This study aims to evaluate the impact of tumor location on key molecular alterations on a single voxel level in patients with newly-diagnosed glioma. A consecutive series of n=237 patients with newly diagnosed glioblastoma and n=131... more
This study aims to evaluate the impact of tumor location on key molecular alterations on a single voxel level in patients with newly-diagnosed glioma. A consecutive series of n=237 patients with newly diagnosed glioblastoma and n=131 patients with lower-grade glioma was analyzed. Volumetric tumor segmentation was performed on preoperative MRI with a semi-automated approach and images were registered to the standard Montreal Neurological Institute-152 space. Using a voxel-based lesion-symptom mapping (VSLM) analysis, we identified specific brain regions that were associated with tumor-specific molecular alterations. We assessed a predefined set of n=17 molecular characteristics in the glioblastoma cohort and n=2 molecular characteristics in the lower-grade glioma cohort. Permutation adjustment (n=1000 iterations) was used to correct for multiple testing and voxel t-values that were greater than the t-value in >95% of the permutations were retained in the VLSM results (α=0.05, powe...
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Research Interests:
Background and Purpose— We sought (1) to identify early metabolic markers for the development of (ir)reversible neurological deficits and cerebral infarction in subarachnoid hemorrhage (SAH) patients by using the microdialysis technique... more
Background and Purpose— We sought (1) to identify early metabolic markers for the development of (ir)reversible neurological deficits and cerebral infarction in subarachnoid hemorrhage (SAH) patients by using the microdialysis technique and (2) to evaluate the influence of intracerebral hemorrhage (ICH) on microdialysis parameters. Methods— We performed a prospective study of 44 SAH patients with acute focal neurological deficits (AFND) occurring acutely with SAH (due to ICH) or directly after surgery (due to clip stenosis, thromboembolism, or early edema). Fifty-one nonischemic SAH patients served as a control group. A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. The microdialysates were analyzed hourly for extracellular glucose, lactate, lactate/pyruvate ratio, glutamate, and glycerol with a bedside analyzer. Microdialysis-related CT findings were evaluated for the presence of ICH and cerebral infarction. Reversibility of neurolog...
Research Interests: Demography, Medicine, Brain, Humans, Glucose, and 15 moreFemale, Male, Anesthesia, Clinical Sciences, Glycerol, Microdialysis, Middle Aged, Intracerebral Hemorrhage, Biological markers, Disease Progression, Lactose, Glutamic Acid, Cerebral Angiography, Acute Disease, and Cardiovascular medicine and haematology
In a prospective clinical investigation on neurochemical intensive care monitoring, the authors' aim was to elucidate the temporal profile of nitric oxide metabolite concentrations—that is, nitrite and nitrate (NOx)—and compounds... more
In a prospective clinical investigation on neurochemical intensive care monitoring, the authors' aim was to elucidate the temporal profile of nitric oxide metabolite concentrations—that is, nitrite and nitrate (NOx)—and compounds related to energy-metabolism in the cerebral interstitium of patients after aneurysmal subarachnoid hemorrhage (SAH). During aneurysm surgery, microdialysis probes were implanted in cerebral white matter of the vascular territory most likely affected by vasospasm. Temporal profiles of NOx were analyzed in a subset of 10 patients (7 female, 3 male, mean age = 47 ± 14 years). Microdialysis was performed for 152 ± 63 hours. Extracellular metabolites (glucose, lactate, pyruvate, glutamate) were recovered from the extracellular fluid of the cerebral parenchyma. NOx was measured using a fluorometric assay. After early surgery, SAH patients revealed characteristic decreases of NOx from initial values of 46.2 ± 34.8 μmol/L to 23.5 ± 9.0 μmol/L on day 7 after SA...
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Research Interests:
This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the... more
This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the EUSI: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.
Research Interests: Magnetic Resonance Imaging, Medicine, Emergency Medical Services, Stroke, Humans, and 11 moreHypertension, Smoking, Cerebrovascular diseases, Risk factors, Clinical Sciences, Time Factors, Risk Factors, Neurosciences, Randomized Controlled Trials as Topic, intracranial haemorrhage, and Intracranial hemorrhages
Research Interests: Cognitive Science, Clinical Trial, Adolescent, Medicine, Comorbidity, and 15 moreGermany, Humans, Female, Male, Clinical Sciences, Aged, Middle Aged, Adult, DDC, Middle Cerebral Artery, Cerebral Infarction, Conservative treatment, Craniotomy, Cardiovascular medicine and haematology, and functional outcome
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Most gliomas are associated with a fatal prognosis and remain incurable because of their infiltrative growth. Consequently, the addition of immunotherapy to conventional therapy may improve patient outcomes. Here, we analyzed T-cell... more
Most gliomas are associated with a fatal prognosis and remain incurable because of their infiltrative growth. Consequently, the addition of immunotherapy to conventional therapy may improve patient outcomes. Here, we analyzed T-cell infiltration and, therefore, a major prerequisite for successful immunotherapy in a series of primary (n = 78) and recurrent (n = 66) isocitrate dehydrogenase (IDH)-mutant glioma and their changes following treatment with radio- and/or chemotherapy. After multicolor immunofluorescence staining, T cells were counted in entire tumor sections using a software-based setup. Newly diagnosed diffuse IDH-mutant gliomas displayed a median T-cell infiltration of 0.99 T cells/mm2 (range: 0–48.97 CD3+ T cells/mm2), which was about two-fold increased for CD3+, helper, and cytotoxic T cells in recurrent glioma. Furthermore, T-cell infiltration of recurrent tumors was associated with the type of adjuvant treatment of the primary tumor. Interestingly, only glioma patien...
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OBJECTIVEIn WHO grade II low-grade gliomas (LGGs), early postoperative MRI (epMRI) may overestimate residual tumor on FLAIR sequences. Consequently, MRI at 3–6 months follow-up (fuMRI) is used for delineation of residual tumor. This study... more
OBJECTIVEIn WHO grade II low-grade gliomas (LGGs), early postoperative MRI (epMRI) may overestimate residual tumor on FLAIR sequences. Consequently, MRI at 3–6 months follow-up (fuMRI) is used for delineation of residual tumor. This study sought to evaluate if integration of apparent diffusion coefficient (ADC) maps permits an accurate estimation of residual tumor early on epMRI.METHODSFrom a consecutive cohort, 43 cases with an initial surgery for an LGG, and complete epMRI (< 72 hours after resection) and fuMRI including ADC maps, were retrospectively identified. Residual FLAIR hyperintense tumor was manually segmented on epMRI and corresponding ADC maps were coregistered. Using an expectation maximization algorithm, residual tumor segments were probabilistically clustered into areas of residual tumor, ischemia, or normal white matter (NWM) by fitting a mixture model of superimposed Gaussian curves to the ADC histogram. Tumor volumes from epMRI, clustering, and fuMRI were stati...
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Optimal timing of tracheostomy in ventilated patients with severe stroke is unclear. We aimed to investigate feasibility, safety, and potential advantages of early tracheostomy in these intensive care unit (ICU) patients. This... more
Optimal timing of tracheostomy in ventilated patients with severe stroke is unclear. We aimed to investigate feasibility, safety, and potential advantages of early tracheostomy in these intensive care unit (ICU) patients. This prospective, randomized, parallel-group, controlled, open, and outcome-masked pilot trial was conducted in neurological/neurosurgical ICUs of a university hospital. Patients with severe ischemic or hemorrhagic stroke and an estimated need for at least 2 weeks of ventilation were randomized to either early tracheostomy (within day 1-3 from intubation; early) or to standard tracheostomy (between day 7-14 from intubation if extubation could not be achieved or was not feasible; standard). The primary outcome was length of stay in the ICU; secondary outcomes were diverse aspects of the ICU course. Sixty patients were randomized and analyzed. No differences were observed with regard to the primary outcome length of stay in the ICU (median 18 [interquartile range 16-...
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Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the... more
Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. Method A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and us...
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Research Interests:
Cancer cells with enhanced self-renewal capacity influence tumour growth in glioblastoma. So far, a variety of surrogate markers have been proposed to enrich these cells, emphasizing the need to devise new characterization methods. Here,... more
Cancer cells with enhanced self-renewal capacity influence tumour growth in glioblastoma. So far, a variety of surrogate markers have been proposed to enrich these cells, emphasizing the need to devise new characterization methods. Here, we screen a large panel of glioblastoma cultures (n = 21) cultivated under stem cell-permissive conditions and identify several cell lines with enhanced self-renewal capacity. These cell lines are capable of matrix-independent growth and form fast-growing, orthotopic tumours in mice. Employing isolation, re-plating, and label-retention techniques, we show that self-renewal potential of individual cells is partitioned asymmetrically between daughter cells in a robust and cell line-specific fashion. This yields populations of fast- and slow-cycling cells, which differ in the expression of cell cycle-associated transcripts. Intriguingly, fast-growing cells keep their slow-cycling counterparts in a reversible state of quiescence associated with high chemoresistance. Our results suggest that two different subpopulations of tumour cells contribute to aberrant growth and tumour recurrence after therapy in glioblastoma.
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The effect of bradykinin on the permeability and vasomotor response of pial vessels has been studied to enhance our understanding of the pathophysiological role of the kallikrein–kinin system in cerebral tissue. Intravital fluorescence... more
The effect of bradykinin on the permeability and vasomotor response of pial vessels has been studied to enhance our understanding of the pathophysiological role of the kallikrein–kinin system in cerebral tissue. Intravital fluorescence microscopy of the pia arachnoidea was conducted using Na+-fluorescein, FITC-dextran, and FITC-albumin as low and high molecular weight blood–brain barrier indicators. Massive arterial dilatation evolved immediately upon administration of bradykinin by superfusion of the exposed cerebral surface. An increase of the arterial diameter by 40% was the maximal response found at bradykinin concentrations of 4 × 10−5 M. Arterial dilatation became attenuated with continuous superfusion of the preparation with bradykinin. In pial veins, a moderate reduction of the vessel diameter was observed, however, only after prolonged superfusion of the preparation. Bradykinin led to selective opening of the blood–brain barrier for Na+-fluorescein at super-fusate concentra...
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Background Patients with severe space-occupying – so-called malignant – middle cerebral artery infarcts have a poor prognosis even under maximum intensive care treatment. Randomised trials demonstrated that early hemicraniectomy reduces... more
Background Patients with severe space-occupying – so-called malignant – middle cerebral artery infarcts have a poor prognosis even under maximum intensive care treatment. Randomised trials demonstrated that early hemicraniectomy reduces mortality from about 70% to 20% without increasing the risk of being very severely disabled. Hemicraniectomy increases the chance to survive completely independent more than fivefold and doubles the chance to survive at least partly independent. Only patients up to 60-years have been included in these trials. However, patients older than 60-years represent about 50% of all patients with malignant middle cerebral artery infarcts. Data from observational studies, suggesting that older patients may not profit from hemicraniectomy, are inconclusive, because these patients have generally been treated later and less aggressively. This leads to great uncertainty in everyday clinical practice. Aims To investigate the efficacy of early hemicraniectomy in pati...
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The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including... more
The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including transcriptional control, DNA synthesis, and apoptosis. Cell proliferation supported by the thioredoxin system can be suppressed by TrxR inhibition. In this study, we assessed the effects of the potent hTrxR inhibitors 4-mercaptopyridine (4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-chloro-2,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;:6&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;-terpyridine)platinum nitrate (I(23)2N) and 2-mercaptopyridine (4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-chloro-2,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;:6&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;-terpyridine)platinum nitrate (I(25)2N) on glioblastoma in a rat model. These compounds show no or little cross-resistance with cisplatin and are thus of great clinical interest. Triple intravenous application of 25-35 mg/kg of the compounds led to a significant decrease of tumor growth as determined by magnetic resonance imaging. Metabolic as well as redox parameters in the blood of the animals were not altered. However, TrxR activity was significantly decreased in the tumor tissue, and redox parameters-including glutathione concentrations, total antioxidant status, and the activities of different antioxidant enzymes-showed tissue-specific variations. As indicated by different apoptotic markers, the antitumor activity of I(23)2N is not mediated by the induction of programmed cell death but rather by hTrxR inhibition and DNA intercalation leading to cell cycle arrest.
Research Interests: Chemistry, Magnetic Resonance Imaging, Apoptosis, Medicine, Free Radical, and 15 moreGlioma, Animals, Male, Oxidoreductases, Glutathione, Antioxidant enzyme, Cell Proliferation, Cell Cycle Arrest, Antitumor Activity, Antineoplastic Agents, Brain Neoplasms, Biochemistry and cell biology, Dna Synthesis, Magnetic resonance image, and Free Radical Biology
Research Interests:
Background Patients with severe space-occupying – so-called malignant – middle cerebral artery infarcts have a poor prognosis even under maximum intensive care treatment. Randomised trials demonstrated that early hemicraniectomy reduces... more
Background Patients with severe space-occupying – so-called malignant – middle cerebral artery infarcts have a poor prognosis even under maximum intensive care treatment. Randomised trials demonstrated that early hemicraniectomy reduces mortality from about 70% to 20% without increasing the risk of being very severely disabled. Hemicraniectomy increases the chance to survive completely independent more than fivefold and doubles the chance to survive at least partly independent. Only patients up to 60-years have been included in these trials. However, patients older than 60-years represent about 50% of all patients with malignant middle cerebral artery infarcts. Data from observational studies, suggesting that older patients may not profit from hemicraniectomy, are inconclusive, because these patients have generally been treated later and less aggressively. This leads to great uncertainty in everyday clinical practice. Aims To investigate the efficacy of early hemicraniectomy in patients older than 60-years with malignant MCA infarcts. Materials &amp;amp;amp;amp;amp; Methods DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY II is a randomised controlled trial including patients 61-years and older with malignant middle cerebral artery infarcts. Patients are randomised to either maximum conservative treatment alone or in addition to early hemicraniectomy within 48 h after symptom onset. The trial uses a sequential design with a maximum number of 160 patients to be enrolled (ISRCTN 21702227). Discussion In the face of an ageing population, the potential benefit of hemicraniectomy in older patients is of major clinical relevance, but remains controversial. Conclusion The results of this trial are expected to directly influence decision making in these patients.
Research Interests:
Research Interests:
The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including... more
The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including transcriptional control, DNA synthesis, and apoptosis. Cell proliferation supported by the thioredoxin system can be suppressed by TrxR inhibition. In this study, we assessed the effects of the potent hTrxR inhibitors 4-mercaptopyridine (4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-chloro-2,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;:6&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;-terpyridine)platinum nitrate (I(23)2N) and 2-mercaptopyridine (4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-chloro-2,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;:6&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;-terpyridine)platinum nitrate (I(25)2N) on glioblastoma in a rat model. These compounds show no or little cross-resistance with cisplatin and are thus of great clinical interest. Triple intravenous application of 25-35 mg/kg of the compounds led to a significant decrease of tumor growth as determined by magnetic resonance imaging. Metabolic as well as redox parameters in the blood of the animals were not altered. However, TrxR activity was significantly decreased in the tumor tissue, and redox parameters-including glutathione concentrations, total antioxidant status, and the activities of different antioxidant enzymes-showed tissue-specific variations. As indicated by different apoptotic markers, the antitumor activity of I(23)2N is not mediated by the induction of programmed cell death but rather by hTrxR inhibition and DNA intercalation leading to cell cycle arrest.
Research Interests: Chemistry, Magnetic Resonance Imaging, Apoptosis, Medicine, Free Radical, and 15 moreGlioma, Animals, Male, Oxidoreductases, Glutathione, Antioxidant enzyme, Cell Proliferation, Cell Cycle Arrest, Antitumor Activity, Antineoplastic Agents, Brain Neoplasms, Biochemistry and cell biology, Dna Synthesis, Magnetic resonance image, and Free Radical Biology
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Research Interests:
Research Interests: Radiology, Molecular Imaging, Brain, Humans, Glucose, and 14 moreGlioblastoma, Female, Male, Young Adult, Aged, Middle Aged, Image Enhancement, Adult, Reproducibility of Results, Sensitivity and Specificity, Contrast Media, Brain Neoplasms, Diffusion magnetic resonance imaging, and Medical and Health Sciences
Chronic or neuropathic trigeminal facial pain can be challenging to treat. Neurosurgical procedures should be applied when conservative treatment fails. Neuromodulation techniques for chronic facial pain include deep brain stimulation and... more
Chronic or neuropathic trigeminal facial pain can be challenging to treat. Neurosurgical procedures should be applied when conservative treatment fails. Neuromodulation techniques for chronic facial pain include deep brain stimulation and motor cortex stimulation, which are complex to perform. Subcutaneous nerve field stimulation is certified for chronic back pain and is the least invasive form of neuromodulation. We applied this technique to treat chronic and neuropathic trigeminal pain as an individual therapy concept. First, trial stimulation is performed. Subcutaneous leads are placed in the painful trigeminal dermatome under local anesthesia. The leads are connected to an external neurostimulator that applies constant stimulation. Patients undergo a 12 day outpatient trial to assess the effect of the stimulation. Electrodes are removed after the trial. If the patient reports pain reduction of at least 50% in intensity and/or attack frequency, a reduction in medication or increase in quality of life, permanent implantation is scheduled. New electrodes are implanted under general anesthesia and are subcutaneously tunneled to an infraclavicular internal pulse generator. Patients are able to turn stimulation on and off and to increase or decrease the stimulation amplitude as needed. This technique represents a minimal invasive alternative to other more invasive means of neuromodulation for trigeminal pain such as motor cortex stimulation or deep brain stimulation.
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Research Interests:
Research Interests:
Glioblastoma (GBM) is a highly aggressive brain tumor and still remains incurable. Among others, an immature subpopulation of self-renewing and therapy-resistant tumor cells-often referred to as glioblastoma stem-like cells (GSCs)-has... more
Glioblastoma (GBM) is a highly aggressive brain tumor and still remains incurable. Among others, an immature subpopulation of self-renewing and therapy-resistant tumor cells-often referred to as glioblastoma stem-like cells (GSCs)-has been shown to contribute to disease recurrence. To target these cells personalized immunotherapy has gained a lot of interest, e.g. by reactivating pre-existing anti-tumor immune responses against GSC antigens. To identify T cell targets commonly presented by GSCs and their differentiated counterpart, we used a proteomics-based separation of GSC proteins in combination with a T cell activation assay. Altogether, 713 proteins were identified by LC-ESI-MS/MS mass spectrometry. After a thorough filtering process, 32 proteins were chosen for further analyses. Immunogenicity of corresponding peptides was tested ex vivo. A considerable number of these antigens induced T cell responses in GBM patients but not in healthy donors. Moreover, most of them were ove...
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The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular... more
The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analy...
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Spontaneous cerebellar hemorrhages (SCH) can lead to life-threatening complications with high mortality rates of 20-50%. Although complications of SCH can be prevented by surgical therapy, there is a lack of consensus concerning the... more
Spontaneous cerebellar hemorrhages (SCH) can lead to life-threatening complications with high mortality rates of 20-50%. Although complications of SCH can be prevented by surgical therapy, there is a lack of consensus concerning the optimal surgical technique for evacuating SCH. In this retrospective study 85 patients with SCH were divided into four treatment groups: (1) Decompression and Hematoma Evacuation via suboccipital craniectomy and removal of the posterior arch of C1 (DHE). (2) Hematoma Evacuation Only via craniotomy (HEO). (3) External Ventricular Drainage (EVD). (4) Conservative treatment (C). To ascertain the level of consciousness, Glasgow Coma Scale (GCS) was calculated. To evaluate the clinical and neurological outcome, modified Rankin Score, Glasgow Outcome Scale and mortality rate were recorded after 6months. The mean volume of hematoma was significant larger in the DHE- and HEO-group compared to the EVD- and C-group before treatment. DHE and HEO could significantly...
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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... more
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 corr...
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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... more
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 ± ...
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Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads... more
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carryi...
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Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic... more
Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic sedation, such as midazolam and propofol, is commonly used. Retrospective cohort study based on a prospectively established database. Single-center neurointensive care unit. Twenty-nine patients after subarachnoid hemorrhage. Noninterventional study. The relationship between mean GABAergic sedative dose during the acute phase and outcome after 6 months according to the Glasgow Outcome Scale, and initial Glasgow Coma Scale was investigated. Use of GABAergic sedatives was negatively correlated with Glasgow Outcome Scale (r(2)=0.267; P=.008). Administration of sedatives was independent of the initial Glasgow Coma Scale. GABAergic sedatives flunitrazepam, midazolam, and propofol were used differently during the first 10 days after ictus. Administration of GABAergic sedation was associated with an unfavorable outcome after 6 months. To avoid bias (mainly through the indication to use sedation), additional experimental and comparative clinical investigation of, for example, non-GABAergic sedation, and clinical protocols of no sedation is necessary.
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Background and Purpose— ABC/2 is still widely accepted for volume estimations in spontaneous intracerebral hemorrhage (ICH) despite known limitations, which potentially accounts for controversial outcome-study results. The aim of this... more
Background and Purpose— ABC/2 is still widely accepted for volume estimations in spontaneous intracerebral hemorrhage (ICH) despite known limitations, which potentially accounts for controversial outcome-study results. The aim of this study was to establish and validate an automatic segmentation algorithm, allowing for quick and accurate quantification of ICH. Methods— A segmentation algorithm implementing first- and second-order statistics, texture, and threshold features was trained on manual segmentations with a random-forest methodology. Quantitative data of the algorithm, manual segmentations, and ABC/2 were evaluated for agreement in a study sample (n=28) and validated in an independent sample not used for algorithm training (n=30). Results— ABC/2 volumes were significantly larger compared with either manual or algorithm values, whereas no significant differences were found between the latter ( P <0.0001; Friedman+Dunn’s multiple comparison). Algorithm agreement with the ma...
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Purpose To evaluate the association of multiparametric and multiregional magnetic resonance (MR) imaging features with key molecular characteristics in patients with newly diagnosed glioblastoma. Materials and Methods Retrospective data... more
Purpose To evaluate the association of multiparametric and multiregional magnetic resonance (MR) imaging features with key molecular characteristics in patients with newly diagnosed glioblastoma. Materials and Methods Retrospective data evaluation was approved by the local ethics committee, and the requirement to obtain informed consent was waived. Preoperative MR imaging features were correlated with key molecular characteristics within a single-institution cohort of 152 patients with newly diagnosed glioblastoma. Preoperative MR imaging features (n = 31) included multiparametric (anatomic and diffusion-, perfusion-, and susceptibility-weighted images) and multiregional (contrast-enhancing regions and hyperintense regions at nonenhanced fluid-attenuated inversion recovery imaging) information with histogram quantification of tumor volumes, volume ratios, apparent diffusion coefficients, cerebral blood flow, cerebral blood volume, and intratumoral susceptibility signals. Molecular c...
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Background The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. Methods From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of... more
Background The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. Methods From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. Results The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are re...
Research Interests: Treatment Outcome, Adolescent, Humans, Child, Female, and 14 moreMale, Glasgow Coma Scale, Young Adult, Aged, Middle Aged, Adult, Intracranial Hypertension, New England Journalof Medicine, Decompressive Craniectomy, Disabled Persons, Brain injuries, Combined Modality Therapy, Persistent Vegetative State, and Medical and Health Sciences
Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In... more
Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In this present study frequency bands of electrocorticographic (ECoG) recordings were investigated with regards to SDs. A total of 43 patients after acute brain injury were included in this retrospective and explorative study. Relative delta 0.5-4Hz, theta 4-8Hz, alpha 8-13Hz and beta 13-40Hz bands were analyzed with regards to SD occurrence and analgesic and sedative administration. Higher frequencies, including gamma 40-70Hz, fast gamma 70-100Hz and high frequency oscillations 100-200Hz were analyzed in a subset of patients with a sampling rate of up to 400Hz. A close association of relative beta frequency and SD was found. Relative beta frequency was suppressed up to two hours prior to SD when compared to hours with no SD. This finding was partially explained by administration of ketamine. Even after removal of all patient data during administration of ketamine, SDs occurred predominantly during times with low relative beta frequency in a patient-independent analysis. Suppression of beta frequency by ketamine or without ketamine is associated with low SD counts. Alteration of beta frequency might help to predict occurrence of SDs in acutely brain injured patients.