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Purpose: The aim of this study was the development and external validation of a logistic regression model to differentiate gliosarcoma (GSC) and glioblastoma multiforme (GBM) on standard MR imaging., Methods: A univariate and multivariate analysis was carried out of a logistic regression model to discriminate patients histologically diagnosed with primary GSC and an age and sex-matched group of patients with primary GBM on presurgical MRI with external validation., Results: In total, 56 patients with GSC and 56 patients with GBM were included. Evidence of haemorrhage suggested the diagnosis of GSC, whereas cystic components and pial as well as ependymal invasion were more commonly observed in GBM patients. The logistic regression model yielded a mean area under the curve (AUC) of 0.919 on the training dataset and of 0.746 on the validation dataset. The accuracy in the validation dataset was 0.67 with a sensitivity of 0.85 and a specificity of 0.5., Conclusions: Although some imaging criteria suggest the diagnosis of GSC or GBM, differentiation between these two tumour entities on standard MRI alone is not feasible.

Background: Glioblastoma of the corpus callosum (ccGBM) are rare tumors, with a dismal prognosis marked by a rapid clinical deterioration. For a long time, surgical treatment was not considered beneficial for most patients with such tumors. Recent studies claimed an improved survival for patients undergoing extensive resection, albeit without integration of the molecular profile of the lesions. The purpose of this study was to investigate the effect of biopsy and surgical resection on oncological and functional outcomes in patients with IDH wild-type ccGBM., Methods: We performed a retrospective analysis of our institution's database of patients having been treated for high-grade glioma between 2005 and 2017. Inclusion criteria were defined as follows: patients older than 18 years, histopathological, and molecularly defined IDH wild-type glioma, major tumor mass (at least 2/3) invading the corpus callosum in the sagittal plane with a uni- or bilateral infiltration of the adjacent lobules. Surgical therapy (resection vs. biopsy), extent of resection according to the remaining tumor volume and adjuvant treatment as well as overall survival and functional outcome using the Karnofsky Performance Score (KPS) were analyzed., Results: Fifty-five patients were included in the study, from which the mean age was 64 years and men (n = 34, 61.8%) were more often affected than women (n = 21, 38.2%). Thirty (54.5%) patients were treated with stereotactic biopsy alone, while 25 patients received tumor resection resulting in 14.5% (n = 8) gross-total resections and 30.9% (n = 17) partial resections. The 2-year survival rate after resection was 30% compared to 7% after biopsy (p = 0.047). The major benefit was achieved in the group with gross-total resection, while partial resection failed to improve survival. Neurological outcome measured by KPS did not differ between both groups either pre- or postoperatively., Conclusions: Our study suggests that in patients with corpus callosum glioblastoma, gross-total resection prolongs survival without negatively impacting neurological outcome as compared to biopsy.

Background: The revised 2016 WHO-Classification of CNS-tumours now integrates molecular information of glial brain tumours for accurate diagnosis as well as for the development of targeted therapies. In this prospective study, our aim is to investigate the predictive value of MR-spectroscopy in order to establish a solid preoperative molecular stratification algorithm of these tumours. We will process a 1H MR-spectroscopy sequence within a radiomics analytics pipeline., Methods: Patients treated at our institution with WHO-Grade II, III and IV gliomas will receive preoperative anatomical (T2- and T1-weighted imaging with and without contrast enhancement) and proton MR spectroscopy (MRS) by using chemical shift imaging (MRS) (5 × 5 × 15 mm 3 voxel size). Tumour regions will be segmented and co-registered to corresponding spectroscopic voxels. Raw signals will be processed by a deep-learning approach for identifying patterns in metabolic data that provides information with respect to the histological diagnosis as well patient characteristics obtained and genomic data such as target sequencing and transcriptional data., Discussion: By imaging the metabolic profile of a glioma using a customized chemical shift 1H MR spectroscopy sequence and by processing the metabolic profiles with a machine learning tool we intend to non-invasively uncover the genetic signature of gliomas. This work-up will support surgical and oncological decisions to improve personalized tumour treatment., Trial Registration: This study was initially registered under another name and was later retrospectively registered under the current name at the German Clinical Trials Register (DRKS) under DRKS00019855.

Background: Oligodendroglioma (ODG) are CNS resistant tumors characterized by their unique molecular signature, namely a combined deletion of 1p and 19q simultaneously to an IDH1/2 mutation. These tumors have a more favorable clinical outcome compared to other gliomas and a long-time survival that ranges between 10 and 20 years. However, during the course of the disease, multiple recurrences occur and the optimal treatment at each stage of the disease remains unclear. Here we report a retrospective longitudinal observation study of 836 MRI examinations in 44 ODG patients., Methods: We quantified the volume of T2-hyperintensity to compute growth behavior in dependence of different treatment modalities, using various computational models., Results: The identified growth pattern revealed dynamic changes, which were found to be patient-specific an did not correlate with clinical parameter or therapeutic interventions. Further, we showed that, surgical resection is beneficial for overall survival regardless the WHO grad or timepoint of surgery. To improve overall survival, an extent of resection above 50% is required. Multiple resections do not generally improve overall survival, except a greater extent of resection than in previous surgeries was achieved., Conclusions: Our data aids to improve the interpretation of MRI images in clinical practice.

Long-term epilepsy-associated tumors (LEATs) represent mostly benign brain tumors associated with drug-resistant epilepsy. The aim of the study was to investigate the specific transcriptional signatures of those tumors and characterize their underlying oncogenic drivers. A cluster analysis of 65 transcriptome profiles from three independent datasets resulted in four distinct transcriptional subgroups. The first subgroup revealed transcriptional activation of STAT3 and TGF-signaling pathways and contained predominantly dysembryoplastic neuroepithelial tumors (DNTs). The second subgroup was characterized by alterations in the MAPK-pathway and up-stream cascades including FGFR and EGFR-mediated signaling. This tumor cluster exclusively contained neoplasms with somatic BRAF V600E mutations and abundance of gangliogliomas (GGs) with a significantly higher recurrence rate (42%). This finding was validated by examining recurrent tumors from the local database exhibiting BRAF V600E in 90% of the cases. The third cluster included younger patients with neuropathologically diagnosed GGs and abundance of the NOTCH- and mTOR-signaling pathways. The transcript signature of the fourth cluster (including both DNTs and GGs) was related to impaired neural function. Our analysis suggests distinct oncological pathomechanisms in long-term epilepsy-associated tumors. Transcriptional activation of MAPK-pathway and BRAF V600E mutation are associated with an increased risk for tumor recurrence and malignant progression, therefore the treatment of these tumors should integrate both epileptological and oncological aspects.

Introduction: Elderly patients constitute an expanding part of our society. Due to a continuously increasing life expectancy, an optimal quality of life is expected even into advanced age. Glioblastoma (GBM) is more common in older patients, but they are still often withheld from efficient treatment due to worry of worse tolerance and have a significantly worse prognosis compared to younger patients. Our retrospective observational study aimed to investigate the therapeutic benefit from a second resection in recurrent glioblastoma of elderly patients., Materials and Methods: We included a cohort of 39 elderly patients (> 65 years) with a second resection as treatment option in the case of a tumor recurrence. A causal inference model was built by multiple non- and semiparametric models, which was used to identify matched patients from our elderly GBM database which comprises 538 patients. The matched cohorts were analyzed by a Cox-regression model adjusted by time-dependent covariates., Results: The Cox-regression analysis showed a significant survival benefit (Hazard Ratio: 0.6, 95% CI 0.36-0.9, p-value = 0.0427) for the re-resected group (18.0 months, 95% CI 13.97-23.2 months) compared to the group without re-resection (10.1 months, 95% CI 8.09-20.9 months). No differences in the co-morbidities or hemato-oncological side effects during chemotherapy could be detected. Anesthetic- and surgical complications were rare and comparable to the complication rate of patients undergoing the first-line resection., Conclusion: Taken together, in elderly patients, re-resection is an acceptable treatment option in the recurrent state of a glioblastoma. The individual evaluation of the patients' medical status as well as the chances of withstanding general anesthesia needs to be done in close interdisciplinary consultation. If these requirements are met, elderly patients benefit from a re-resection.

When it comes to the human brain, models that closely mimic in vivo conditions are lacking. Living neuronal tissue is the closest representation of the in vivo human brain outside of a living person. Here, we present a method that can be used to maintain therapeutically resected healthy neuronal tissue for prolonged periods without any discernible changes in tissue vitality, evidenced by immunohistochemistry, genetic expression, and electrophysiology. This method was then used to assess glioblastoma (GBM) progression in its natural environment by microinjection of patient-derived tumor cells into cultured sections. The result closely resembles the pattern of de novo tumor growth and invasion, drug therapy response, and cytokine environment. Reactive transformation of astrocytes, as an example of the cellular nonmalignant tumor environment, can be accurately simulated with transcriptional differences similar to those of astrocytes isolated from acute GBM specimens. In a nutshell, we present a simple method to study GBM in its physiological environment, from which valuable insights can be gained. This technique can lead to further advancements in neuroscience, neuro-oncology, and pharmacotherapy., (© 2019 Ravi et al.)

Background: In recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). Based on the results of our earlier work, which showed a reduction of PD-L1 expression in patients treated with temozolomide (TMZ), we aimed to investigate the link between TMZ therapy and the immune control point target PD-L1., Methods: RNA-sequencing data from de-novo and recurrent glioblastoma were analyzed by AutoPipe algorithm. Results were confirmed either in a cell model by two primary and one established GBM cell line and specimens of de-novo and recurrent GBM. PD-L1 and pathway activation of the JAK/STAT pathway was analyzed by quantitative real-time PCR and western blot., Results: We found a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFNγ treatment, while additional TMZ treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma., Conclusions: Our results suggest that TMZ therapy leads to a down-regulation of PD-L1 in primary GBM cells. These results support the clinical findings where PD-L1 is significantly reduced in recurrent GBMs. If the target is diminished, it may also lead to impaired efficacy of PD-1/PD-L1 inhibitors such as nivolumab.

Background and Purpose: GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI)., Material and Methods: We prospectively evaluated 41 patients, who received a fractionated stereotactic re-irradiation for rGBM. GTV-PET was generated automatically (tumor-to-background ratio 1.7-1.8) and manually customized. GTV-ADClow was manually defined based on DWI data (3D diffusion gradients, b = 0, 1000 s/mm 2 ) and parametric ADC maps. The localization of recurrence was correlated with initial GdT1w-MRI and PET data., Results: In 30/41 patients, DWI-MRI showed areas with restricted diffusion (mean ADC-value 0.74 ± 0.22 mm 2 /s). 66% of GTVs-ADClow were located outside the GdT1w-MRI volume and 76% outside increased FET uptake regions. Furthermore, GTVs-ADClow were only partially included in the high dose volume and received in mean 82% of the reference dose. An adjusted volume including GdT1w-MRI, PET-positive and restricted diffusion areas would imply a GTV increase of 48%. GTV-PET and GdT1w-MRI correlated better with the localization of re-recurrence in comparison to GTV-ADClow., Conclusion: Unexpectedly, GTV-ADClow overlapped only partially with FET-PET and GdT1w-MRI in rGBM. Moreover, GTV-ADClow correlated poorly with later rGBM-recurrences. Seeing as a restricted diffusion is known to correlate with hypercellularity, this imaging discrepancy could only be further explained in histopathological studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: According to the 2016 WHO classification lower-grade gliomas consist of three groups: IDH-mutated and 1p/19q co-deleted, IDH-mutated and IDH-wildtype tumors. The aim of this study was to evaluate the impact of surgical therapy for lower-grade gliomas with a particular focus on the molecular subgroups., Methods: This is a bi-centric retrospective analysis including 299 patients, who underwent treatment for lower-grade glioma between 1990 and 2016. All tumors were re-classified according to the 2016 WHO classification. Data concerning baseline and tumor characteristics, overall survival, different treatment modalities and functional outcome were analyzed., Results: A total of 112 (37.5%) patients with IDH-mutation and 1p/19q co-deletetion, 86 (28.8%) patients with IDH-mutation and 101 (33.8%) patients with IDH-wildtype tumors were identified. The median overall survival (mOS) differed significantly between the groups (p < 0.001). Surgical resection was performed in 226 patients and showed significantly improved mOS compared to the biopsy group (p = 0.001). Gross total resection (GTR) was associated with better survival (p = 0.007) in the whole cohort as well as in the IDH-mutated and IDH-wildtype groups compared to partial resection or biopsy. IDH-wildtype patients presented a significant survival benefit after combined radio-chemotherapy compared to radio- or chemotherapy alone (p = 0.02). Good clinical status (NANO) was associated with longer OS (p = 0.001)., Conclusion: The impact of surgical treatment on the outcome of lower-grade gliomas depends to a great extent on the molecular subtype of the tumors. Patients with more aggressive tumors (IDH-wildtype) seem to profit from more intensive treatment like GTR, multiple resections and combined radio-/chemotherapy.

Background: The purpose of this study is to map spatial metabolite differences across three molecular subgroups of glial tumors, defined by the IDH1/2 mutation and 1p19q-co-deletion, using magnetic resonance spectroscopy. This work reports a new MR spectroscopy based classification algorithm by applying a radiomics analytics pipeline., Materials: 65 patients received anatomical and chemical shift imaging (5 × 5 × 20 mm voxel size). Tumor regions were segmented and registered to corresponding spectroscopic voxels. Spectroscopic features were computed (n = 860) in a radiomic approach and selected by a classification algorithm. Finally, a random forest machine-learning model was trained to predict the molecular subtypes., Results: A cluster analysis identified three robust spectroscopic clusters based on the mean silhouette widths. Molecular subgroups were significantly associated with the computed spectroscopic clusters (Fisher's Exact test p < 0.01). A machine-learning model was trained and validated by public available MRS data (n = 19). The analysis showed an accuracy rate in the Random Forest model by 93.8%., Conclusions: MR spectroscopy is a robust tool for predicting the molecular subtype in gliomas and adds important diagnostic information to the preoperative diagnostic work-up of glial tumor patients. MR-spectroscopy could improve radiological diagnostics in the future and potentially influence clinical and surgical decisions to improve individual tumor treatment.

The evolving and highly heterogeneous nature of malignant brain tumors underlies their limited response to therapy and poor prognosis. In addition to genetic alterations, highly dynamic processes, such as transcriptional and metabolic reprogramming, play an important role in the development of tumor heterogeneity. The current study reports an adaptive mechanism in which the metabolic environment of malignant glioma drives transcriptional reprogramming. Multiregional analysis of a glioblastoma patient biopsy revealed a metabolic landscape marked by varying stages of hypoxia and creatine enrichment. Creatine treatment and metabolism was further shown to promote a synergistic effect through upregulation of the glycine cleavage system and chemical regulation of prolyl-hydroxylase domain. Consequently, creatine maintained a reduction of reactive oxygen species and change of the α-ketoglutarate/succinate ratio, leading to an inhibition of HIF signaling in primary tumor cell lines. These effects shifted the transcriptional pattern toward a proneural subtype and reduced the rate of cell migration and invasion in vitro Implications: Transcriptional subclasses of glioblastoma multiforme are heterogeneously distributed within the same tumor. This study uncovered a regulatory function of the tumor microenvironment by metabolism-driven transcriptional reprogramming in infiltrating glioma cells. Mol Cancer Res; 16(4); 655-68. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The purpose of this study was to map the landscape of metabolic-transcriptional alterations in glioblastoma multiforme. Omic-datasets were acquired by metabolic profiling (1D-NMR spectroscopy n=33 Patient) and transcriptomic profiling (n=48 Patients). Both datasets were analyzed by integrative network modeling. The computed model concluded in four different metabolic-transcriptomic signatures containing: oligodendrocytic differentiation, cell-cycle functions, immune response and hypoxia. These clusters were found being distinguished by individual metabolism and distinct transcriptional programs. The study highlighted the association between metabolism and hallmarks of oncogenic signaling such as cell-cycle alterations, immune escape mechanism and other cancer pathway alterations. In conclusion, this study showed the strong influence of metabolic alterations in the wide scope of oncogenic transcriptional alterations.

Purpose: Achieving higher spatial resolution and improved brain coverage while mitigating in-plane susceptibility artifacts in the assessment of perfusion parameters, such as cerebral blood volume, in echo planar imaging (EPI)-based dynamic susceptibility contrast weighted cerebral perfusion measurements., Methods: PEAK-EPI, an EPI sequence with interleaved readout trajectories and three different strategies for autocalibration-signal acquisition (inplace, dynamic extra and extra) is presented. Performance of each approach is analyzed in vivo based on flip angle variation induced dynamics, assessing temporal fidelity, temporal SNR and g-factors. All approaches are compared with conventional GRAPPA reconstructions. PEAK-EPI with inplace autocalibration-signal at R = 5 is then compared with the standard clinical EPI protocol in six patients, using two half-dose dynamic susceptibility contrast weighted cerebral perfusion measurements per subject., Results: PEAK-EPI acquisition facilitates a substantial increase of spatial resolution at a higher number of slices per TR and provides improved SNR compared to conventional GRAPPA. High dependency of the resulting reconstruction quality on the type of autocalibration-signal acquisition is observed. PEAK-EPI with inplace autocalibration-signal achieves high temporal fidelity and initial feasibility is shown., Conclusion: The obtained high resolution cerebral blood volume maps reveal more detailed information than in corresponding standard EPI measurements and facilitate detailed delineation of tumorous tissue. Magn Reson Med 77:2153-2166, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

In the past, changes of the Apparent Diffusion Coefficient in glioblastoma multiforme have been shown to be related to specific genes and described as being associated with survival. The purpose of this study was to investigate diffusion imaging parameters in combination with genome-wide expression data in order to obtain a comprehensive characterisation of the transcriptomic changes indicated by diffusion imaging parameters. Diffusion-weighted imaging, molecular and clinical data were collected prospectively in 21 patients. Before surgery, MRI diffusion metrics such as axial (AD), radial (RD), mean diffusivity (MD) and fractional anisotropy (FA) were assessed from the contrast enhancing tumour regions. Intraoperatively, tissue was sampled from the same areas using neuronavigation. Transcriptional data of the tissue samples was analysed by Weighted Gene Co-Expression Network Analysis (WGCNA) thus classifying genes into modules based on their network-based affiliations. Subsequent Gene Set Enrichment Analysis (GSEA) identified biological functions or pathways of the expression modules. Network analysis showed a strong association between FA and epithelial-to-mesenchymal-transition (EMT) pathway activation. Also, patients with high FA had a worse clinical outcome. MD correlated with neural function related genes and patients with high MD values had longer overall survival. In conclusion, FA and MD are associated with distinct molecular patterns and opposed clinical outcomes.

The purpose of this study was to investigate the molecular background of cerebral blood volume (CBV) and vessel size (VS) of capillaries in glioblastoma multiforme (GBM). Both parameters are derived from extended perfusion MR imaging.A prospective case study including 21 patients (median age 66 years, 10 females) was performed. Before operation, CBV and VS of contrast enhancing tumor were assessed. Tissue was sampled from the assessed areas under neuronavigation control. After RNA extraction, transcriptional data was analyzed by Weighted Gene Co-Expression Network Analysis (WGCNA) and split into modules based on its network affiliations. Gene Set Enrichment Analysis (GSEA) identified biological functions or pathways of the genetic modules. These were applied on 484 GBM samples of the TCGA database.Ten modules were highly correlated to CBV and VS. One module was exclusively associated to VS and highly correlated to hypoxia, another one exclusively to CBV showing strong enrichments in the Epithelial Growth Factor (EGF) pathway and Epithelial-to-Mesenchymal-Transition (EMT). Moreover, patients with increased CBV and VS predominantly showed a mesenchymal gene-expression, a finding that could be corroborated by TCGA data.In conclusion, CBV and VS mirror different genetic pathways and reflect certain molecular subclasses of GBM.

The purpose of this study was to identify markers from perfusion, diffusion, and chemical shift imaging in glioblastomas (GBMs) and to correlate them with genetically determined and previously published patterns of structural magnetic resonance (MR) imaging. Twenty-six patients (mean age 60 years, 13 female) with GBM were investigated. Imaging consisted of native and contrast-enhanced 3D data, perfusion, diffusion, and spectroscopic imaging. In the presence of minor necrosis, cerebral blood volume (CBV) was higher (median ± SD, 2.23% ± 0.93) than in pronounced necrosis (1.02% ± 0.71), p corr  = 0.0003. CBV adjacent to peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity was lower in edema (1.72% ± 0.31) than in infiltration (1.91% ± 0.35), p corr  = 0.039. Axial diffusivity adjacent to peritumoral FLAIR hyperintensity was lower in severe mass effect (1.08*10 -3 mm 2 /s ± 0.08) than in mild mass effect (1.14*10 -3 mm 2 /s ± 0.06), p corr  = 0.048. Myo-inositol was positively correlated with a marker for mitosis (Ki-67) in contrast-enhancing tumor, r = 0.5, p corr  = 0.0002. Changed CBV and axial diffusivity, even outside FLAIR hyperintensity, in adjacent normal-appearing matter can be discussed as to be related to angiogenesis pathways and to activated proliferation genes. The correlation between myo-inositol and Ki-67 might be attributed to its binding to cell surface receptors regulating tumorous proliferation of astrocytic cells.

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone., Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRI- or PET-derived target volumes, rate of long term survivors (>1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation., Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning., Trial Registration: The GLIAA trial is registered with ClinicalTrials.gov ( NCT01252459 , registration date 02.12.2010), German Clinical Trials Registry ( DRKS00000634 , registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012).

Objectives: To differentiate between abnormal tumor vessels and regular brain vasculature using new quantitative measures in time-of-flight (TOF) MR angiography (MRA) data., Materials and Methods: In this work time-of-flight (TOF) MR angiography data are acquired in 11 glioma patients to quantify vessel abnormality. Brain vessels are first segmented with a new algorithm, efficient monte-carlo image-analysis for the location of vascular entity (EMILOVE), and are then characterized in three brain regions: tumor, normal-appearing contralateral brain, and the total brain volume without the tumor. For characterization local vessel orientation angles and the dot product between local orientation vectors are calculated and averaged in the 3 regions. Additionally, correlation with histological and genetic markers is performed., Results: Both the local vessel orientation angles and the dot product show a statistically significant difference (p < 0.005) between tumor vessels and normal brain vasculature. Furthermore, the connection to both histology and the gene expression of the tumor can be found-here, the measures were compared to the proliferation marker Ki-67 [MIB] and genome-wide expression analysis. The results in a subgroup indicate that the dot product measure may be correlated with activated genetic pathways., Conclusion: It is possible to define a measure of vessel abnormality based on local vessel orientation angles which can differentiate between normal brain vasculature and glioblastoma vessels.

The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS).

Purpose: To compare the vessel size and the cerebral blood volume in human gliomas with histopathology. Vessel size imaging (VSI) is a dynamic susceptibility contrast method for the assessment of the vessel size in normal and pathological tissue. Previous publications in rodents showed a satisfactory conformity with the vessel size derived from histopathology. To assess the clinical value, further, the progression-free interval was determined and correlated., Materials and Methods: Twenty-five gliomas (WHO grade °II [n = 10], °III [n = 3], °IV [n = 12]) were prospectively included and received a stereotaxic biopsy after VSI. The vessel size and the cerebral blood volume (CBV) were calculated in regions of interest at the tumor edge and correlated with the vessel size measured by histopathology., Results: Both VSI and CBV showed a good correlation with the vessel size in histopathology (up to r = 0.84, P < 0.001, and r = 0.62, P < 0.001, respectively). Slope and offset of the linear regression (y = 0.77x + 0.36 μm) suggest that the size of normal capillaries is overestimated with VSI, while for grossly enlarged vessels an underestimation occurs. Both VSI and CBV were negatively correlated with the progression-free interval (r = -0.57, P = 0.008, and r = -0.50, P = 0.025, respectively)., Conclusion: The correlation between VSI and vessel size from histopathology is in good accordance with the animal studies. The overestimation of small capillary sizes is also known from the animal trials. Vessel size and CBV showed similar results, both for the correlation with the histopathological vessel size and the progression-free interval., (© 2014 Wiley Periodicals, Inc.)

Background: In contrast to the abundance of seizure outcome reports in epilepsy surgery for glioneuronal tumors in childhood and adolescence, there is a dearth of information regarding cognitive outcomes., Objective: To investigate the seizure and cognitive outcome of children and adolescents that underwent resective surgery for glioneuronal tumor-associated refractory epilepsy and determine their predictive factors., Methods: We retrospectively analyzed the presurgical findings, resection types, and outcomes over 1.3 to 12.3 years (mean, 7.3) of 29 consecutive patients, who underwent resection in 2000 to 2011. The mean age at epilepsy onset was 7.9 years (range, 0-15.4), the mean age at surgery was 11.7 years (range, 2.6-17.3), and the mean epilepsy duration to surgery was 3.8 years (range, 0.3-15.3). Etiology comprised 13 dysembryoplastic neuroepithelial tumors and 16 gangliogliomas, with additional focal cortical dysplasia in 5 cases., Results: Eighty-six percent of children were seizure free 12 months after surgery; at final follow-up, 76% remained seizure free and 62% had discontinued antiepileptic drugs. Gross total resection was related to significantly higher rates of seizure freedom. Higher presurgical cognitive functioning (full-scale IQ, verbal IQ) was related to shorter epilepsy duration to surgery independent of age at epilepsy onset, thus determining postsurgical functioning. Improvements in verbal IQ, performance IQ, and visual memory as well as a trend toward improvement in full-scale IQ were established after surgery. Despite individual losses in full-scale IQ, verbal or visual memory, no deterioration was noted in any cognitive variable on a group level., Conclusion: Completeness of resection predisposes to favorable outcomes regarding seizure alleviation. Whereas cognitive functioning deteriorates with time in glioneuronal tumor-related refractory epilepsy, surgery is linked to improvement rather than to deterioration on a group level.

Purpose: Global tracking (GT) is a recently published fibre tractography (FT) method that takes simultaneously all fibres into account during their reconstruction. The purpose of this study was to compare this new method with fibre assignment by continuous tracking (FACT) and probabilistic tractography (PT) for the detection of the corticospinal tract (CST) in patients with gliomas., Methods: Tractography of the CST was performed in 17 patients with eight low grade and nine anaplastic astrocytomas located in the motor cortex or the corticospinal tract. Diffusions metrics as fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD) were obtained. The methods were additionally applied on a physical phantom to assess their accuracy., Results: PT was successful in all (100 %), GT in 16 (94 %) and FACT in 15 patients (88 %). The case where GT and FACT, both, missed the CST showed the highest AD and RD, whereas the one where FACT algorithm, alone, was not successfully showed the lowest AD and RD of the group. FA was reduced on the pathologic side (FApath 0.35 ± 0.16 (mean ± SD) versus FAcontralateral 0.51 ± 0.15, pcorr < 0.03). RD was increased on the pathologic side (RDpath 0.67 ± 0.29 × 10(-3) mm(2)/s versus RDcontralateral 0.46 ± 0.08 × 10(-3) mm(2)/s, pcorr < 0.03). In the phantom measurement, only GT did not detect false positive fibres at fibre crossings., Conclusion: PT performed well even in areas of increased diffusivities indicating a severe oedema or disintegration of tissue. FACT was also susceptible to a decrease of diffusivities and to a susceptibility artefact, where GT was robust.

Short echo time (TE) proton MR spectra of the brain include signals of several metabolites as well as macromolecules. In various pathologies, such as brain tumors and multiple sclerosis (MS), the presence of mobile lipids or pathologically altered macromolecules may provide useful additional diagnostic information. A reliable quantitation of these resonances, however, is often not possible due to the lack of adequate prior knowledge. Furthermore, even if advanced fitting procedures are used, a reliable evaluation of metabolites in the presence of pathological lipids or macromolecules often fails if the latter are omitted in the spectral evaluation. In this study, a method is presented for the simultaneous evaluation of all visible components, including metabolites, lipids, and macromolecules, by the use of the fitting procedure LCModel. A standard basis set of brain metabolites was extended by inclusion of parameterized components for macromolecules and lipids that were derived from metabolite-nulled in vivo spectra of normal brain and high-grade gliomas, respectively. The improved spectral quantitation is demonstrated in glial brain tumors and MS lesions as well as in normal brain. It is pointed out that both macromolecules and lipids must be included to provide a proper spectral evaluation., (Copyright 2003 Wiley-Liss, Inc.)

This study presents a simple approach for the noninvasive assignment of glial brain tumors according to malignancy by single-voxel proton magnetic resonance spectroscopy at short echo times (TE < or = 50 milliseconds). Based on peak area ratios, a five-dimensional data set was obtained for each investigated subject. This vector was then projected along metabolic coordinates in a two-dimensional metabolic space. These coordinates had been determined in a previous study (Hagberg G et al., 1995, Magn Reson Med 34: 242-252). Tumor assignment was done without any knowledge of histology by comparing the location of the new cases to the features of the previous study. All 11 investigated glioblastomas multiforme, as well as 4 of 5 astrocytomas grade II, could easily be assigned to the groups of high- and low-grade tumors, respectively. Classification was more difficult in the case of a cystic astrocytoma grade II and one astrocytoma grade III. Two spectra measured in normal-appearing matter of glioblastoma patients were not classified as healthy. Using single-voxel proton magnetic resonance spectroscopy at short echo times with the knowledge of a base study, a straightforward, fast, and noninvasive differential diagnosis of glial brain tumors is possible.

Seventeen patients with presumed glial brain tumors were examined with proton chemical shift imaging and single voxel spectroscopy that used different echo times. Metabolite resonances were evaluated by metabolic ratios and absolutely by correcting for coil load and comparison to phantom measurements. Metabolic images were created to visualize the metabolic changes. All patients showed spectra that were different from those measured in healthy control subjects. Spectral changes were also present in normal-appearing matter (NAM) that was distant from lesions. The resonance at 3.55 ppm which is usually assigned to both myo-inositol and glycine, was the only one to allow a discrimination between healthy volunteers, astrocytoma grade II, and glioblastoma multiforme (GBM) (p < 0.02). From the different echo times used we conclude that an increase in this resonance has to be assigned to glycine rather than myo-inositol. This resonance might be used to grade human gliomas more reliably. Total creatine (Cr) decreased more drastically with malignancy than N-acetylated metabolites (NA). This led to a higher NA/Cr ratio in GBM compared to astrocytoma grade II. NA/Cr was thus pseudonormal in GBM due to a change in both nominator and denominator. This study reveals the importance of comparing magnetic resonance spectroscopy data of lesions to spectra measured in identical localizations in healthy control subjects instead of NAM and the importance of quantifying single metabolic peaks instead of creating metabolic ratios in clinical magnetic resonance spectroscopy.

Several multi-dimensional statistical evaluation methods were applied to single-voxel proton MR spectra of glial brain tumors and of healthy volunteers. Metabolic coordinates with histological relevance for future diagnosis were found by which spectra from controls, low-grade tumors, and high-grade tumors were completely separated. Significant differences between low-grade and high-grade glioma patients and controls were found for several metabolic ratios by variance analysis. Cluster analysis both with and without principal component analysis was applied. The outcome of these two approaches depended mainly on the lipid-to-creatine ratio. Two other approaches, discriminant factor analysis and the orthonormal discriminant vector method were then used to find discriminatory metabolic coordinates. It turned out that a linear combination of all evaluable metabolic ratios made it possible to separate the three groups completely. On the basis of these results, a classification method that uses the entire proton MRS spectrum is proposed.