IMG-17. Advanced MRI On The Cellular and Vascular Phenotype of Mouse Ependymoma Models and Chemo-Radiation Treatment Response

Abstract

Ependymoma (EPN) is an aggressive pediatric brain tumor, for which the benefits of chemotherapy in pediatric patients have not been defined. EPN treated with surgery and radiation recur in 23-66% of patients. Our group has previously established aggressive behaviors of EPN, including high tumor cellularity, cytological anaplasia, high mitotic index, tumor necrosis, and the presence of inflammatory cells such as M2-type myeloid cells. Here we report on an advanced 9.4 Tesla MRI protocol for characterizing the cellular and vascular phenotype and treatment response to chemo-radiation therapy (CRT) in an orthotopic mouse model of patient derived xenografts (PDX) of pediatric EPN . Female severely immune deficient (SCID) mice were used for intracranial inoculation of disaggregated tumors from pediatric EPN patients (n=22). High-resolution T2w-MRI was able to detect cerebellar microlesions as small as 0.2 mm diameter; the median tumor volumes at the baseline were 21±12 mm3. Using diffusion-weighted based cell-size imaging, iron-oxide based vessel-size imaging and quantitative T2-maps, the EPN-specific phenotype was characterized by an increased cell size (S=14 microns), increased vessel density index (Q=0.54), and low ADC values (0.63x10-3). Once the intracranial tumors reached at least 5 mm3, animals were treated with CRT (10 Gy radiation plus 30 mg/kg 5-fluorouracil, n=6). CRT resulted in a tumor shrinkage, tumor necrosis with decreased cell sizes and increased ADC values, and a dramatic vascular-inflammatory response (decreased Q and DT2 values with the injection of iron oxide nanoparticles as macrophage-specific contrast). In summary, orthotopically implanted PDX EPN in mice closely mimic histological features, anatomical location and radiological features of the primary tumors. A significant decrease in vessel size density and an increase in inflammatory cells were seen as soon as 2 days after CRT. The late response (2 weeks post CRT) is characterized by decreased cellularity, cell size, and tumor volumes.