Table 1.
Biopsied samples and map characteristics.
Figure 1.
Examples of axial high resolution T1-weighted MR images acquired 2 min (A), 15 min (B) and 75 min (C) after contrast administration in a patient (#3) with newly diagnosed GBM undergoing standard chemoradiation are shown. Subtraction maps were calculated from the data acquired at 2 and 15 min (D) and 2 and 75 min (E) post contrast administration. Blue regions represent fast clearance of the contrast agent from the tumor while red regions represent slow accumulation of the contrast in the tissue. It can be seen that abnormal enhancement patterns in the 75 min map are depicted more clearly and over larger regions than in the 15 min map. The signal intensity of regions with different enhancement patterns as a function of time post contrast administration is shown in the plot. It can be seen that the red and blue components of the tumor enhance and decay at different rates.
Figure 2.
Histological determination of tumor and non-tumoral components – GBM.
Examples of contrast-enhanced T1-weighted MRI (A–C), enhancement subtraction maps calculated from the 2 and 75 min data (D–F) and H&E stained histological samples of a rapidly growing lesion in patient #1 with newly diagnosed GBM undergoing standard chemoradiation are shown. Data was acquired prior to surgery, 6 months after initiation of treatment. Samples were taken from a mixed blue and red region (A, D, arrows), a blue region (B, E, arrows) and a red region (C, F, arrows). Histological analysis reveals mixed regions of tumor and necrosis (G, magnification×200), hypercellular tumor (H, magnification×400) and radiation necrosis (J, magnification×400), respectively.
Figure 3.
Histological determination of tumor and non-tumoral components – brain metastases.
Examples of contrast-enhanced T1-weighted MRI (A, E), enhancement subtraction maps calculated from the 2 and 75 min data (B, F) and H&E stained histological samples (C, D, G) of a cortical breast cancer brain metastasis of patient #30, 2 years post radiosurgery, are shown. Sample #4 taken from a red region marked by arrows in A and B shows a small tumor foci, surrounding a viable blood vessel, within a larger region of necrosis (magnification x100). An example of necrotic blood vessels within the necrotic region (x400) is shown in D. Sample #3 taken from a blue region on the border of normal brain marked by arrows in E and F shows a highly cellular tumor adjacent to normal cortex (G, x200).
Figure 4.
Histological determination of tumor and non-tumoral components – brain metastases.
Examples of contrast-enhanced T1-weighted MRI (A), enhancement subtraction map calculated from the 2 and 75 min data (B), macro H&E stained histological sample (C, magnification x20), tumor region from a peripheral region of the sample (D, magnification x400) and radiation necrosis from the central region of the sample (E, magnification x400) of a medial NSCLC brain metastasis of patient #23 (metastasis #1), 1 year post radiosurgery, are shown. The metastasis was resected unblock and marked by the neurosurgeon to enable comparison with the MRI data. H&E staining shows a large central necrotic region surrounded by a rim of morphologically active tumoral tissue, in agreement with the subtraction map. It is also possible to see part of a necrotic blood vessel in the region of radiation necrosis (E) and scattered blood cells in the tissue.
Table 2.
Non-biopsied tumors histology and map characteristics.
Figure 5.
Examples of vessel morphology sampled from regions appearing blue in the maps of patients with primary brain tumors are shown in images A–F. Vessels from regions appearing red in the maps are shown in G–I. Samples D and G were taken from patient #4. Samples B, E, H and I were taken from patient #1. A and C were taken from patient #11 and F was taken from patient #13. It can be seen that the samples obtained from blue regions in the maps (A–F) present swollen endothelial cells, dilated lumen, peri-vascular dense fibrous tissue and glomeruloid lumen. Samples taken from red regions in the maps show different stages of vessel necrosis. The vessels shown in G show early necrosis, with scattered blood cells surrounding the necrotic vessels, while the vessels in H and I show later stages of vessel necrosis. The silhouette is reserved and there are residual red blood cells but the endothelial cells are necrotic.
Figure 6.
Contrast-enhanced T1-weighted MRI without (A) and with (B) a mask selecting the enhancing portion of a GBM tumor (patient #4) are shown. The enhancing lesion volume was calculated from the pixels marked pink in (B). Enhancement subtraction maps calculated at 15 min (C) and 75 min (D) demonstrate the contributions of the red/non-tumor and blue/tumor contributions to the enhancing lesion volume.
Figure 7.
Contrast-enhanced T1-weighted MRI (A, D, G), enhancement subtraction maps (B, E, H) and rCBV maps (C, F, I) of patients # 6 (A–C), #3 (D–F) and #26 (G–I) are shown. Patient #6 (GBM) shows a blue rim surrounding the surgery site, representing morphologically active tumor, in agreement with high rCBV values in the corresponding rCBV map. Patient #3 (GBM) is a contradicting example, showing a massive lesion dominated by the blue population in the subtraction maps (confirmed by histology to consist of ∼70% morphologically active tumor), in contrast to low rCBV values in the corresponding rCBV map. Patient #26 (breast cancer brain metastases) shows a thin rim of the blue populations in our maps in agreement with a thin rim of increased rCBV values. The advantages of our vessel function maps over rCBV acquired using DSC in means of high resolution, high sensitivity to contrast and minimum sensitivity to susceptibility artifacts can be seen.
Figure 8.
Correlation with time to progression.
The correlation between the late enhancement subtraction maps and time to progression was studied in a small cohort of 13 GBM patients post chemoradiation. Kaplan-Meier curves of time to progression in patients above and below the median of four predictors are shown: Initial fast volume (A), initial enhanced volume (B), initial fast growth rate (C) and initial enhanced growth rate (D). The curves are plotted for each predictor for patients above (black) and below (gray) the median. It can be seen that the initial fast growth rate predictor provides a near-significant difference between the two groups of patients, suggesting this predictor may be a candidate for prediction of time to progression.
Table 3.
Newly diagnosed GBM cohort.
Figure 9.
Examples of progression and pseudoprogression in GBM patients post chemoradiation.
Late enhancement subtraction maps of a patient (#6) with significant increase in the enhancing lesion due to increase in the red volume (A–C) and a patient (#3) with significant increase in the blue component (D–F) with minor changes in the enhancing volume are shown. In the first example, the total enhancing volume has increased by 34% from 3 weeks (A) to 4.2 months (B) post chemoradiation, and then decreased to 33% below the initial volume (C) 9 months post treatment. The blue volume slightly increased by 6% in the first 4 months (A, B) and then significantly decreased to 47% below the initial volume at 9 months (C) while the red volume increased by 51% in the first 4.2 months (A, B) and decreased to 13% above the initial volume by 9 months (C). This patient progressed 11.6 months post treatment. In the second example, the total enhancing volume has increased by 16% from 3 weeks (D) to 2.5 months (E) and then remained 17% above the initial volume (F) 6.5 months post treatment. The blue volume slightly increased by 2% in the first 2.5 months (D,E) and then significantly increased to 57% above the initial volume at 6.5 months (F) while the red volume increased by 39% in the first 2.5 months (D, E) and decreased to 61% below the initial volume by 6.5 months (F). This patient progressed 6.5 months post treatment when he was referred to surgery.