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  • 1
    Language: English
    In: Acta Neuropathologica, 2013, Vol.126(3), pp.443-451
    Description: Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked ( ATRX ) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients ( n  = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p  = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis.
    Keywords: ATRX ; IDH ; 1p/19q ; Anaplastic glioma ; MGMT
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 2
    In: Stroke, 2017, Vol.48(10), pp.2776-2783
    Description: BACKGROUND AND PURPOSE—: White matter (WM) is less vulnerable to ischemia than gray matter. In ischemic stroke caused by acute large-vessel occlusion, successful recanalization might therefore sometimes selectively salvage the WM, leading to infarct patterns confined to gray matter. This study examines occurrence, determinants, and clinical significance of such effects. METHODS—: Three hundred twenty-two patients with acute middle cerebral artery occlusion subjected to mechanical thrombectomy were included. Infarct patterns were categorized into WM (sparing the WM) and WM (involving WM). National Institutes of Health Stroke Scale–based measures of neurological outcome, including National Institutes of Health Stroke Scale improvement or National Institutes of Health Stroke Scale worsening, good functional midterm outcome (day 90-modified Rankin Scale score of ≤2), the occurrence of malignant swelling, and in-hospital mortality were predefined outcome measures. RESULTS—: WM infarcts occurred in 118 of 322 patients and were associated with successful recanalization and better collateral grades (P〈0.05). Shorter symptom-onset to recanalization times were also associated with WM infarcts in univariate analysis, but not when adjusted for collateral grades. WM infarcts were independently associated with good neurological outcome (adjusted odds ratio, 3.003; 95% confidence interval, 1.186–7.607; P=0.020) and good functional midterm outcome (adjusted odds ratio, 8.618; 95% confidence interval, 2.409–30.828; P=0.001) after correcting for potential confounders, including final infarct volume. Only 2.6% of WM patients, but 20.5% of WM patients exhibited neurological worsening, and none versus 12.8% developed malignant swelling (P〈0.001), contributing to lower mortality in this group (2.5% versus 10.3%; P=0.014). CONCLUSIONS—: WM infarction commonly commences later than gray matter infarction after acute middle cerebral artery occlusion. Successful recanalization can therefore salvage completely the WM at risk in many patients even several hours after symptom onset. Preservation of the WM is associated with better neurological recovery, prevention of malignant swelling, and reduced mortality. This has important implications for neuroprotective strategies, and perfusion imaging-based patient selection, and provides a rationale for treating selected patients in extended time windows.
    Keywords: Medicine;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Sept 3, 2013, Vol.110(36), p.14735(6)
    Description: Disruption of the blood--brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase C[beta], which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase C[beta] in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS. EAE | enzastaurin | CNS www.pnas.org/cgi/doi/10.1073/pnas.1302569110
    Keywords: Protein Kinases -- Physiological Aspects ; Protein Kinases -- Health Aspects ; Blood-brain Barrier -- Physiological Aspects ; Blood-brain Barrier -- Health Aspects ; Encephalomyelitis -- Physiological Aspects
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(11), p.e110727
    Description: PURPOSE: To analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering. MATERIALS AND METHODS: Twelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160 × 210 mm(2), voxel size: 0.31 × 0.31 × 0.40 mm(3)) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ. RESULTS: Tumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3 ± 13.9 mm(2) vs. 29.0 ± 21.0 mm(2) (p〈0.035)) and number of branches (3.5 ± 1.8 vs. 1.0 ± 0.6 (p〈0.001) per cubic centimeter were significantly higher, while mean vessel branch length was significantly lower (3.8 ± 1.5 mm vs 7.2 ± 2.8 mm (p〈0.001)) in the tumor. DISCUSSION: ToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    In: Nature, 2014
    Description: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas (1-3) and other types of tumour (4-6). They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG) (7,8), genomic hypermethylation (9-11), genetic instability and malignant transformation (12). More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells (13,14). Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific [CD4.sup.+] T-helper-1 ([T.sub.H]1) responses. [CD4.sup.+] [T.sub.H]1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a [CD4.sup.+] T-cell-dependent manner. As IDH1(R132H) is presentin all tumour cells of these slow-growing gliomas (15), a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
    Keywords: Gene Mutation -- Identification And Classification ; Drug Targeting -- Research ; Gliomas -- Care And Treatment ; Gliomas -- Development And Progression ; Oxidoreductases -- Health Aspects ; Immune Response -- Research ; Cancer Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(3), p.e0121220
    Description: To explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells.For 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST-contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTRasym) at 3.3ppm, B1 = 0.7 μT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTRasym values within both regions of interest were correlated voxelwise yielding the correlation coefficient rSpearman (rSp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTRasym and ADC values of the biopsy site.Eight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16≤rSp≤0.53, p〈0.05). Seven correlations were statistically insignificant (p〉0.05, n = 4) or yielded rSp≈0 (p〈0.05, n = 3). No trend towards a correlation between MTRasym and ADC was found in CE-T1 tumor (-0.31〈rSp〈0.28, p〈0.05, n = 9; p〉0.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTRasym values in two of the three patients (rSppatient3 = 0.69 and rSppatient15 = 0.87, p〈0.05), while the correlation of ADC and cellularity was heterogeneous (rSppatient3 = 0.545 (p = 0.067), rSppatient4 = -0.021 (p = 0.948), rSppatient15 = -0.755 (p = 0.005)).NOE-imaging is a new contrast promising insight into pathophysiologic processes in glioblastoma regarding cell density and protein content, setting itself apart from DWI. Future studies might be based on the assumption that NOE-mediated CEST visualizes cellularity more accurately than ADC, especially in the CE-T1 tumor region.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Journal of Neuro-Oncology, 2014, Vol.117(1), pp.85-92
    Description: Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p  = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p  = 0.03). Survival times were similar for patients with grade III ( n  = 9) and grade IV ( n  = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs.
    Keywords: Bevacizumab ; Malignant glioma ; Nitrosourea ; Therapy on recurrence
    ISSN: 0167-594X
    E-ISSN: 1573-7373
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  • 8
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.464-464
    Description: CD95 (APO-1Fas) is a member of the Tumor Necrosis Factor Receptor Super Family. Binding of CD95-ligand (CD95L) to CD95 triggers intracellular signal transduction that is critically involved in the invasive growth of glioblastoma cells. Invasion of malignant glioblastoma cells into the brain parenchyma is responsible for poor therapeutic outcome of currently available treatments. The inhibition of CD95CD95L mediated invasive growth of glioblastoma cells represents an attractive novel therapeutic concept. Apogenix has developed APG101, a fully human fusion protein consisting of the extracellular domain of CD95 and the Fc-domain of an IgG. APG101 has been confirmed as a potent inhibitor of CD95L induced invasion of glioblastoma cells in vitro.
    Keywords: Parenchyma ; Glioblastoma ; Invasiveness ; Glioblastoma Cells ; Fasl Protein ; Brain ; Cpg Islands ; Biomarkers ; Tumor Necrosis Factor Receptors ; Promoters ; Immunoglobulin G ; DNA Methylation ; Cd95 Antigen ; Fusion Protein ; Signal Transduction ; Neurology & Neuropathology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.LB-80-LB-80
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 10
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(4), p.e0174620
    Description: The purpose of this study was to investigate whether a voxel-wise analysis of apparent diffusion coefficient (ADC) values may differentiate between progressive disease (PD) and pseudoprogression (PsP) in patients with high-grade glioma using the parametric response map, a newly introduced postprocessing tool.Twenty-eight patients with proven PD and seven patients with PsP were identified in this retrospective feasibility study. For all patients ADC baseline and follow-up maps on four subsequent MRIs were available. ADC maps were coregistered on contrast enhanced T1-weighted follow-up images. Subsequently, enhancement in the follow-up contrast enhanced T1-weighted image was manually delineated and a reference region of interest (ROI) was drawn in the contralateral white matter. Both ROIs were transferred to the ADC images. Relative ADC (rADC) (baseline)/reference ROI values and rADC (follow up)/reference ROI values were calculated for each voxel within the ROI. The corresponding voxels of rADC (follow up) and rADC (baseline) were subtracted and the percentage of all voxels within the ROI that exceeded the threshold of 0.25 was quantified.rADC voxels showed a decrease of 59.2% (1st quartile (Q1) 36.7; 3rd quartile (Q3) 78.6) above 0.25 in patients with PD and 18.6% (Q1 3.04; Q3 26.5) in patients with PsP (p = 0.005). Receiver operating characteristic curve analysis showed the optimal decreasing rADC cut-off value for identifying PD of 〉 27.05% (area under the curve 0.844±0.065, sensitivity 0.86, specificity 0.86, p = 0.014).This feasibility study shows that the assessment of rADC using parametric response maps might be a promising approach to contribute to the differentiation between PD and PsP. Further research in larger patient cohorts is necessary to finally determine its clinical utility.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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