Orthotopic xenograft mice models for glioblastoma (GBM) are a powerful tool to elucidate mechanisms of tumorigenesis and the evolution of GBM^1,2. More recently, intracranial implantation of freshly dissected human GBM cells has been employed, referred to as patient derived xenografts (PDX), with the aim of obtaining a mouse xenograft model closer to its parental tumor and to investigate its related metabolic modifications^3,4: Avoiding cell selection and in vitro culture minimizes genetic and phenotypic drift as compared to the original cells, due to the selective pressure generated by the artificial environment. In this study in vivo ¹H MRS and MRI were employed in parallel to monitor GBM growth and migration in terms of early morphological and metabolic modification in the aforementioned mouse model of primary GBM. Longitudinal follow-up was compared between groups of mice derived from different human GBM in order to elucidate possible metabolic peculiarity of each tumor as well as growth reproducibility and predictability.Fresh human GBM specimens were dissociated, and the tumor cells were kept in stem cell medium overnight. Cells (N=10⁵) were injected stereotactically into the striatum of immunodeficient mice (NOD-SCID). Starting from 9 weeks after the injection, mice were monitored for structural (T2-weighted images) and early metabolic modifications using in vivo short-TE localized ¹H MRS⁵ in the injected and contralateral side (VOI=2x2x2mm³). Animals were sacrificed at the time of appearance of neurological symptoms or weight loss. All measurements were performed in a 14.1T/26cm system (Varian/Magnex Scientific) and a home-built 12mm surface coil in quadrature configuration. Immunohistochemical staining for H&E, EGFR and MIB1 were compared in mice brain sections and their respective human specimen. Three groups of mice injected with human GBM cells from three respective patients (P1, N=6; P4, N=3, P6, N=4) developed first signs of tumor within 9 to 15 weeks post-injection: first signs were determined as first appearance of structural modification on MRI or significant variations in the metabolic profile (NAA at first). However, the inter-subject variability of the appearance of first signs among animals derived from the same patient was limited to 1-2 weeks. Metabolic profiles at the late stage show group-to-group peculiarities especially in terms of Lac, myo-Ins, Gln, total Creatine and total Choline variations (Fig.1). No sign of necrosis was observed in MRI as a result of tumor progression (Fig.1). Longitudinal follow up of metabolic modifications showed a decreasing pattern for NAA, Glu and GABA whereas other metabolic markers showed distinct evolution (Fig.2). A general decrease in NAA, Glu and GABA possibly reflect neuronal loss or dysfunction. Two models (P1, P6) showed Gln decrease and relatively stable levels in Gly, whereas P4 group showed a progressive Gln and Gly accumulation. Lactate levels were generally increased while moderate variations were observed in myo-Ins. Total Cho increased reproducibly among the different groups and seemed to be driven by GPC increase. Cr and PCr contribute in different way to total Cr increase or decrease in the different groups and appeared uncorrelated. Direct comparison of the original human GBM specimen (P1) revealed that the mouse xenograft had retained overexpression of the EGFR, a characteristic feature (Fig.3). We conclude that mouse GBM models derived from freshly injected human cells are quite predictable in their appearance and evolution. Short-TE MRS at 14.1 Tesla allowed reliable detection of a wide range of glioma markers, such as distinct quantification of myo-Ins and Gly as well as Cr and PCr, which are often inaccessible in clinical scanners. Moreover the tight SD implied the high reproducibility within the same groups, representing a stable characteristic for a mouse model of GBM. Patient-specific variations among different groups point out heterogeneity in GBM evolution that needs to be further investigated and correlated with histopathological features, possibly contributing to the elucidation of the role of several GBM biomarkers.