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  • Wiley Online Library  (14)
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  • 1
    In: Journal of Magnetic Resonance Imaging, March 2019, Vol.49(3), pp.777-785
    Description: Byline: Constantin Dreher, Johanna Oberhollenzer, Jan-Eric Meissner, Johannes Windschuh, Patrick Schuenke, Sebastian Regnery, Felix Sahm, Sebastian Bickelhaupt, Martin Bendszus, Wolfgang Wick, Andreas Unterberg,Moritz Zaiss, Peter Bachert, Mark E. Ladd, Heinz-Peter Schlemmer, Alexander Radbruch,Daniel Paech Keywords: magnetic resonance imaging; neuroimaging; biomarkers; glioma; glioblastoma; CEST Background Chemical exchange saturation transfer (CEST) is a novel MRI technique applied to brain tumor patients. Purpose To investigate the anatomic location dependence of CEST MRI obtained at 7T and histopathological/molecular parameters in WHO IV[degrees] glioma patients. Study Type Analytic prospective study. Population Twenty-one patients with newly diagnosed WHO IV[degrees] gliomas were studied prior to surgery; 11 healthy volunteers were investigated. Field Strength/Sequence Conventional MRI (contrast-enhanced, T.sub.2w and diffusion-weighted imaging) at 3T and T.sub.2w and CEST MRI at 7T was performed for patients and both patients and volunteers. Assessment Mean CEST signal intensities (nuclear-Overhauser-enhancement [NOE], amide-proton-transfer [APT], downfield NOE-suppressed APT [dns-APT]), ADC values, and histopathological/molecular parameters were evaluated with regard to hemisphere location and contact with the subventricular zone. CEST signal intensities of cerebral tissue of healthy volunteers were evaluated with regard to hemisphere discrimination. Statistical Tests Spearman correlation, Mann-Whitney U-test, Wilcoxon signed-rank-test, Fisher's exact test, and area under the receiver operating curve. Results Maximum APT and dns-APT signal intensities were significantly different in right vs. left hemisphere gliomas (P=0.037 and P=0.007), but not in right vs. left hemisphere cerebral tissue of healthy subjects (P=0.062-0.859). Mean ADC values were significantly decreased in right vs. left hemisphere gliomas (P=0.044). Mean NOE signal intensity did not differ significantly between gliomas of either hemisphere (P=0.820), but in case of subventricular zone contact (P=0.047). A significant correlation was observed between APT and dns-APT and ADC signal intensities (r.sub.s=-0.627, P=0.004 and r.sub.s=-0.534, P=0.019), but not between NOE and ADC (r.sub.s=-0.341, P=0.154). Histopathological/molecular parameters were not significantly different concerning the tumor location (P=0.104-1.000, P=0.286-0.696). Data Conclusion APT, dns-APT, and ADC were inversely correlated and depended on the gliomas' hemisphere location. NOE showed significant dependence on subventricular zone contact. Location dependency of APT- and NOE-mediated CEST effects should be considered in clinical investigations of CEST MRI. Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:777-785.
    Keywords: Magnetic Resonance Imaging ; Neuroimaging ; Biomarkers ; Glioma ; Glioblastoma ; Cest
    ISSN: 1053-1807
    E-ISSN: 1522-2586
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  • 2
    In: Journal of Neurochemistry, March 2016, Vol.136(6), pp.1142-1154
    Description: We proposed that in malignant gliomas prostaglandin E (PGE) produced by cyclooxygenases (COX) up‐regulates tryptophan‐2,3‐dioxygenase (TDO) expression and enzyme activity through binding to its Gs‐coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.
    Keywords: Tryptophan‐2 ; 3‐Dioxygenase ; Glioma ; Immunosuppression ; Prostaglandin
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 3
    In: Genes, Chromosomes and Cancer, May 2016, Vol.55(5), pp.418-427
    Description: Intraocular medulloepithelioma (IO‐MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. Little is known about the cytogenetics, molecular biology, and pathogenesis of this tumor. In the present study we investigated the mutational landscape of 19 IO‐MEPL using targeted next‐generation sequencing. Routinely prepared paraffin‐embedded samples were assessed with high‐coverage genome sequencing on the Illumina NextSeq 500 platform using a customized gene panel set covering the coding region of 130 genes. This revealed several notable genomic alterations, including mutations of (6 tumors) and (also known as ; 5 tumors)—which are frequently recurrent and mutually exclusive molecular events for IO‐MEPL. Non‐recurrent mutations in the cancer‐associated genes , and were also identified. IO‐MEPL samples harboring a mutation disclosed few chromosomal alterations and formed a separate DNA methylation cluster, indicating potential differences in genetic and epigenetic events arising perhaps from the presence of this aberration in the tumor genome. The high proportion of recurrent somatic and mutations in this series of sporadic IO‐MEPL points to their likely important roles in the molecular pathogenesis of these rare embryonal tumors, and perhaps suggests the existence of distinct molecular variants of IO‐MEPL. Although the precise role of these recurrent mutations in the development of IO‐MEPL, and their relationship to pro‐oncogenic molecular mechanisms, have yet to be determined, unraveling their roles could eventually be exploited for nonsurgical therapies of these neoplasms. © 2016 Wiley Periodicals, Inc.
    Keywords: Tumors – Genetic Aspects;
    ISSN: 1045-2257
    E-ISSN: 1098-2264
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  • 4
    In: Pediatric Blood & Cancer, March 2018, Vol.65(3), pp.n/a-n/a
    Description: Infants with low‐grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re‐)treatment regimens are briefly discussed.
    Keywords: Braf V600e Inhibitor ; Child ; Desmoplastic Infantile Astrocytoma ; Infant ; Low‐Grade Glioma ; Vemurafenib
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 5
    In: Brain Pathology, January 2012, Vol.22(1), pp.26-31
    Description: Mutations in the isocitrate dehydrogenase () 1 and 2 genes occur frequently in diffuse astrocytoma and oligodendroglioma. The consecutive amino acid substitutions in the mutant proteins result in a gain of the function to catalyze the reduction of alpha‐ketoglutarate to 2‐hydroxyglutarate (2HG). So far, all investigated mutations share this gain of function. We here describe a method to detect 2HG levels in archival formalin‐fixed paraffin‐embedded tumor specimens by stable isotope dilution using gas chromatography followed by mass spectrometry (GC/MS). While 2HG levels are notably decreased during the routine embedding process, preserved amounts are still sufficient to indicate a mutation. Detection of 2HG in archival specimens could make routinely processed tissue accessible for research on 2HG accumulation and may allow studies on correlation with clinical data.
    Keywords: 2‐Hydroxyglutarate ; Ffpe ; Gc/Ms ; Glioma ; Idh1 ; Idh2 ; Stable Isotope Dilution
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 6
    In: Brain Pathology, April 2014, Vol.24(3), pp.221-229
    Description: V600E mutation and homozygous deletion of (16) are frequent molecular alterations in pleomorphic xanthoastrocytomas (s). We investigated 49 for clinical, histological and immunohistochemical characteristics related to mutation status. mutation was detected by immunohistochemical assay and DNA sequencing in 38/49 (78%) tumors. All but one located in the temporal lobe harbored a V600E mutation (23/24; 96%) compared with 10/19 nontemporal (53%;  = 0.0009). Histological and immunohistochemical analysis demonstrated increased reticulin deposition (76% vs. 27%;  = 0.003) and a more frequent expression of 34 in ‐mutant (76% vs. 27%;  = 0.003). We further investigated the utility of combined V600E (1) and 16 analysis by immunohistochemistry to distinguish from relevant histological mimics like giant‐cell glioblastoma. Among , 38/49 (78%) were 1‐positive, and 30/49 (61%) had a loss of p16 expression. The combined features (1 positivity/16 loss) were observed in 25/49 (51%) but were not observed in giant‐cell glioblastoma (1 0/28, 16 loss 14/28). We demonstrate that temporal location, reticulin deposition and 34 expression are associated with mutation in . Combined 1 positivity and 16 loss represents a frequent immunoprofile of and may therefore constitute an additional diagnostic tool for its differential diagnosis.
    Keywords: Brain Tumor ; Braf V600e ; Cdkn2a ; 34 ; Immunohistochemistry ; Pleomorphic Xanthoastrocytoma ; 16 ; 1
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 7
    In: International Journal of Cancer, 01 September 2018, Vol.143(5), pp.1176-1187
    Description: The () gene maps to chromosome arm 1p and is hemizygously deleted and epigenetically silenced in or ‐mutant and 1p/19q‐codeleted oligodendroglial tumors. In contrast, ‐wildtype astrocytic gliomas including glioblastomas mostly lack epigenetic silencing and express PRDX1 protein. In our study, we investigated how PRDX1 contributes to the infiltrative growth of ‐wildtype gliomas. Focusing on p38α‐dependent pathways, we analyzed clinical data from 133 patients of the NOA‐04 trial cohort to look for differences in the gene expression profiles of gliomas with wildtype or mutant . Biochemical interaction studies as well as and migration studies were used to establish a biological role of PRDX1 in maintaining pathway activity. Whole‐brain high‐resolution ultramicroscopy and survival analyses of pre‐clinical mouse models for ‐wildtype gliomas were then used for confirmation. Based on clinical data, we found that the absence of PRDX1 is associated with changes in the expression of MET/HGF signaling components. PRDX1 forms a heterodimer with p38α mitogen‐activated protein kinase 14 (MAPK14), stabilizing phospho‐p38α in glioma cells. This process amplifies hepatocyte growth factor (HGF)‐mediated signaling and stimulates actin cytoskeleton dynamics that promote glioma cell migration. Whole‐brain high‐resolution ultramicroscopy confirms these findings, indicating that PRDX1 promotes glioma brain invasion . Finally, reduced expression of PRDX1 increased survival in mouse glioma models. Thus, our preclinical findings suggest that PRDX1 expression levels may serve as a molecular marker for patients who could benefit from targeted inhibition of MET/HGF signaling. What's new? The () gene frequently is silenced by epigenetic mechanisms in gliomas with 1p/19q codeletion or mutated or (). By contrast, is strongly expressed in ‐wildtype gliomas. This study shows that forms a heterodimer with p38α, which sustains p38α phosphorylation in glioma cells. High p38α phospho‐levels were found to amplify MET proto‐oncogene/hepatocyte growth factor (HGF) signaling and to stimulate dynamic actin cytoskeleton remodeling, thereby promoting glioma invasion. The findings suggest that patients with gliomas expressing high levels of might benefit from targeted inhibition of the MET/HGF signaling.
    Keywords: Peroxiredoxin 1 ; P38α ; C‐Met ; Gliomas ; Invasion
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: John Wiley & Sons, Inc.
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  • 8
    In: Glia, January 2015, Vol.63(1), pp.78-90
    Description: Tryptophan catabolism is increasingly recognized as a key and druggable molecular mechanism active in cancer, immune, and glioneural cells and involved in the modulation of antitumor immunity, autoimmunity and glioneural function. In addition to the pivotal rate limiting enzyme indoleamine‐2,3‐dioxygenase, expression of tryptophan‐2,3‐dioxygenase (TDO) has recently been described as an alternative pathway responsible for constitutive tryptophan degradation in malignant gliomas and other types of cancer. In addition, TDO has been implicated as a key regulator of neurotoxicity involved in neurodegenerative diseases and ageing. The pathways regulating TDO expression, however, are largely unknown. Here, a siRNA‐based transcription factor profiling in human glioblastoma cells revealed that the expression of human TDO is suppressed by endogenous glucocorticoid signaling. Similarly, treatment of glioblastoma cells with the synthetic glucocorticoid dexamethasone led to a reduction of TDO expression and activity and . TDO inhibition was dependent on the immunophilin FKBP52, whose FK1 domain physically interacted with the glucocorticoid receptor as demonstrated by bimolecular fluorescence complementation and proximity ligation assays. Accordingly, gene expression profile analyses revealed negative correlation of FKBP52 and TDO in glial and neural tumors and in normal brain. Knockdown of FKBP52 and treatment with the FK‐binding immunosuppressant FK506 enhanced TDO expression and activity in glioblastoma cells. In summary, we identify a novel steroid‐responsive FKBP52‐dependent pathway suppressing the expression and activity of TDO, a central and rate‐limiting enzyme in tryptophan metabolism, in human gliomas. GLIA 2015;63:78–90 This study demonstrates that TDO‐mediated tryptophan catabolism in glioblastoma cells is negatively regulated by the glucocorticoid receptor (GR) signaling. The suppression of TDO by the GR seems to be dependent on the immunophilin FKBP52 and specific for human neural cells.
    Keywords: Tryptophan ; Glucocorticoid ; Glioma ; Tumor Immune Escape ; Kynurenine
    ISSN: 0894-1491
    E-ISSN: 1098-1136
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  • 9
    In: Histopathology, April 2016, Vol.68(5), pp.738-745
    Description: Byline: Christian Koelsche, Marcus Renner, Pascal Johann, Irina Leiss, Felix Sahm, Simon Schimmack, Eva Wardelmann, Eva-Kristin Renker, Peter Schirmacher, Andrey Korshunov, Andreas Deimling, Gunhild Mechtersheimer Keywords: ALT ; ATRX ; immunohistochemistry; sarcomas; telomeres Aim Nuclear [alpha]-thalassemia/mental retardation X-linked (ATRX) loss and alternative lengthening of telomeres (ALT) are linked in distinct malignancies. We therefore aimed to determine the nuclear ATRX expression correlated with ALT in a comprehensive series of sarcomas. Methods and results A total of 573 formalin-fixed paraffin-embedded sarcomas comprising 28 entities were investigated for nuclear ATRX expression by immunohistochemistry. Telomere-specific fluorescence in-situ hybridization (FISH) was used to determine the ALT phenotype in 50 sarcomas with complete or heterogeneous ATRX loss. Complete nuclear ATRX loss was detected in 58 of 573 sarcomas, all high-grade, with the highest prevalence in undifferentiated pleomorphic sarcomas (38%) and pleomorphic liposarcomas (38%), followed by dedifferentiated liposarcomas (24%), osteosarcomas (21%), leiomyosarcomas (17%), myxofibrosarcomas (11%) and malignant peripheral nerve sheath tumours (4%). Interestingly, a further 20 sarcomas, all belonging to the aforementioned entities with complete ATRX loss, presented with a heterogeneous ATRX expression pattern. ALT was observed in 41 of 42 sarcomas with complete ATRX loss, but only in two of eight sarcomas with heterogeneous expression. Conclusion Nuclear ATRX loss, either complete or heterogeneous, is encountered in a considerable number of high-grade sarcomas with non-specific genetic alterations. A causal relationship with ALT might be indicated at least in cases with a complete nuclear ATRX loss. CAPTION(S): Table S1. ATRX Primer Sequences.
    Keywords: Alt ; Atrx ; Immunohistochemistry ; Sarcomas ; Telomeres
    ISSN: 0309-0167
    E-ISSN: 1365-2559
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  • 10
    In: Histopathology, November 2014, Vol.65(5), pp.613-622
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/his.12431/abstract Byline: Christian Koelsche, Leonille Schweizer, Marcus Renner, Arne Warth, David T W Jones, Felix Sahm, David E Reuss, David Capper, Thomas Knosel, Birte Schulz, Iver Petersen, Alexis Ulrich, Eva Kristin Renker, Burkhard Lehner, Stefan M Pfister, Peter Schirmacher, Andreas Deimling, Gunhild Mechtersheimer Keywords: amplification; fusion; liposarcoma; NAB2; solitary fibrous tumour; STAT6 Aims Nuclear relocation of STAT6 has been shown in tumours with NAB2-STAT6 fusion, and has been proposed as an ancillary marker for the diagnosis of solitary fibrous tumours (SFTs). The aim of this study was to verify the utility of STAT6 immunohistology in diagnosing SFT. Methods and results A total of 689 formalin-fixed paraffin-embedded tumours comprising 35 pleural SFTs and 654 other mesenchymal tumours were investigated for STAT6 expression using immunohistochemistry. Nine dedifferentiated liposarcomas (DDLSs) and five SFTs were also examined for the presence of NAB2-STAT6 fusion at the protein level using the proximity ligation assay (PLA), and for copy number variants (CNVs) with the Illumina Infinium Human Methylation450 array. Thirty-four of 35 SFTs showed strong nuclear STAT6 expression. Furthermore, five of 68 DDLSs, two of 130 undifferentiated pleomorphic sarcomas and one of 63 cases of nodular fasciitis showed moderate to strong nuclear STAT6 expression. The PLA indicated the presence of NAB2-STAT6 fusion protein in SFTs, but signal was also detected in some DDLSs. Copy number analysis showed an overall low frequency of chromosomal imbalances in SFTs, but complex karyotypes in DDLSs, including amplification of STAT6 and MDM2 loci. Conclusions The detection of nuclear relocation of STAT6 with immunohistochemistry is a characteristic of SFTs, and may serve as a diagnostic marker that indicates NAB2-STAT6 fusion and helps to discriminate SFTs from histological mimics. Article Note: A.v.D. and G.M. contributed equally to this work. CAPTION(S): Figure S1. Copy number plots of five solitary fibrous tumours (SFTs) and nine dedifferentiated liposarcomas (DDLSs) derived from 450k array data with chromosomal gains (green) and chromosomal losses (red). Figure S2. Histological mimic of a solitary fibrous tumour (SFT) with absence of nuclear STAT6 expression (also depicted in Figure 1B). Figure S3. Solitary fibrous tumour (SFT) with strong nuclear STAT6 expression (A) and absence of MDM2 expression (B).
    Keywords: Amplification ; Fusion ; Liposarcoma ; 2 ; Solitary Fibrous Tumour ; 6
    ISSN: 0309-0167
    E-ISSN: 1365-2559
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