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Multiparametric Advanced Fast Imaging (MAFI) to Characterize Tumor Habitat in Orthotopic Mouse Models of Pediatric Brain Tumors1Radiology, University of Colorado Denver, Aurora, CO, United States, 2University of Colorado Denver, Aurora, CO, United States, 3Neurooncology, Children's Hospital Colorado, Aurora, CO, United States
Synopsis
Brain tumors are the second most common malignancy in childhood (exceeded only by leukemia). Clinically, multiparametric MRI is now considered to be the neuroimaging standard for detecting brain tumors. Pediatric brain tumors have a diverse array of clinical manifestations, cellular and molecular phenotypes, and tumor habitats. There is an unmet need to develop human-faithful pediatric mouse models and fast high-resolution physiological MRI for their detection and characterization. Here, we report on a non-gadolinium, Multiparametric Advanced Fast Imaging (MAFI) approach followed by radiomics analysis to detect, characterize and differentiate three distinct brain tumor subtypes in mouse patient-derived xenograft (PDX) models.
Introduction:
Adult brain tumors vastly outnumber pediatric tumors and are therefore better studied. Brain tumors in children, as opposed to those in adults, are characterized by more diverse tumor types, lower incidence, and a prognosis that at times depends on age 1. Current proven therapies that are effective in treating a variety of pediatric high grade brain malignancies include neurosurgery, radiotherapy, and chemotherapy. Multiparametric Magnetic Resonance Imaging (MRI) remains a gold standard for detection and follow-up of pediatric brain tumors. The goal of this pre-clinical MRI study was to develop a Multiparametric Advanced Fast Imaging (MAFI) approach for a rapid and sensitive localization of intracranial tumors and characterization of tumor “habitat” including development of angiogenesis, peritumoral edema and metastatic spread. Mouse patient-derived xenograft (PDX) models for pediatric medulloblastomas (the most common malignant brain tumor in childhood, 18% of all brain neoplasms), high-grade gliomas (the second most common, 15%) and ependymoma (the third most common, 12%), were employed in this study 2,3.Methods:
All animal protocols were reviewed and approved by the University of Colorado IACUC. Female severely immunodeficient (scid) mice were used for intracranial orthotopical inoculation of pediatric PDX: medulloblastomas into the fourth ventricle (n=6); diffuse intrinsic pontine gliomas (DIPG) directly into the pons (n=6), and ependymomas into the fourth ventricle (n=12). All image acquisition was performed one, three and over five weeks after inoculation using an ultra-high field Bruker 9.4 Tesla BioSpec MR scanner. A Bruker mouse head array RF cryo-coil was used for all experiments. Non-gadolinium MAFI protocols were developed based on high-resolution T2w turboRARE (3D, 5min22s), FLAIR (sagittal, 1min54s), fast spin echo diffusion weighted imaging (DWI axial, 1min17s) with 6 b-values. Analytical methodologies included (i) conventional volumetric analysis, blood vessel density and apparent diffusion coefficient (ADC) values using ParaVision NEO software, as well as (ii) shape and texture based radiomics descriptors to characterize tumor habitat of each tumor sub-type using a modified COLIAGE software 4,5Results:
High-resolution turboRARE T2w-MRI (0.62 microns in-plane resolution) clearly showed that all PDX were inoculated and homed at the proper anatomical location: the posterior fossa for medulloblastomas; the pons for PDIG; and the cerebellum for ependymomas (Figure 1A-C). The sensitivity of T2w-MRI scans was 0.2 mm3 for the smallest tumor detected (Figure 1D). They also revealed increased blood vessel densities (in the early stage, mean tumor volume 0.2 – 30 mm3), necrosis and intracranial metastases (the late stage, mean tumor volume >40 mm3) (Figure 2A-C). FLAIR MRI precisely identified peritumoral regions of the diffuse disease, and together with DWI, of vasogenic edema. The ADC values were notably low in medulloblastomas (as low as 0.58x10-3 mm/s) (Figure 3A). For radiomics analysis, each scan was segmented into three regions: (i) well defined tumor (including distant metastases); (ii) peritumoral edema; (iii) tumor necrosis (Figure 3B). 360 radiomics features (capturing co-occurrence, grey-level dependence and directional gradients) were obtained for each region from the MAFI protocol. A subset of twelve tumoral, six peritumoral and two distant MRI radiomics features were found to be predictive of the tumor sub-type (p=0.00024) independently of tumor anatomical location (Figure 3C).Discussion:
Orthotopically implanted PDX xenografts closely mimic histological features, invasiveness, metastasis and radiological features of the primary tumors. Applied MAFI MRI protocol followed by radiomics feature analysis discriminated among specific radiological features for three distinct orthotopic PDX models: medulloblastomas exhibit higher levels of necrosis, lower ADC values, and higher angiogenesis as compared to ependymomas (a higher level of edema and inflammation, spinal metastatic spread) and DIPG (low blood vessel densities) (Figure 4).Conclusion:
We successfully developed a comprehensive MAFI approach and radiomics analysis to make accurate and rapid detection and characterization of tumor anatomy and microenvironment in mouse models of pediatric PDX brain tumor models. Radiomics features from tumor and peritumoral regions capture tumor habitat specific for each tumor sub-type. Future studies will include injections of iron-oxide based dynamic susceptibility contrast (DSC-MRI) and quantitative T2/T2* maps for additional imaging features related to perfusion and inflammation in pediatric brain tumor models, especially during the course of radiation therapy.Acknowledgements
No acknowledgement found.References
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