SUMMARY The sleep and awake EEG's of 90 epileptics and 30 normal controls were evaluated. The epileptics were divided into three groups: (1) Nocturnal seizures predominately, (2) Diurnal seizures predominately, (3) Mixed diurnal and nocturnal seizures. Patients with nocturnal seizures showed greater numbers and degrees of abnormalities during sleep EEG's. In patients with diurnal seizures abnormalities appeared about equally in sleep and awake EEG's. The stage of sleep most useful for detecting abnormalities was drowsiness‐light sleep. Depriving the patient of anticonvulsant medication for 24 hours did not increase the chance of abnormalities occurring during sleep recordings. The sleep recordings were conducted on a 16 channel electroencephalograph using bipolar and monopolar recording techniques simultaneously. Except that bipolar recordings seemed to detect foci better, these techniques appeared to be equal in their ability to display abnormalities associated with epilepsy. RÉSUMÉ Les E.E.G. enregistrés en sommeil ou en veille chez 90 épileptiques et 30 témoins normaux ont étéétudiés. Les épileptiques avaient été répartis en trois groupes: (1) Crises nocturnes prédominantes, (2) Crises diurnes prédominantes et (3) Crises diurnes et nocturnes mélangées. Les malades ayant des crises nocturnes ont donné dans ľE.E.G. en sommeil des anomalies en chiffres et en dégres plus élevés. Chez les malades souffrant de crises diurnes, les anomalies se sont manifestées à peu prés également dans ľE.E.G. pendant le sommeil et pendant la veille. La phase du sommeil la plus favorable à la détection ďanomalies a été celle ďun sommeil léger. La privation de médicament anticonvulsif infligée au malade pendant 24 heures n'a pas augmenté la chance des anomalies se produisant lors de ľenregistrement pendant le sommeil. Les E.E.G. pris pendant le sommeil ľont été avec électroencéphalographe à 16 canaux faisant un usage simultané de techniques bipolaires et monopolaires ďenregistrement. Exception faite du fait que ľenregistrement bipolaire a semblé mieux révéler les foci, ces techniques se sont montrées de valeur égale dans la détection des anomalies associées àľépilepsie.

Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague–Dawley Rag2-Rag2tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.

An important obstacle to translating promising drug treatments against glioblastoma (GBM) to the clinic is lack of resistant GBM animal models that more accurately parallel the clinical course of GBM drug resistance found in patients. In this project, a recurrent patient derived intracranial GBM tumor model (GB10) was developed for the first time in the novel Rag2 Null transgenic rat to establish a reproducible preclinical brain tumor model. Histologic characterization confirmed markers of high nuclear proliferation (30% Ki67) and presence of neovascularity (3% Von Willebrand Factor VIII) in all tumors. Serial in vivo imaging was performed to determine a clinically relevant late stage of tumor across all rats before initiation of treatment, accounting for heterogeneity of tumor size and growth rate characteristics. Overall survival was measured following oral administration of control, Temozolomide (TMZ), or combination therapy with TMZ and Idasanutlin. Eighteen Rag2 Null rats were intracranially implanted with GB10, a well characterized, recurrent cell line from the Mayo Clinic Brain Tumor Patient-Derived Xenograft National Resource. Bi-weekly high resolution, 2-dimensional T2 magnetic resonance imaging (2DT2 MRI) was performed on a Bruker 9.4 tesla scanner until tumor volume reached 30 µL. 14 days later, simultaneous positron emission tomography and magnetic resonance imaging (PET MRI) was performed on each rat with three dimensional T1 post-contrast (3DT1 CE), amino acid-based 18F-Flouroethyltyrosine (18F-FET), and amide proton transfer-chemical exchange saturation transfer (amide-CEST). Measured tumor parameters included volumetry (3DT1 CE), metabolic activity (18F-FET), and mobile phase intracellular protein content (amide-CEST), to confirm late-stage viable tumors of similar size (15.3 mm^2 +/-1.38 based on SEM, N=16) and metabolism (2:1 ratio of activity of tumor relative to contralateral control brain tissue). Two rats were removed: 1 died prematurely of infection and 1 had extra-axial tumor location. Oral treatment groups were as follows: Control (N= 5), TMZ (N=6) or TMZ + Idasanutlin (N=5). Kaplan Meier survival curves for the TMZ treated group (80.2+/-4.1 days) and combined TMZ + Idasanutlin group (93.8+/-6.2 days) were both significantly increased (P<0.001) compared to control (67.4+/-4.5 days). Survival for the TMZ + Idasanutlin treated group was also significantly increased (P<0.001) relative to TMZ treated group indicating efficacy of combination therapy. In conclusion, a robust, resistant, patient derived GBM animal model was developed using serial, high field, non-invasive, multimodality, molecular imaging along with histopathologic analysis. Feasibility of assessing treatment response was also demonstrated with both a standard of care and experimental combination therapy, in the late stage of GBM growth. Citation Format: Luke R. Jackson, Megan R. Masi, Hamideh zarrinmayeh, Sudip K. Das, Mark A. Green, Scott E. Snyder, Nian Wang, Karen Pollok, Gary D. Hutchins, Elizabeth R. Butch, Michael C. Veronesi. Development of a patient-derived glioblastoma model in the transgenic Rag2 Null rat: In vivo imaging, histology, and combination therapy assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1661.