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Berlin Brandenburg

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  • 1
    Language: English
    In: Nature, 03 December 2015, Vol.528(7580), pp.93-8
    Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
    Keywords: Astrocytoma -- Pathology ; Brain Neoplasms -- Pathology ; Gap Junctions -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 2
    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...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(3), p.e57924
    Description: OBJECTIVES: The application of susceptibility weighted imaging (SWI) in brain tumor imaging is mainly used to assess tumor-related "susceptibility based signals" (SBS). The origin of SBS in glioblastoma is still unknown, potentially representing calcifications or blood depositions. Reliable...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Radiology, September 2014, Vol.272(3), pp.843-50
    Description: To compare multiparametric diagnostic performance with diffusion-weighted, dynamic susceptibility-weighted contrast material-enhanced perfusion-weighted, and susceptibility-weighted magnetic resonance (MR) imaging for differentiating primary central nervous system lymphoma (PCNSL) and atypical glioblastoma. This retrospective study was institutional review board-approved and informed consent was waived. Pretreatment MR imaging was performed in 314 patients with glioblastoma, and a subset of 28 patients with glioblastoma of atypical appearance (solid enhancement with no visible necrosis) was selected. Parameters of diffusion-weighted (apparent diffusion coefficient [ADC]), susceptibility-weighted (intratumoral susceptibility signals [ITSS]), and dynamic susceptibility-weighted contrast-enhanced perfusion-weighted (relative cerebral blood volume [rCBV]) imaging were evaluated in these 28 patients with glioblastoma and 19 immunocompetent patients with PCNSL. A two-sample t test and χ(2) test were used to compare parameters.The diagnostic performance for differentiating PCNSL from glioblastoma was evaluated by using logistic regression analyses with leave-one-out cross validation. Minimum, maximum, and mean ADCs and maximum and mean rCBVs were significantly lower in patients with PCNSL than in those with glioblastoma (P 〈 .01, respectively), whereas mean ADCs and mean rCBVs allowed the best diagnostic performance. Presence of ITSS was significantly lower in patients with PCNSL (32% [six of 19]) than in those with glioblastoma (82% [23 of 28]) (P 〈 .01). Multiparametric assessment of mean ADC, mean rCBV, and presence of ITSS significantly increased the probability for differentiating PCNSL and atypical glioblastoma compared with the evaluation of one or two imaging parameters (P 〈 .01), thereby correctly predicting histologic results in 95% (18 of 19) of patients with PCNSL and 96% (27 of 28) of patients with atypical glioblastoma. Combined evaluation of mean ADC, mean rCBV, and presence of ITSS allowed reliable differentiation of PCNSL and atypical glioblastoma in most patients, and these results support an integration of advanced MR imaging techniques for the routine diagnostic workup of patients with these tumors.
    Keywords: Brain Neoplasms -- Pathology ; Diffusion Magnetic Resonance Imaging -- Methods ; Glioblastoma -- Pathology ; Image Interpretation, Computer-Assisted -- Methods ; Lymphoma -- Pathology ; Magnetic Resonance Angiography -- Methods ; Multimodal Imaging -- Methods
    ISSN: 00338419
    E-ISSN: 1527-1315
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  • 5
    Language: English
    In: Archives of neurology, April 2012, Vol.69(4), pp.523-6
    Description: To analyze infiltration patterns of IDH1 mutant diffuse gliomas into the brain by identification of single tumor cells applying an antibody specific to mutant IDH1 R132H protein. Immunohistochemical analysis. University hospital. Whole-brain and hemisphere sections of 4 patients diagnosed with diffuse glioma. Tumor cells were identified in areas that appeared inconspicuous macroscopically and at histological analysis with respect to cellularity, cellular pleomorphism, or mitotic activity in all cases. Detection of single tumor cells throughout the brain demonstrates diffuse glioma to represent systemic brain disease.
    Keywords: Brain Neoplasms -- Genetics ; Glioma -- Genetics ; Isocitrate Dehydrogenase -- Genetics ; Mutation -- Genetics
    ISSN: 00039942
    E-ISSN: 1538-3687
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(1), p.e0169292
    Description: To correlate histopathologic findings from biopsy specimens with their corresponding location within enhancing areas, non-enhancing areas and necrotic areas on contrast enhanced T1-weighted MRI scans (cT1).In 37 patients with newly diagnosed glioblastoma who underwent stereotactic biopsy, we...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    In: Neurology, 2017, Vol.89(5), pp.475-484
    Description: OBJECTIVE:: To detect and quantify lesions of the small-caliber sural nerve (SN) in symptomatic and asymptomatic transthyretin familial amyloid polyneuropathy (TTR-FAP) by high-resolution magnetic resonance neurography (MRN) in correlation with electrophysiologic and histopathologic findings. METHODS:: Twenty-five patients with TTR-FAP, 10 asymptomatic carriers of the mutated transthyretin gene (mutTTR), and 35 age- and sex-matched healthy controls were prospectively included in this cross-sectional case-control study. All participants underwent 3T MRN with high-structural resolution (fat-saturated, T2-weighted, and double-echo sequences). Total imaging time was ≈45 minutes per patient. Manual SN segmentation was performed from its origin at the sciatic nerve bifurcation to the lower leg with subsequent evaluation of quantitative microstructural and morphometric parameters. Additional time needed for postprocessing was ≈1.5 hours per participant. Detailed neurologic and electrophysiologic examinations were conducted in the TTR group. RESULTS:: T2 signal and proton spin density (ρ) reliably differentiated between TTR-FAP (198.0 ± 13.3, 429.6 ± 15.25), mutTTR carriers (137.0 ± 16.9, p = 0.0009; 354.7 ± 21.64, p = 0.0029), and healthy controls (90.0 ± 3.4, 258.2 ± 9.10; p 〈 0.0001). Marked differences between mutTTR carriers and controls were found for T2 signal (p = 0.0065) and ρ (p 〈 0.0001). T2 relaxation time was higher in patients with TTR-FAP only (p = 0.015 vs mutTTR carriers, p = 0.0432 vs controls). SN caliber was higher in patients with TTR-FAP vs controls and in mutTTR carriers vs controls (p 〈 0.0001). Amyloid deposits were histopathologically detectable in 10 of 14 SN specimens. CONCLUSIONS:: SN injury in TTR-FAP is detectable and quantifiable in vivo by MRN even in asymptomatic mutTTR carriers. Differences in SN T2 signal between controls and asymptomatic mutTTR carriers are derived mainly from an increase of ρ, which overcomes typical limitations of established diagnostic methods as a highly sensitive imaging biomarker for early detection of peripheral nerve lesions. CLASSIFICATION OF EVIDENCE:: This study provides Class III evidence that MRN accurately identifies asymptomatic mutTTR carriers.
    Keywords: Adult–Diagnostic Imaging ; Aged–Genetics ; Amyloid Neuropathies, Familial–Pathology ; Case-Control Studies–Genetics ; Cross-Sectional Studies–Diagnostic Imaging ; Disability Evaluation–Injuries ; Early Diagnosis–Pathology ; Female–Pathology ; Heterozygote–Pathology ; Humans–Pathology ; Image Processing, Computer-Assisted–Pathology ; Magnetic Resonance Imaging–Pathology ; Male–Pathology ; Middle Aged–Pathology ; Neural Conduction–Pathology ; Prealbumin–Pathology ; Prodromal Symptoms–Pathology ; Prospective Studies–Pathology ; Sural Nerve–Pathology ; Abridged ; Prealbumin;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 8
    Language: English
    In: The Journal of clinical investigation, February 2015, Vol.125(2), pp.593-606
    Description: For a targeted cancer vaccine to be effective, the antigen of interest needs to be naturally processed and presented on MHC by the target cell or an antigen-presenting cell (APC) in the tumor stroma. The presence of these characteristics is often assumed based on animal models, evaluation of antigen-overexpressing APCs in vitro, or assays of material-consuming immune precipitation from fresh solid tissue. Here, we evaluated the use of an alternative approach that uses the proximity ligation assay (PLA) to identify the presentation of an MHC class II-restricted antigen in paraffin-embedded tissue sections from patients with brain tumors. This approach required a specific antibody directed against the epitope that was presented. We used an antibody that specifically binds an epitope of mutated isocitrate dehydrogenase type 1 (IDH1R132H), which is frequently expressed in gliomas and other types of tumors. In situ PLA showed that the IDH1R132H epitope colocalizes with MHC class II in IDH1R132H-mutated glioma tissue. Moreover, PLA demonstrated colocalization between the class II epitope-containing melanoma antigen New York esophageal 1 and MHC class II. Collectively, our data suggest that PLA may be a useful tool to acquire information on whether an antigen is presented in situ, and this technique has potential to guide clinical studies that use antigen-specific cancer immunotherapy.
    Keywords: Antigen Presentation ; Mutation, Missense ; Antigen-Presenting Cells -- Immunology ; Brain Neoplasms -- Immunology ; Glioma -- Immunology ; Immunohistochemistry -- Methods ; Isocitrate Dehydrogenase -- Immunology
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 9
    Language: English
    In: Journal of Clinical Neuroscience, April 2016, Vol.26, pp.145-146
    Description: Intravenous administration of thrombolytic agents is considered to be contraindicated in patients with intracranial neoplasms. However, only a single case of thrombolysis-related intracranial tumour haemorrhage has been reported to our knowledge and several studies have suggested that systemic thrombolysis can be safely carried out in these patients. Here we report a patient who developed haemorrhage into a previously unknown intracranial tumour following intravenous thrombolysis for acute myocardial ST-elevation infarction. Identification of abnormal tissue during surgical haematoma evacuation initiated histopathological examination which revealed meningioma World Health Organization Grade I. Intracranial tumours may represent the causative pathology in cases of thrombolysis-related intracranial haemorrhage and this should be considered in the treatment of these patients.
    Keywords: Fibrinolysis ; Haemorrhage ; Intracranial Neoplasm ; Thrombolysis ; Medicine
    ISSN: 0967-5868
    E-ISSN: 1532-2653
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  • 10
    Language: English
    In: The Journal of neuroscience : the official journal of the Society for Neuroscience, 19 July 2017, Vol.37(29), pp.6837-6850
    Description: Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (〉10 to hundreds of microns) membrane protrusions [tumor microtubes (TMs)] extended by glioma cells. TMs have been associated with the capacity of glioma cells to effectively invade the brain and proliferate. Moreover, TMs are also used by some tumor cells to interconnect to one large, resistant multicellular network. Here, we performed a correlative gene-expression microarray and imaging analysis, and identified novel molecular candidates for TM formation and function. Interestingly, these genes were previously linked to normal CNS development. One of the genes scoring highest in tests related to the outgrowth of TMs was (), which was highly expressed in a fraction of TMs in mice and patients. Ttyh1 was confirmed to be a potent regulator of normal TM morphology and of TM-mediated tumor-cell invasion and proliferation. Glioma cells with one or two TMs were mainly responsible for effective brain colonization, and Ttyh1 downregulation particularly affected this cellular subtype, resulting in reduced tumor progression and prolonged survival of mice. The remaining Ttyh1-deficient tumor cells, however, had more interconnecting TMs, which were associated with increased radioresistance in those small tumors. These findings imply a cellular and molecular heterogeneity in gliomas regarding formation and function of distinct TM subtypes, with multiple parallels to neuronal development, and suggest that Ttyh1 might be a promising target to specifically reduce TM-associated brain colonization by glioma cells in patients. In this report, we identify tweety-homolog 1 (Ttyh1), a membrane protein linked to neuronal development, as a potent driver of tumor microtube (TM)-mediated brain colonization by glioma cells. Targeting of Ttyh1 effectively inhibited the formation of invasive TMs and glioma growth, but increased network formation by intercellular TMs, suggesting a functional and molecular heterogeneity of the recently discovered TMs with potential implications for future TM-targeting strategies.
    Keywords: Ttyh1 ; Glioblastoma ; Glioma ; Invasion ; Migration ; Tumor Microtubes ; Brain Neoplasms -- Metabolism ; Glioblastoma -- Metabolism ; Membrane Proteins -- Metabolism
    ISSN: 02706474
    E-ISSN: 1529-2401
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