## 3 Translational Studies
### Can Steady State MRI Monitor Response to Anti-Angiogenic Therapy?  
[PERSON]'s _et al._[35] also studied the effect of anti-angiogenic therapies (rapamycin (mTOR inhibitor) and sorafenib (VEGF inhibitor) on renal cell carcinoma using MRI with magnetic nanoparticles. They found that the VVF in all treatment arms differed from control (P \(<\) 0.05) and declined weekly with treatment (Figure 3).  
[PERSON] _et al._[22] investigated steady state blood volume measurements for early quantitative monitoring of anti-angiogenic treatment of fibrosarcoma bearing nude mice. They found that the VVF measured with USPIO-enhanced MR imaging correlated well with the grade of tumor thrombosis, necrosis or both. Moreover, the MR data were in line with independent perfusion measurements obtained by using fluorescent intravascular microspheres. A second study by the same group found that for responders there was a significant decrease in \(\Delta\)R\({}_{2}\)* and VVF compared with the control group, whereas \(\Delta\)R\({}_{2}\)* and VVF remained nearly unchanged for nonresponders [37].  
Another study by [PERSON] _et al._[36] tested whether MR imaging measures of VVF using magnetic iron oxide nanoparticles were sensitive to the anti-angiogenic effect of targeted sonic hedgehog (Shh) therapies in a pancreatic cancer xenograft model. They found that in response to anti-Hh treatment, tumors showed a decrease in VVF compared with controls (P \(<\) 0.001).  
[PERSON] _et al._[32] performed a study on nude mice implanted with human glioma cells comparing cytotoxic and anti-angiogenic drug effects using multiparametric MRI. In mice treated with an anti-angiogenic therapy (Sorafenib), the tumoral VSI was significantly larger than in the untreated  
Figure 3: T1-weighted MRI of mice with pseudocolorized VVF maps superimposed over the center of the tumor within the right flank for each treatment arm (control (**a**), sorafenibib (**b**), and Rapamycin (**c**)) of the trial at baseline, and at the end of therapy. Note the heterogeneity of signal intensity and color spread throughout all cohorts at baseline, with marked decrease in vascularity in the rapamycin (**b**) and sorafenibib (**c**) treated animals as compared to control (**a**). Of note, only 3 mice survived all 3 weeks of therapy within the rapamycin treated arm. Figure from [PERSON] _et al._ (unpublished data)group. Also in the Sorafenib group, tumoral BVf decreased from treatment onset, whereas it remained stable in the untreated groups. VSI and BVf in the cytotoxic group did not differ from the values measured in the untreated group.  
A study by [PERSON] _et al._[28] to evaluate the anti-angiogenic effect of Sunitinib in squamous cell carcinoma tumor bearing mice revealed \(\sim\)46% reduction in tumor blood volume 4 days after start of Sunitinib treatment.  
[PERSON] _et al._ evaluated whether \"steady state\" MRI using a robust multiecho \(\Delta\)R\({}_{2}\)* MR relaxometry technique was suitable for the early assessment of rahbdomyosarcoma-bearing mice treated with bevacizumab [38]. They found that the bevacizumab resulted in a significant reduction of the \(\Delta\)R\({}_{2}\)* values compared with the control group, reflecting a significant decrease of the VVF by 33%. Immunohistochemistry confirmed the MR results showing an approximately 25% reduction of the MVD after treatment.