Complementary but Distinct Roles for MRI and¹⁸F-Fluoromisonidazole PET in the Assessment of Human Glioblastomas

Abstract

Glioblastoma multiforme is a primary brain tumor known for its rapid proliferation, diffuse invasion, and prominent neovasculature and necrosis. This study explores the in vivo link between these characteristics and hypoxia by comparing the relative spatial geometry of developing vasculature inferred from gadolinium-enhanced T1-weighted MRI (T1Gd), edematous tumor extent revealed on T2-weighted MRI (T2), and hypoxia assessed by 18F-fluoromisonidazole PET (18F-FMISO). Given the role of hypoxia in upregulating angiogenic factors, we hypothesized that the distribution of hypoxia seen on 18F-FMISO is correlated spatially and quantitatively with the amount of leaky neovasculature seen on T1Gd. Methods A total of 24 patients with glioblastoma underwent T1Gd, T2, and 18F-FMISO—11 studies preceded surgical resection or biopsy, 7 followed surgery and preceded radiation therapy, and 11 followed radiation therapy. Abnormal regions seen on the MRI scan were segmented, including the necrotic center (T0), the region of abnormal blood–brain barrier associated with disrupted vasculature (T1Gd), and infiltrating tumor cells and edema (T2). The 18F-FMISO images were scaled to the blood 18F-FMISO activity to create tumor-to-blood ratio (T/B) images. The hypoxic volume (HV) was defined as the region with T/Bs greater than 1.2, and the maximum T/B (T/Bmax) was determined by the voxel with the greatest T/B value. Results The HV generally occupied a region straddling the outer edge of the T1Gd abnormality and into the T2. A significant correlation between HV and the volume of the T1Gd abnormality that relied on the existence of a large outlier was observed. However, there was consistent correlation between surface areas of all MRI-defined regions and the surface area of the HV. The T/Bmax, typically located within the T1Gd region, was independent of the MRI-defined tumor size. Univariate survival analysis found the most significant predictors of survival to be HV, surface area of HV, surface area of T1Gd, and T/Bmax. Conclusion Hypoxia may drive the peripheral growth of glioblastomas. This conclusion supports the spatial link between the volumes and surface areas of the hypoxic and MRI regions; the magnitude of hypoxia, T/Bmax, remains independent of size.

Applying a patient-specific bio-mathematical model of glioma growth to develop virtual [18F]-FMISO-PET images

“…All patient FMISO-PET images were reconstructed with a Hanning filter after scatter correction, resulting in a reconstructed spatial resolution of ∼12 mm (Degrado et al, 1994). Further details of the MRI and PET imaging protocols are given by Rajendran et al (2003), Swanson et al (2009) and in Section 2.4.…”

Hypoxia Imaging with 18F-FMISO PET for Brain Tumors

“…In general, the hypoxic volume is distinguished with tissue-to-blood ratios ! 1.2 in images acquired 2 h after FMISO injection with venous blood samples [28][29][30][31]. In brain tumor segmentation for MET PET, a tumor-to-normal ratio !…”

“…Our results in the first study are consistent with this previous data, except for the grade III patients, as all of our grade III gliomas were FMISO negative. Cher et al used 2 h as the waiting time before conducting the FMISO PET scanning, while the study here used 4 h. Many FMISO PET protocols have used 2 h as the uptake time [24,25,[27][28][29][30][31][32], while Thorwarth et al questioned the adequacy of 2 h for imaging of FMISO [34]. There, the kinetic analysis of dynamic datasets of FMISO PET suggested that the hot spots at 2 h did not reflect actual hypoxia but rather showed a high initial influx of the FMISO due to increased blood flow to the tumor.…”

“…Early reports by Grunbaum et al [33] and Thorwarth et al [34] addressing this issue suggested a 4-h acquisition as suitable. Despite this, most research adopted 2-h protocols [24,25,[27][28][29][30][31][32], possibly because a shorter protocol would be more generally acceptable in clinical settings. Based on this, the second part of our project was to directly compare 2-h and 4-h images from the same patients [2].…”

“…An alternative is presented by 18 F-fluoromisonidazole (FMISO) PET which is a widely used method for in vivo hypoxia imaging [20][21][22][23]. Valk et al first introduced the use of FMISO for glioma imaging in 1992 [24], and the usefulness of FMISO for glioma imaging has been extensively investigated [25][26][27][28][29][30][31][32]. The FMISO is also known to accumulate in severe hypoxic structures but not in mildly hypoxic structures, suggesting that FMISO would be able to discriminate severe from mild hypoxia.…”