Multiparametric Magnetic Resonance Imaging for Immediate Target Hit Assessment of CD13—Targeted Tissue Factor tTF-NGR in Advanced Malignant Disease

Figures

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  Figure 1. Multiparametric MR imaging shows a decrease in perfusion after therapy with tTF-NGR. Overview of the change in perfusion parameters DCE (measured as k-trans) (A) and vascular volume fraction (VVF) (B) in comparison to the ADC value (C) over the course of the first therapy cycle with tTF-NGR. MRI assessment was performed before therapy initiation, five hours after the first infusion and after five days of therapy. A decrease in perfusion parameters DCE and VVF and an increase in ADC were assessable as early as five hours after the first therapy, with an even further reduction after five days of therapy in some of the patients. Values are given as the change from baseline (set to 100% for each individual patient) for better comparison of the three evaluated parameters. One-way ANOVA revealed high statistical significance of p < 0.0001 overall for all three parameters. Not all imaging techniques for all time points were available (see manuscript for details), so only data of patients with completed imaging and analysis are shown here.

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  Figure 2. Exemplary imaging data. Imaging of patient 13 with a desmoplastic round cell tumor with multiple liver metastases (marked with an asterisk) before therapy. (A) T2 for anatomical information, (B) T2* after injection of ferucarbotran for calculation of VVF, (C) ADC map, (D) ADC, (E) DCE scan after injection of gadobutrol, (F) calculated K-trans map. The imaging protocol thus comprises different sequences to first acquire anatomical information, followed by different possibilities for the assessment of tumor perfusion and its changes after therapy. Color scale in C represents the ADC value, color scale in F represents the k-trans value.

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  Figure 3. Imaging of patient 16 with colorectal carcinoma and liver metastases (marked with an asterisk) before (A,B) and after (C,D) the second cycle shows an increase in ADC value (B + D) and changes in T2 weighted imaging (A + C). These morphological changes can be further assessed with the multiparametric MRI protocol.

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  Figure 4. Correlation between imaging parameters DCE and VVF before and after therapy with tTF-NGR. Correlation of the values of DCE and VVF over the first cycle of tTF-NGR therapy visualizes that either value can be used for assessment of perfusion after treatment targeting the tumor vasculature, for the pre-scan (A), as well as for the scan after five hours (B) and five days (C). Spearman two-tailed correlation revealed a significant correlation between the respecting values over the entire course of the first cycle (baseline scan r = 0.046, p = 0.046, five-hours scan r = 0.881, p = 0.007, five-days scan r = 0.881, p = 0.007).

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  Figure 5. Correlation between DCE and ADC as well as VVF and ADC imaging parameters before and after therapy with tTF-NGR. Correlation of DCE and ADC (A–C) as well as VVF and ADC (D–F) shows a good correlation of the individual perfusion parameters with the ADC values. Spearman two-tailed correlation revealed a significant correlation between the respecting values over the course of the first cycle (A–C baseline scan r = −0.9301, p = 0.0003, five-hours scan r = 0.8693, p = 0.0018, five-days scan r = −0.8511, p = 0.0029; D–F baseline scan r = −0.8, p = 0.0138, five-hours scan r = −0.8068, p = 0.0119, five-days scan r = −0.7395, p = 9.0275).

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  Figure 6. All imaging parameters show a fast normalization of perfusion after effective anticoagulation. Four patients needed a withdrawal of the study medication tTF-NGR due to elevation of troponin T hs or Grade 2 thrombotic events. These patients were immediately anticoagulated with enoxaparin, patient 6 and patient 11 on day 3, patient 7 on day 1 and patient 8 on day 2. Imaging was performed one day after anticoagulation (patient 6, patient 8) or two days after anticoagulation (patient 7, patient 11) and showed the reversibility of the therapeutic effect of tTF-NGR on the parameters DCE (A), VVF (B) and ADC (C). Overall one-way ANOVA was significant for all three parameters (DCE p = 0.0209, VVF p = 0.0044, ADC p = 0.0010).