss4, Andreas Unterberg5, Wolfgang Wick6, Martin Bendszus7, Peter Bachert2, Mark Edward Ladd2, and Heinz-Peter Schlemmer1

1Radiology, German Cancer Research Center, Heidelberg, Germany, 2Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany, 3Radiology, University Hospital Essen, Essen, Germany, 4Max-Planck-Institut Tuebingen, Tuebingen, Germany, 5Neurosurgery, University of Heidelberg, Heidelberg, Germany, 6Neurology, University of Heidelberg, Heidelberg, Germany, 7Neuroradiology, University of Heidelberg, Heidelberg, Germany

Synopsis

In this work we show that relaxation-compensated amide proton transfer (APT) imaging at 7.0 T is associated with overall survival and progression-free survival in newly-diagnosed, previously untreated glioma patients. The current study showed that glioma patients with increased APT values were more likely to progress sooner and live shorter, respectively. This effect may be caused by strong alterations of amino acid concentrations and global upregulation of protein expression in more aggressive brain tumors. Therefore, APT CEST imaging may help to enhance the prognostic value of non-invasive MRI tools at the time of initial diagnosis and during follow-up.

Background and Purpose

Patient overall survival (OS) is the most objective and relevant measure of meaningful clinical efficacy while the duration of progression-free survival (PFS) commonly serves as surrogate endpoint for OS [1]. Possible association of chemical exchange saturation transfer (CEST) MRI and patient OS or PFS have so far not been assessed. Therefore, the study purpose was to investigate the predictability of patient OS and PFS in newly-diagnosed high grade glioma (HGG) patients using amide proton transfer (APT) MRI at 7 Tesla (7T).

Methods

Twenty-six patients with newly-diagnosed high-grade glioma (WHO grade III-IV) were included in this prospective IRB-approved study. CEST MRI was performed on a 7.0 Tesla whole-body scanner. APT-weighted CEST contrasts were calculated using the relaxation-compensated apparent exchange-dependent relaxation (AREX) approach [2] and the downfield relayed nuclear Overhauser effect (rNOE)-suppressed APT (dns-APTAREX) metric [3]. B0 and B1 field inhomogeneities were determined using the water shift and B1 method (WASABI) [4] and reconstructed corresponding to B1=0.6 µT saturation amplitude [5]. Association of patient OS and PFS with relaxation-compensated APT MRI (APTAREX and dns-APTAREX) were assessed using the univariate Cox proportional-hazards regression model. Hazard ratios (HR) and corresponding 95% confidence intervals were calculated. Moreover, Kaplan-Meier analyses with two-sided log-rank statistics were additionally performed for OS and PFS for both APT contrasts after dichotomization into two groups at the median. Furthermore, OS/PFS association with clinical parameters (age, gender, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status, and therapy: biopsy + radiochemotherapy vs. debulking surgery + radiochemotherapy) were tested accordingly.

Results

The APTAREX contrast was significantly associated with patient OS (HR=3.15, p=0.02) and PFS (HR=1.83, p=0.009). Median OS/PFS of patients with low tumor signal intensities (APTAREX ≤4.23%) was 411/293 days compared to 292/112 days for patients with increased APT values (APTAREX>4.23%) (Fig. 1A,C). Strongest association with PFS was found for the dns-APT metric (HR=2.61, p=0.002) (Fig. 1D). Among the tested clinical parameters, patient age (HR=1.1, p=0.001) and therapy (HR=3.68, p=0.026) were significant for OS; age additionally for PFS (HR=1.04, p=0.048).

Discussion and Conclusion

The study showed that glioma patients with increased APT values were more likely to progress sooner and live shorter, respectively. This effect may be caused by strong alterations of amino acid concentrations and global upregulation of protein expression in more aggressive brain tumors. This is the first study reporting an association of APT MRI with overall survival and progression-free survival in newly-diagnosed, previously untreated glioma patients. Therefore, the study adds an important element to the fast growing body of evidence regarding the prognostic value of CEST MRI in neuro-oncology.

Acknowledgements

none.

References

[1] Kim KB (2014) PFS as a surrogate for overall survival in metastatic melanoma. The Lancet Oncology 15:246-248 2

[2] Zaiss M, Windschuh J, Paech D et al (2015) Relaxation-compensated CEST-MRI of the human brain at 7 T: Unbiased insight into NOE and amide signal changes in human glioblastoma. NeuroImage 112:180-188 4

[3] Zaiss M, Windschuh J, Goerke S et al (2017) Downfield-NOE-suppressed amide-CEST-MRI at 7 Tesla provides a unique contrast in human glioblastoma. Magn Reson Med 77:196-208 5

[4] Schuenke P, Windschuh J, Roeloffs V, Ladd ME, Bachert P, Zaiss M (2017) Simultaneous mapping of water shift and B1(WASABI)—Application to field-Inhomogeneity correction of CESTMRI data. Magnetic Resonance in Medicine 77:571-580 6

[5] Windschuh J, Zaiss M, Meissner JE et al (2015) Correction of B1‐inhomogeneities for relaxation‐compensated CEST imaging at 7 T. NMR in Biomedicine 28:529-537

Figures

Figure 1: Kaplan-Meier analysis and log-rank statistics for overall survival (OS: A-B) and progression-free survival (PFS: C-D) after data dichotomization at the median. Significant association with patient OS was found for the relaxation-compensated APTAREX contrast (A, p=0.009), while a tendency toward longer survival was also observed for the dns-APT metric (B, p=0.25). Significant association with PFS was found for both relaxation-compensated APT metrics (C: APTAREX, p=0.005; dns-APTAREX, p=0.004).

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