Neurochirurgische Klinik und Poliklinik
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Background: Glioblastomas (GBM), the most frequent malignant brain tumors in adults, are characterized by an aggressive local growth pattern and highly invasive tumor cells. This invasion is facilitated by expression of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases. They mediate the degradation of protein components of the extracellular matrix. Twenty-three family members are known. Elevated levels of several of them have been reported in GBM. GBM cell-lines are used for in vitro studies of cell migration and invasion. Therefore, it is essential to know their MMP expression patterns. Only limited data for some of the cell-lines are published, yet. To fill the gaps in our knowledge would help to choose suitable model systems for analysis of regulation and function of MMPs during GBM tumorigenesis, cell migration and invasion. Findings: We analysed MMP-1, -8, -9, -10, -11, -13, -17, -19, -20, -21, -23, -24, -26, -27, and MMP-28 expression in seven GBM cell-lines (SNB-19, GaMG, U251, U87, U373, U343, U138) and in four primary cell cultures by semiquantitative RT-PCR, followed changes in the MMP expression pattern with increasing passages of cell culture and examined the influence of TNF-a and TGF-b1 stimulation on the expression of selected MMPs in U251 and U373 cells. MMP-13, -17, -19 and -24 were expressed by all analyzed cell-lines, whereas MMP-20 and MMP-21 were not expressed by any of them. The other MMPs showed variable expression, which was dependent on passage number. Primary cells displayed a similar MMP-expression pattern as the cell-lines. In U251 and U373 cells expression of MMP-9 and MMP-19 was stimulated by TNF-a. MMP-1 mRNA expression was significantly increased in U373 cells, but not in U251 cells by this cytokine. Whereas TGF-b1 had no impact on MMP expression in U251 cells, it significantly induced MMP-11 and MMP-24 expression in U373 cells. Conclusions: Literature-data and our own results suggest that the expression pattern of MMPs is highly variable, dependent on the cell-line and the cell-culture conditions used and that also regulation of MMP expression by cytokines is cell-line dependent. This is of high impact for the transfer of cell-culture experiments to clinical implementation.
Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy.
This article reviews experimental and clinical data on the use of magnesium as a neuroprotective agent in various conditions of cerebral ischemia. Whereas magnesium has shown neuroprotective properties in animal models of global and focal cerebral ischemia, this effect could not be reproduced in a large human stroke trial. These conflicting results may be explained by the timing of treatment. While treatment can be started before or early after ischemia in experimental studies, there is an inevitable delay of treatment in human stroke. Magnesium administration to women at risk for preterm birth has been investigated in several randomized controlled trials and was found to reduce the risk of neurological deficits for the premature infant. Postnatal administration of magnesium to babies after perinatal asphyxia has been studied in a number of controlled clinical trials. The results are promising but the trials have, so far, been underpowered. In aneurysmal subarachnoid hemorrhage (SAH), cerebral ischemia arises with the onset of delayed cerebral vasospasm several days after aneurysm rupture. Similar to perinatal asphyxia in impending preterm delivery, treatment can be started prior to ischemia. The results of clinical trials are conflicting. Several clinical trials did not show an additive effect of magnesium with nimodipine, another calcium antagonist which is routinely administered to SAH patients in many centers. Other trials found a protective effect after magnesium therapy. Thus, it may still be a promising substance in the treatment of secondary cerebral ischemia after aneurysmal SAH. Future prospects of magnesium therapy are discussed.
Introduction
Structural plasticity with synapse formation and elimination is a key component of memory capacity and may be critical for functional recovery after brain injury. Here we describe in detail two surgical techniques to create a cranial window in mice and show crucial points in the procedure for long-term repeated in vivo imaging of synaptic structural plasticity in the mouse neocortex.
Methods
Transgenic Thy1-YFP(H) mice expressing yellow-fluorescent protein (YFP) in layer-5 pyramidal neurons were prepared under anesthesia for in vivo imaging of dendritic spines in the parietal cortex either with an open-skull glass or thinned skull window. After a recovery period of 14 days, imaging sessions of 45–60 min in duration were started under fluothane anesthesia. To reduce respiration-induced movement artifacts, the skull was glued to a stainless steel plate fixed to metal base. The animals were set under a two-photon microscope with multifocal scanhead splitter (TriMScope, LaVision BioTec) and the Ti-sapphire laser was tuned to the optimal excitation wavelength for YFP (890 nm). Images were acquired by using a 20×, 0.95 NA, water-immersion objective (Olympus) in imaging depth of 100–200 μm from the pial surface. Two-dimensional projections of three-dimensional image stacks containing dendritic segments of interest were saved for further analysis. At the end of the last imaging session, the mice were decapitated and the brains removed for histological analysis.
Results
Repeated in vivo imaging of dendritic spines of the layer-5 pyramidal neurons was successful using both open-skull glass and thinned skull windows. Both window techniques were associated with low phototoxicity after repeated sessions of imaging.
Conclusions
Repeated imaging of dendritic spines in vivo allows monitoring of long-term structural dynamics of synapses. When carefully controlled for influence of repeated anesthesia and phototoxicity, the method will be suitable to study changes in synaptic structural plasticity after brain injury.
Background
The human endogenous retrovirus K (HERV-K) has been acquired by the genome of human ancestors million years ago. It is the most complete of the HERVs with transcriptionally active gag, pol and env genes. Splice variants of env, which are rec, 1.5 kb transcript and Np9 have been suggested to be tumorigenic. Transcripts of HERV-K have been detected in a multitude of human cancers. However, no such reports are available concerning glioblastomas (GBM), the most common malignant brain tumor in adults. Patients have a limited prognosis of 14.6 months in median, despite standard treatment. Therefore, we elucidated whether HERV-K transcripts could be detected in these tumors and serve as new molecular target for treatment.
Findings
We analyzed human GBM cell lines, tissue samples from patients and primary cell cultures of different passages for HERV-K full length mRNA and env, rec and 1.5 kb transcripts. While the GBM cell lines U138, U251, U343 and GaMG displayed weak and U87 strong expression of the full length HERV-K, the splice products could not be detected, despite a weak expression of env mRNA in U87 cells. Very few tissue samples from patients showed weak expression of env mRNA, but none of the rec or 1.5 kb transcripts. Primary cells expressed the 1.5 kb transcript weakly in early passages, but lost HERV-K expression with extended culture time.
Conclusions
These data suggest that HERV-K splice products do not play a role in human malignant gliomas and therefore, are not suitable as targets for new therapy regimen.
Background
Glioblastoma multiforme located in the posterior fossa is extremely rare with a frequency up to 3.4%. Compared with glioblastoma of the hemispheres the prognosis of infratentorial glioblastoma seems to be slightly better. Absence of brainstem invasion and low expression rates of epidermal growth factor receptor are described as factors for long-time survival due to the higher radiosensitivity of these tumors.
Case presentation
In this case study, we report a German female patient with an exophytic glioblastoma multiforme arising from the cerebellar tonsil and a secondary spinal manifestation. Furthermore, the tumor showed no O (6)-Methylguanine-DNA methyltransferase promotor-hypermethylation and no isocitrate dehydrogenase 1 mutations. All these signs are accompanied by significantly shorter median overall survival. A long-term tumor control of the spinal metastases was achieved by a combined temozolomide/bevacizumab and irradiation therapy, as part of a standard care administered by the treating physician team.
Conclusion
To our knowledge this is the first published case of a combined cerebellar exophytic glioblastoma with a subsequent solid spinal manifestation. Furthermore this case demonstrates a benefit undergoing this special adjuvant therapy regime in terms of overall survival. Due to the limited overall prognosis of the disease, spinal manifestations of glioma are rarely clinically relevant. The results of our instructive case, however, with a positive effect on both life quality and survival warrant treating future patients in the frame of a prospective clinical study.
Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor.
15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples.
\(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression.
In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.
Object:
Several previous studies reported metabolic derangements and an accumulation of metabolic products in the early phase of experimental subarachnoid hemorrhage (SAH), which may contribute to secondary brain damage. This may be a result of deranged oxygen utilization due to enzymatic dysfunction in aerobic glucose metabolism. This study was performed to investigate, if pyruvate dehydrogenase enzyme (PDH) is affected in its activity giving further hints for a derangement of oxidative metabolism.
Methods:
Eighteen male Sprague-Dawley rats were randomly assigned to one of two experimental groups (n = 9): (1) SAH induced by the endovascular filament model and (2) sham-operated controls. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and local cerebral blood flow (LCBF; laser-Doppler flowmetry) were continuously monitored from 30 min before until 3 h after SAH. Thereafter, the animals were sacrificed and PDH activity was measured by ELISA.
Results:
PDH activity was significantly reduced in animals subjected to SAH compared to controls.
Conclusion: The results of this study demonstrate for the first time a reduction of PDH activity following SAH, independent of supply of substrates and may be an independent factor contributing to a derangement of oxidative metabolism, failure of oxygen utilization, and secondary brain damage.
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor.
Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.
Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.
Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
Methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for the clinical course of patients. In recent years, there have been observations of patients changing their MGMT promoter methylation from primary tumor to relapse. Still, data on this topic are scarce. Studies often consist of only few patients and provide rather contrasting results, making it hard to draw a clear conclusion on clinical implications. Here, we summarize the previous publications on this topic, add new cases of changing MGMT status in relapse and finally combine all reports of more than ten patients in a statistical analysis based on the Wilson score interval. MGMT promoter methylation changes are seen in 115 of 476 analyzed patients (24%; CI: 0.21–0.28). We discuss potential reasons like technical issues, intratumoral heterogeneity and selective pressure of therapy. The clinical implications are still ambiguous and do not yet support a change in clinical practice. However, retesting MGMT methylation might be useful for future treatment decisions and we encourage clinical studies to address this topic