The shape of DSC derived signal-time courses depends on numerous influencing factors (section 3.1.3). The effects of contrast agent extravasation on signal-time courses were simulated as a combination of initial tissue T1, CA extraction rate and blood flow using three tissue compartments. Within the context of the used correction methods, the signal-modifying leakage effects are represented by the extravasation correction parameter
Vascular Permeability and Tumor Heterogeneity
πΎπΎ2. In contrast, the transfer constant πΎπΎπ‘π‘πππππ’π’π‘π‘ (Eq. (3.25)) is only determined by the tissue and vessel properties. To analyze the relation of πΎπΎ2 and πΎπΎπ‘π‘πππππ’π’π‘π‘ values, simulations and patient data analyses were used. Additionally, the impact of SNR and reference curves on πΎπΎ2 was simulated. In patient data, the percentage of positive πΎπΎ2 values within the tumor VOIs allowed the study of the heterogeneity of tumors (section 3.7.5).
Simulations: in order to optimize πΎπΎ2 determination (method III, section 3.6.2), different starting points of the extravasation phase, i.e. averaging intervals, were simulated. In accordance with CBV results (section 4.1.2), πΎπΎ2 of methods III changed with differently defined extravasation phases. With later thresholds, the calculated πΎπΎ2s and their standard deviations increased. In other words, with shorter averaging intervals the estimated T2/T2* effects decreased and the estimated T1 effects of methods III increased. In general, the variance of πΎπΎ2 values was high and input πΎπΎπ‘π‘πππππ’π’π‘π‘ values could never be reproduced. Nevertheless, πΎπΎ2 showed a certain dependence on the extravasation strength. With increasing πΎπΎπ‘π‘πππππ’π’π‘π‘, the πΎπΎ2 values of methods I, II and III increased for T1 effects and decreased for T2/T2* effects. In contrast, πΎπΎ2 values obtained by method IV only showed a small variation for T2/T2* effects, whereby πΎπΎ2 values decreased for smaller input transfer rates. Furthermore, πΎπΎ2 depended on the noise level, where a decreasing SNR increased standard deviations similar as for CBV. For methods I and II, πΎπΎ2 depended on the applied reference curve, where different MTTs, CBFs and CBVs were used to imitate different reference tissue types. In contrast to CBV, the evaluation of those simulated reference curves showed smaller variations for πΎπΎ2 values of method II compared to those of method I.
Comparison of correction methods: Using patient data from the hypoxia study group, the spatial distribution of πΎπΎ2 values demonstrated large differences between methods.
The percentage of predominant T1 effects (πΎπΎ2 > 0) in VOICET over all patients with PB (n = 36) ranged between 2.4 Β± 4.5 % for method IV and 55.0 Β± 35.1 % for method III (sSVD, ATC). In the small subgroup of patients with two consecutive DSC scans (n = 8), πΎπΎ2 was not reproducible and changed to more negative values for the second bolus. In the first bolus, without PB, a larger tumor area exhibited predominant T1 effects. Figure 4.28-A shows one patient example with color-coded πΎπΎ2 maps of the first and second bolus. The red areas indicate positive, the blue ones negative values.
Corresponding to this, Figure 4.28-B shows patient averages of the percentage tumor volume exhibiting T1 (red) and T2/T2* (blue) effects, respectively.
Figure 4.29 shows a voxel-wise correlation between πΎπΎ2 values of methods II to IV against πΎπΎ2 values of method I in VOICET of one representative patient with PB. Even though for several patients significant correlations were observed, the heterogeneity among patients was high. πΎπΎ2 values obtained from the first and the second bolus did not correlate, and their differences became larger with increasing deviation from zero.
Figure 4.28: Predominant extravasation effects in patients, for the first and second bolus. (A) Example slices with color-coded K2(blue = T2/T2* effect, red = T1 effect) within the tumor region for 1st (top) and 2nd bolus (bottom). (B) Patient averages (n = 8) of respective percentages of T1 (red) and T2/T2* (blue) effects for 1st (deep colors) and 2nd (pale colors) bolus. Dotted line indicates 50 %.
Figure 4.29: Voxel-wise correlation between K2 values obtained with different methods in VOICET of one representative patient. Methods II to IV plotted against method I showing the regression line and the corresponding correlation coefficient r.
Vascular Permeability and Tumor Heterogeneity
Comparison of contrast agents: Over the entire brain, πΎπΎ2 values were different between both CAs, where πΎπΎ2 values obtained with Vasovist were in parts higher than those obtained with Gd-DTPA. The relative amounts of both leakage effects were estimated to be similar for both CAs, when calculated by the same method. The voxel-wise concordance of πΎπΎ2 values between both contrast agents was best for method I, which is in accordance with the similar rPSR values (section 4.7). One patient example of voxel-wise πΎπΎ2 correlation in the solid tumor region (VOIT2T) is shown in Figure 4.30-A.
Figure 4.30: Comparison of K2 values obtained from Vasovist and Gd-DTPA data for one exemplary patient. (A) Scatterplot of K2 values obtained with method I and (B) one corresponding slice for each of the K2 parameter maps: Vasovist against Gd-DTPA. All values are in arbitrary units. Positive K2 values (T1 effects) are depicted in red, negative K2
values (T2/T2* effects) in blue.
Relation of π²π²ππππππππππ and π²π²ππ: Difficulties that had been observed in correlations between CBVDSC and CBVDCE (section 4.6), were also noted for correlations between the parameters πΎπΎπ‘π‘πππππ’π’π‘π‘ (DCE) and πΎπΎ2 (DSC). In most patients, πΎπΎπ‘π‘πππππ’π’π‘π‘ values correlated best with πΎπΎ2 of methods I, III (sSVD) and IV, even though the quality of correlations varied widely. Figure 4.31 shows the voxel-wise correlation between πΎπΎπ‘π‘πππππ’π’π‘π‘ and πΎπΎ2
(method I) for two exemplary patients. The Spearman correlation coefficient was slightly larger than the Pearson correlation coefficient indicating a non-linear relationship.
Table 4.2 separately summarizes positive and negative median values of πΎπΎ2 for all methods. Method IV generated the largest and method III (TiSVD) the smallest πΎπΎ2
values.
Table 4.2: Positive and negative K2 values obtained with each method; * = Ktrans, all values in min-1, medians as well as upper and lower quartiles of patient values in contrast enhancing tumor tissue (VOICET), (n = 17).
Figure 4.31: Voxel-wise comparison of Ktrans versus K2 (method I) within VOICET. Two patient examples showing rather good correlation results (patient A, patient B). The regression line in black. Correlation coefficients r for Spearman and Pearson correlations.