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  • Bendszus, Martin  (39)
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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Central Nervous System Neoplasms -- Diagnosis;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    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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  • 4
    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 differentiation between both entities may be important to evaluate treatment response and to identify glioblastoma with oligodendroglial components that are supposed to present calcifications. Since calcifications and blood deposits are difficult to differentiate using conventional MRI, we investigated whether a new post-processing approach, quantitative susceptibility mapping (QSM), is able to distinguish between both entities reliably. MATERIALS AND METHODS: SWI, FLAIR, and T1-w images were acquired from 46 patients with glioblastoma (14 newly diagnosed, 24 treated with radiochemotherapy, 8 treated with radiochemotherapy and additional anti-angiogenic medication). Susceptibility maps were calculated from SWI data. All glioblastoma were evaluated for the appearance of hypointense or hyperintense correlates of SBS on the susceptibility maps. RESULTS: 43 of 46 glioblastoma presented only hyperintense intratumoral SBS on susceptibility maps, indicating blood deposits. Additional hypointense correlates of tumor-related SBS on susceptibility maps, indicating calcification, were identified in 2 patients being treated with radiochemotherapy and in one patient being treated with additional anti-angiogenic medication. Histopathologic reports revealed an oligodendroglial component in one patient that presented calcifications on susceptibility maps. CONCLUSIONS: QSM provides a quantitative, local MRI contrast, which reliably differentiates between blood deposits and calcifications. Thus, quantitative susceptibility mapping appears promising to identify rare variants of glioblastoma with oligodendroglial components non-invasively and may allow monitoring the role of calcification in the context of different therapy regimes.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    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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  • 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 obtained a correlation of 561 1mm3 biopsy specimens with their corresponding position on the intraoperative cT1 image at 1.5 Tesla. Biopsy points were categorized as enhancing (CE), non-enhancing (NE) or necrotic (NEC) on cT1 and tissue samples were categorized as "viable tumor cells", "blood" or "necrotic tissue (with or without cellular component)". Cell counting was done semi-automatically.NE had the highest content of tissue categorized as viable tumor cells (89% vs. 60% in CE and 30% NEC, respectively). Besides, the average cell density for NE (3764 ± 2893 cells/mm2) was comparable to CE (3506 ± 3116 cells/mm2), while NEC had a lower cell density with 2713 ± 3239 cells/mm2. If necrotic parts and bleeds were excluded, cell density in biopsies categorized as "viable tumor tissue" decreased from the center of the tumor (NEC, 5804 ± 3480 cells/mm2) to CE (4495 ± 3209 cells/mm2) and NE (4130 ± 2817 cells/mm2).The appearance of a glioblastoma on a cT1 image (circular enhancement, central necrosis, peritumoral edema) does not correspond to its diffuse histopathological composition. Cell density is elevated in both CE and NE parts. Hence, our study suggests that NE contains considerable amounts of infiltrative tumor with a high cellularity which might be considered in resection planning.
    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
    In: The New England Journal of Medicine, 2017, Vol.377(20), pp.1954-1963
    Description: Background Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma. Methods We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O 6 -methylguanine–DNA methyltransferase ( MGMT ) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. Results A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P〈0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic. Conclusions Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann–La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .) The addition of bevacizumab to lomustine in patients with recurrent glioblastoma failed to increase overall survival but was associated with a small increase in progression-free survival.
    Keywords: Antineoplastic Agents, Alkylating -- Administration & Dosage ; Antineoplastic Combined Chemotherapy Protocols -- Therapeutic Use ; Bevacizumab -- Administration & Dosage ; Brain Neoplasms -- Drug Therapy ; Glioblastoma -- Drug Therapy ; Lomustine -- Administration & Dosage;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(7), p.e0160250
    Description: Several studies have analyzed a correlation between the apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI and the tumor cellularity of corresponding histopathological specimens in brain tumors with inconclusive findings. Here, we compared a large dataset of ADC and cellularity values of stereotactic biopsies of glioblastoma patients using a new postprocessing approach including trajectory analysis and automatic nuclei counting.Thirty-seven patients with newly diagnosed glioblastomas were enrolled in this study. ADC maps were acquired preoperatively at 3T and coregistered to the intraoperative MRI that contained the coordinates of the biopsy trajectory. 561 biopsy specimens were obtained; corresponding cellularity was calculated by semi-automatic nuclei counting and correlated to the respective preoperative ADC values along the stereotactic biopsy trajectory which included areas of T1-contrast-enhancement and necrosis.There was a weak to moderate inverse correlation between ADC and cellularity in glioblastomas that varied depending on the approach towards statistical analysis: for mean values per patient, Spearman's ρ = -0.48 (p = 0.002), for all trajectory values in one joint analysis Spearman's ρ = -0.32 (p 〈 0.001). The inverse correlation was additionally verified by a linear mixed model.Our data confirms a previously reported inverse correlation between ADC and tumor cellularity. However, the correlation in the current article is weaker than the pooled correlation of comparable previous studies. Hence, besides cell density, other factors, such as necrosis and edema might influence ADC values in glioblastomas.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 01 December 2018, Vol.102(5), pp.1472-1480
    Description: Because treatment options at progression are limited for patients with glioma, accuracy in definition of progression is pivotal. Clinically asymptomatic, newly detected, nonmeasurable, speckled contrast-enhancing lesions (SCEs) without immediate relation to prior immune therapy or radiation therapy appear relatively frequently during the course of disease in patients with glioma and challenge the definition of progression based on Response Assessment in Neuro-oncology criteria. Therefore, data characterizing these SCEs are needed for recommendations of subsequent clinical management. Magnetic resonance imaging of 746 patients with glioma included in this study were retrospectively revised for appearance of newly detected SCEs during the course of disease. Associations with molecular and clinical baseline parameters and their prognostic impact were statistically analyzed, and frequency, natural course, and location of SCEs were described. SCEs occurred more frequently in World Health Organization grade 2 and 3 astrocytoma and oligodendroglial tumors and were significantly associated with isocitrate dehydrogenase mutation in World Health Organization grade 3 astrocytoma and glioblastoma. SCEs mostly remained stable or dissolved in follow-up magnetic resonance imaging, even if no new treatment was initiated. SCEs were frequently located within the tumor or tumor-associated fluid-attenuated inversion recovery abnormalities, but distant appearance also occurred. In patients with glioblastoma, SCEs were associated with a favorable prognosis, which was also observed in the subgroup of patients with glioblastoma with isocitrate dehydrogenase wildtype status. The data demonstrate a predominantly benign course of SCEs after their appearance and emphasize cautious definitions of progression and regular clinical and radiographic follow-up rather than premature initiation of new antitumor therapies until progression is confirmed.
    Keywords: Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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