Patient characteristic.

<p>Patient characteristic.</p

Analysis of a 38-year-old female patient with pseudoprogression (PsP).

<p>Contrast enhanced T1w MR images (A-B). Follow-up image with delineated tumor region of interest (ROI) (A). Parametric response map of relative apparent diffusion coefficient (rADC) (B). The resulting quantitave scatter plot (C). The voxels are color-coded corresponding to their changes between baseline and follow-up examinations. Blue is designated to voxels with a decrease of rADC ≥ 0.25, red to an increase of rACD < 0.25 and green to changes in between these thresholds.</p

Boxplots of relative apparent diffusion coefficient (rADC) from patients with progressive disease (PD) and pseudoprogression (PsP).

<p>Boxplots showing the percentage of voxels with a decrease of rADC ≥ 0.25 between baseline and follow-up rADC values for patients with PD (n = 28) and PsP (n = 7). The percentage of rADC is higher in patients with PD (59.2%; Q1 36.7; Q3 78.6) than in those with PsP (18.6%; Q1 3.04; Q3 26.5) (<i>p</i> = 0.005).</p

Patient-individual Spearman correlation coefficients (r_Sp) with 95% confidence intervals.

<p>Positive correlations are marked blue, negative correlations are red, insignificant correlations (p>0.05) are grey. No trend towards any correlation between MTR_asym and ADC could be found in the CE-T1 tumor region (left diagram), since correlation coefficients scatter around r_Sp≈0. For the T2 edema region (right diagram) a trend towards a positive correlation could be observed. Eight of fifteen patients correlate weakly or moderately positive, while seven coefficients are insignificant (n = 4) or too low to claim an association (n = 3). The trend towards a positive correlation within the T2 edema region is suspected to be due its more homogeneous structure, compared to the CE-T1 tumor which is characterized by different cell types, vasculogenesis and necrotic foci.</p

Correlation analysis of MTR_asym values and ADC values with the cell density of corresponding biopsy sites.

<p>* significant correlations are marked. r_Sp = Spearman rho</p><p>Correlation analysis of MTR_asym values and ADC values with the cell density of corresponding biopsy sites.</p

Tumor cell density and the corresponding MTR_asym values/ADC values at the origin of the biopsy.

<p>• Biopsy from contrast-enhancing parts on CE-T1. ◊ Biopsy from necrotic areas as visible on CE-T1. ▲Biopsy from non-enhancing areas on CE-T1 (“edema”). <b>A₁/A₂)</b> 12 biopsies were obtained along a trajectory in a 67-year-old female with glioblastoma (patient 3). Linear regression of cell density and MTR_asym values yielded R² = 0.323 (p = 0.054). Linear regression of cell density and ADC values yielded R² = 0.419 (p = 0.023). <b>B₁/B₂)</b> 12 biopsies were obtained along a trajectory in a 60-year-old female with glioblastoma (patient 4). Linear regression of cell density and MTR_asym values yielded R² = 0.109 (p = 0.294). Linear regression of cell density and ADC values yielded R² = 0.003 (p = 0.876). <b>C₁/C₂)</b> 12 biopsies were obtained along a trajectory in a 45-year-old male with glioblastoma (patient 15). Linear regression of cell density and MTR_asym values yielded R² = 0.959 (p<0.001). Linear regression of cell density and ADC values yielded R² = 0.475 (p = 0.013).</p

Region specific Spearman correlation analysis of MTR_asym and ADC contrast.

<p>*significant positive correlations. Correlation coefficients (r_Sp) sorted by their values for the ROI T2 peritumoral edema. Insignificant values (p >0.05) or values around r_Sp≈0 [-0.15:+0.15] are not considered as tendency towards any correlation.</p><p>Region specific Spearman correlation analysis of MTR_asym and ADC contrast.</p

Voxelwise correlation of ADC and MTR_asym contrast for patient 6.

<p>The shown scatterplots correspond to the volumetric segmentation of the CE-T1 tumor and T2 peritumoral edema region for an exemplary patient (Patient 6). A linear regression (red line) was additionally plotted for both regions. For the CE-T1 tumor, no correlation could be observed over the 1515 voxel, whereas a weak positive correlation over the 3044 voxel of the T2 edema region of this patient is found. The weakly positive correlation within the T2 edema signifies that high MTR_asym values (caused by decreased NOE effects) tend to correspond to high ADC values in this region. The graphs represent the generally observed trend within the patient collective.</p

Correlation of the biopsy point on the MTRasym image and the ADC image with histology and semi-automatic cell counting.

<p><b>A)</b> Target point T of the biopsy trajectory on the intraoperative CE-T1 image of a 45-year-old male with glioblastoma (patient 15). It lies in the contrast-enhancing area. Marks of the stereotactic biopsy ring are visible frontally and occipitally. <b>B)</b> Target point T on the ADC image which was coregistered to the intraoperative CE-T1 image in MITK with an automatic multi modal rigid registration algorithm. The average ADC value of 3x3x3 voxels (= 27mm³) was read out to account for possible inaccuracies in coregistration and biopsy sampling. In the shown example, it yielded ADC = 659mm²/s. <b>C)</b> Target point T on the MTR_asym image which was coregistered to the intraoperative CE-T1 image in MITK with an automatic multi modal rigid registration algorithm. The average MTR_asym value of 3x3x3 voxels (= 27mm³) was read out to account for possible inaccuracies in coregistration and biopsy sampling. In the shown example, it yielded MTR_asym = -1,72% <b>D)</b> Corresponding slice of the 1 mm³ biopsy specimen (HE stain) in x20 magnification obtained at the target point T. <b>E)</b> Exemplary section to illustrate semi-automatic cell counting with the ImageJ plugin ITCN. Tumor cells that were recognized by the algorithm are marked red. Overall cell density of the shown biopsy specimen was 1684 cells/mm².</p

Segmentation of the regions of interest (ROI) CE-T1 tumor and T2 peritumoral edema.

<p>Glioblastoma of the left temporal lobe in patient 6. Coregistered images from the different sequences showing an exemplary slice of the whole tumor volume for this patient. <b>A)</b> CE-T1 tumor ROI (red line) segmented on CE T1-weighted image while thoroughly excluding central necrosis. <b>B)</b> T2 peritumoral edema ROI (green line) segmented on T2-weighted image. <b>C)</b> Coregistered ADC map and <b>D)</b> MTR_asym contrast illustrating both ROIs. The glioblastoma tumor and the cerebrospinal fluid in sulci and ventricles display hyperintense on NOE mediated CEST based on MTR_asym.</p