Dynamic contrast-enhanced magnetic resonance imaging biomarkers in head and neck cancer: potential to guide treatment? A systematic review.

Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways.

Purpose To compare the effects of two anti-angiogenic drugs, bevacizumab and a cytosolic phospholipase A2-α inhibitor (AVX235), on the relationship between vascular structure and dynamic contrast enhanced (DCE)-MRI measurements in a patient-derived breast cancer xenograft model. Methods Mice bearing MAS98.12 tumors were randomized into three groups: bevacizumab-treated (n = 9), AVX235-treated (n = 9), and control (n = 8). DCE-MRI was performed pre- and post-treatment. Median initial area under the concentration-time curve (IAUC60 ) and volume transfer constant (Ktrans ) were computed for each tumor. Tumors were excised for ex vivo micro-CT (computed tomography) angiography, from which the vascular surface area (VSA) and fractional blood volume (FBV) were computed. Spearman correlation coefficients (ρ) were computed to evaluate the associations between the DCE-MRI and micro-CT parameters. Results With the groups pooled, IAUC60 and Ktrans correlated significantly with VSA (ρ = 0.475 and 0.527; P = 0.019 and 0.008). There were no significant correlations within the control group. There were various significant correlations within the treatment groups, but the correlations in the bevacizumab group were of opposite sign, for example, Ktrans versus FBV: AVX235, ρ = 0.800 (P = 0.014); bevacizumab, ρ = -0.786 (P = 0.023). Conclusion DCE-MRI measurements can highly depend on vascular structure. The relationship between vascular structure and function changed markedly after anti-angiogenic treatment. Magn Reson Med 78:1513-1522, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

/pdf/anti-angiogenic-therapy-affects-the-relationship-between-3zm5azhq2q.pdf

Anti-angiogenic therapy affects the relationship between tumor vascular structure and function: A correlation study between micro–computed tomography angiography and dynamic contrast enhanced MRI

Mri and pet

We aimed to develop and evaluate a new method that reliably differentiates between cerebral arteries and veins using voxel-wise CT-perfusion-derived parameters. Fourteen consecutive patients with suspected stroke but without pathological findings were examined on a multi-detector CT system: 32 dynamic phases (∆t = 1.5 s) during application of 35 mL iomeprol-350 were acquired at 80 kV/200mAs. Three hemodynamic parameters were calculated for 18 arterial and venous vessel segments: A (maximum of the time-density-curve), T (time-to-peak), and W (full-width-at-half-maximum). Using receiver operator characteristic (ROC) curve analysis and Fisher’s linear discriminant analysis (FLDA), the performance of every classifier (A, T, W) and of all linear combinations for the differentiation of arterial and venous vessels was determined. A maximum area under the ROC-curve (AUC) of 0.945 (accuracy = 86.8 %) was obtained using the FLDA combination of A&T or the triplet FLDA of A&T&W for the classification of venous and arterial vessels. The best single parameter was T with an AUC of 0.871 (accuracy = 79.0 %), which performed significantly worse than the combination A&T (p < 0.001). Arteries and veins can be accurately differentiated based on dynamic CT perfusion data using the maximum of the time-density curve, its time-to-peak, its width, and FLDA combinations of these parameters, which yield accuracies up to 87 %. • For classification of cerebral vasculature, time-to-peak has the best single-parameter accuracy.
 • Fisher’s linear discriminant analysis improves the performance of the individual classifiers.
 • Combining signal maximum and time-to-peak parameters significantly increased the classifying potential.
 • Pre-processing of time-density-curves by Gaussian filtering or fitting can improve diagnostic accuracy.

Validation of a method to differentiate arterial and venous vessels in CT perfusion data using linear combinations of quantitative time-density curve characteristics.

BackgroundNovel anti-angiogenic treatments are increasingly complementing established cancer therapy strategies in head and neck tumors. Contrast-enhanced magnetic resonance imaging (MRI) can be ap...

DCE-MRI biomarkers for monitoring an anti-angiogenic triple combination therapy in experimental hypopharynx carcinoma xenografts with immunohistochemical validation

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.

/pdf/monitoring-early-response-to-anti-angiogenic-therapy-3qlombgo58.pdf

Monitoring Early Response to Anti-Angiogenic Therapy: Diffusion-Weighted Magnetic Resonance Imaging and Volume Measurements in Colon Carcinoma Xenografts

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DCE-MRI biomarkers for monitoring an anti-angiogenic triple combination therapy in experimental hypopharynx carcinoma xenografts with immunohistochemical validation

Monitoring Early Response to Anti-Angiogenic Therapy: Diffusion-Weighted Magnetic Resonance Imaging and Volume Measurements in Colon Carcinoma Xenografts