Abstract
Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p < 0.0001; MTRasym×R2': p < 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p < 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.