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Schneider, Moritz Jörg; Cyran, Clemens Christian; Nikolaou, Konstantin; Hirner, Heidrun; Reiser, Maximilian F. and Dietrich, Olaf (2014): Monitoring Early Response to Anti-Angiogenic Therapy: Diffusion-Weighted Magnetic Resonance Imaging and Volume Measurements in Colon Carcinoma Xenografts.
In: PLOS ONE 9(9), e106970 [PDF, 1MB]

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Objectives: To evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model. Materials and Methods: 23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n=12) or placebo (n=11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10-800 s/mm(2)) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher's linear discriminant analysis (FLDA). Results: All ADCs and volumes are stated as median +/- standard deviation. Tumor ADC increased significantly in the therapy group (0.76 +/- 0.09x10(-3) mm(2)/s to 0.90 +/- 0.12x10(-3) mm(2)/s;p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10 +/- 0.11x10(-3) mm(2)/s vs. 0.03 +/- 0.09x10(-3) mm(2)/s;p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8 +/- 449.1 to 405.3 +/- 823.6 mm(3);p = 0.034;control: 219.7 +/- 79.5 to 443.7 +/- 141.5 mm(3);p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30 +/- 47.30% vs. 96.43 +/- 31.66%;p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%;and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%. Conclusions: Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring.

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