Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

Comparison between autologous bone grafts and acrylic (PMMA) implants - A retrospective analysis of 286 cranioplasty procedures.

Decompressive craniectomy (DC) is an accepted surgical technique for reducing life-threatening levels of intracranial pressure. Remodelling the cranial vault following DC can constitute a reconstructive challenge and is known to carry significant morbidity. The aim of our study was to evaluate acrylic versus autologous cranioplasty with regard to specific complication rates. A retrospective analysis was conducted of 286 consecutive adult patients who underwent cranioplasty following supratentorial decompressive craniectomy at our institution between January 2003 and June 2013. The patients were followed based on medical records, operative reports, imaging and outpatient contacts in the postoperative course. A total of 221/286 patients in our series received an autologous bone flap. 65/286 cranioplasty procedures were carried out using acrylic (PMMA) implants to cover uni- or bilateral defects. Within the follow-up period a total of 100 operative revisions were performed. 33.3% patients in the autologous bone group and 40.6% of patients in the acrylic group developed complications requiring surgical attention. The main reason for revision was infection with a total of 37 revisions necessary to treat disturbed wound healing. Postoperative sub- and epidural hematomas requiring revision were more frequent in the acrylic group. Resorption of the autologous bone flap requiring operative revision was seen in 8/222 (3.6%) cases. Other complications included loosening of the implant or dislocation. From our data it can be concluded that cranioplasty procedures using autologous bone-flaps and acrylic implants carry signifikant morbidity, but that both are justifiable techniques for cranioplasty in adult patients.

Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood.

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

Fatal recurrent subarachnoid hemorrhage after complete endovascular aneurysm occlusion.

Endovascular treatment of aneurysms has become an alternative to the neurosurgical approach. Here, we describe a patient presenting with a subarachnoid hemorrhage (SAH) due to a basilar tip aneurysm, which was completely occluded with coils. Fourteen days later the patient died due to massive recurrent SAH. Histologic evaluation showed aneurysm rerupture with coil dislocation in the subarachnoid space. This is a rare histologically documented case of fatal recurrent hemorrhage early after coil embolization of cerebral aneurysms.

Interrelations of laser doppler flowmetry and brain tissue oxygen pressure during ischemia and reperfusion induced by an experimental mass lesion.

The objective of this study was to assess interrelations between bilateral changes of cortical laser doppler flowmetry and intraparenchymal, subcortical partial tissue oxygen tension in the course of an experimental trauma. Ten animals served as a sham group, 8 Sprague-Dawley rats received an unilateral, focal parietal mass lesion. The bilateral course of cortical blood flow measured by laser doppler flowmetry (LDF) was correlated with subcortical, intraparenchymal partial tissue oxygen tension [p(ti)O2]. In the sham-operated group, laser doppler mean flow values drifted between 9.0% and 9.5% and showed no significant changes over time neither between the hemispheres nor within each hemisphere. Absolute mean p(ti)O2 in sham-operated animals was 32.4 mm Hg in the left and 30.5 mm Hg in the right hemisphere. In the trauma group, mean laser doppler flow values during maximum brain compression decreased ipsilateral to 20.3% and contralateral to 34.4% of the baseline values. P(ti)O2 decreased ipsilateral from 25.9 to 6.6 mm Hg (25.4%) and contralateral from 22.6 to 9.8 mm Hg (43.6%). After balloon deflation, cortical LDF was restored much faster compared to p(ti)O2, but did not reach baseline values [ipsilateral 61.6% (p < 0.05); contralateral 75.8% of baseline values]. The p(ti)O2 values reached 25.2 mm Hg (97%) ipsilateral and 23.7 mm Hg (105%) contralateral. A temporary phase of reactive hyperemia occurred sporadically shortly after decompression. Both parameters showed a significant but rather weak correlation (r = 0.56; p < 0.001). Based upon these findings, we conclude that intraparenchymal, subcortical p(ti)O2 measurements supplemented on-line cortical CBF monitoring and score out discontinuous alternative measurement techniques in detecting hemodynamically relevant events. The small spatial resolution of LDF and p(ti)O2 probes, however, which in the small animal model may be of negligible influence, does raise the question whether the values obtained represent the microcirculatory situation of the human brain.

Heterogeneous regional expression patterns of matrix metalloproteinases in human malignant gliomas.

The aim of the study was to assess the differential intra- and intertumoral heterogeneity and patterns of matrix metalloproteinase expression in human glioblastomas in vivo. 12 glioblastoma samples were analyzed for MMP expression by semi-quantitative RT-PCR. A total of 56 samples (8 adjoining regions of 6 glioblastoma tumors) were immunohistochemically examined for the expression and regional distribution of gelatinase-A (MMP-2), gelatinase-B (MMP-9), matrilysin (MMP-7) and stromelysin-1 (MMP-3). Gelatinase-A mRNA was detected in all samples, gelatinase-B was found in numerous samples. Correspondingly, strong expression levels of both gelatinase protein was seen in immunohistochemistry. Gelatinase-A was expressed by both tumor cells and endothelium while gelatinase-B was found to be restricted to endothelial cells. Stromelysin-1 protein was not detected in any of the samples. Matrilysin was found around tumor cells of three samples from one patient only. The strong immunoreactivity seen for gelatinase-A around tumor cells and blood vessels suggests a role in both tissue degradation and tumor neoangiogenesis which is in accordance with previously published in vitro data. The marked localization of gelatinase-B to the endothelium and its presence in non-infiltrative benign lesions, however, makes a direct proteolytic role of gelatinase-B on ECM components during glioma invasion appear unlikely. Its close association with vascular structures, however, might indicate a link to neoangiogenesis. The significance of matrilysin which was only seen in tumor cells in three samples remains unclear. Stromelysin-1, though strongly expressed in cell lines, does not appear to play a role in glioblastoma tumors in vivo.

Different vascular patterns of medulloblastoma and supratentorial primitive neuroectodermal tumors.

Astrocytoma vasculature patterns differ according to histological grade of malignancy with glioblastoma multiforme (WHO grade IV) showing most extensive endothelial proliferation. Here, we determined whether the vascular patterns of medulloblastoma and supratentorial primitive neuroectodermal tumors (PNETs), which can be hardly distinguished histopathologically, differ. We evaluated the spatial organization of vessels in medulloblastomas and PNETs using antibodies to von Willebrand factor (vWF) and CD34. Medulloblastoma capillaries showed slight endothelial cell hyperplasia. Microvessels sprouted from the capillaries and formed glomeruloid clusters. There were areas with chains of unopposed endothelial cells (3-10 cells). Supratentorial PNETs had highly branched capillaries with extensive endothelial cell hyperplasia. Glomeruloid arrays of microvessels extended from the capillaries. Small fragments of endothelial tubes were scattered throughout the tumor. Therefore, medulloblastomas and supratentorial PNETs showed different spatial organization of tumor vessels which can be used for differentiation of each tumor entity. These vascular patterns may reflect different tumor derived angiogenic stimuli.

Fast blue, a fluorescent tracer in glioma cell culture, affects cell proliferation and motility.

The azo-dye, Fast Blue (FB), initially employed for retrograde neuronal tracing is increasingly used in cell invasion and migration studies to detect living cells in monolayer and glioma tumor cell spheroid models. As yet, it is assumed that a cell stained with a tracker dye retains the characteristics of the original cell. The following experiments compared the adhesion, migration and proliferation properties of the cell lines U373 and GaMG with and without FB staining. FB staining reduced cell adhesion (P < 0.01) and proliferative activity (P < 0.01) and also had a significant inhibitory effect on cell migration (P < 0.001). From the results presented it follows that FB staining markedly influences basic cell characteristics.

Transfection and dye premarking of human and rat glioma cell lines affects adhesion, migration and proliferation.

It is assumed that a cell that is transfected for any gene addition or replacement or was premarked with a cell tracker dye retains the characteristics of the original cell. The following experiments compare the original C6 rat glioma cell line with C6 cells transfected with the retroviral plasmid LacZ, and the human glioma cell lines GaMG, U373, U251, and D54 with cells stained with tracker dyes (Dil and DiO). We tested adhesion, migration and proliferation. C6 cell transfection did not affect adhesion but decreased (p < 0.05) migration. Dil staining resulted in a significant decrease (p < 0.01) in adhesion in all cell lines but U251. After DiO staining human cell lines U373 and D54 displayed a decrease in adhesion (p < 0.01) whereas U251 and GaMG cells had enhanced adhesion (p < 0.01). Dye marking of C6, GaMG and U373 cells did not alter migratory capacity. In contrast, Dil and DiO reduced migration of U251 and D54 cells (p < 0.05). There was a decrease (p < 0.01) in proliferation of the human cell lines after Dil staining. Transfection or membrane dyes can alter basic cell characteristics. The assumption that a transfected or dye marked cell is the same as the original cell but with an additional gene or the presence of a dye in the membrane is untenable.

Guanidinobenzoatase and UPA in high-grade human astrocytomas and after xenografting cell suspensions into the rat cerebral cortex: proteases for metastasis and disease progression.

BACKGROUND: Invasion and metastasis is aided by the secretion of guanidinobenzoatase, that cleaves the link peptide to fibronectin, and urokinase plasminogen activator (uPA), which initiates a molecular cascade to activate plasmin and collagenases. This process permits malignant cell migration through the extracellular matrix. MATERIALS: Original human astrocytomas were examined for guanidinobenzoatase and uPA. Suspensions of high-grade human astrocytomas were xenografted into pockets in host cerebral cortex for 1-7 days. RESULTS: A class of guanidinobenzoatase positive cells was observed in the original human astrocytomas and in tumor masses formed in the implantation pocket and around blood vessels. Secondary foci containing guanidinobenzoatase positive cells formed around blood vessels and individual positive astrocytoma cells migrated on the glia limitans along parallel and intersecting nerve fiber fascicles and the corpus callosum. uPA and GFAP were colocalized with guanidinobenzoatase. CONCLUSION: The high-grade astrocytomas reestablish themselves and maintain their characteristics as a tissue although grafted as individual cells.

New ultrasound techniques and their application in neurosurgical intra-operative sonography.

We describe a variety of new ultrasound techniques by their physical background, potentials and applications regarding usefulness during intra-operative neurosurgical procedures. Transducers like high-frequency and small rotating probes fitting into neuroendoscopes, imaging techniques as extended field-of-view technique, harmonic imaging, echo-enhancers, 3-D imaging and the real-time integration of neurosonography with pre-operative CT- or MR-data are mentioned. The technical or physical principles are explained, followed by a discussion of these techniques from available literature dealing with their intra-operative neurosurgical applications and the experience of the authors with the techniques. With higher frequencies micromillimeter imaging is possible and small probe allows endoneurosonography. Echo-enhancers and harmonic imaging improve the signal-to-noise ratio and 3-D imaging and extended field-of-view techniques allows a better understanding of the pathoanatomy. With the real-time integration of intra-operative ultrasound images and pre-operative CT or MR images additional information, like hemodynamic pattern, are available for the neurosurgeon. Although until now only a limited number of reports about new sonographic techniques during intra-operative application in neurosurgery exist, the methods seem to be promising in creating images easier to understand, incorporating more information about pathoanatomy and supplying the neurosurgeon with information additional to that provided by CT and MRI.

An electronic tutorial of neurosurgical pathology--application of multi-media in clinical pathology.

We present an electronic tutorial of neurosurgical pathology developed for standard MS-DOS-computers. No additional software requirements are necessary. Digital pictures are displayed on the computer screen in Super-VGA quality. The user interface allows a dialogue between the pathologist and the engine. The dialogue component consists of scroll bar menus with lists of possible suggestions and answers. For each case the user is supplied with the basic clinical information and a set of representative pictures of the histological specimens. In some cases radiographs and CT-images are available. During the consultation session both routine and special staining methods are available on request. If the user proposes a wrong diagnosis the system offers a commentary. The presented cases are part of a teaching series developed for residents in neuropathology.

Primary Ki-1-positive T-cell lymphoma of the brain--an aggressive subtype of lymphoma: case report and review of the literature.

BACKGROUND: By detection of the Ki-1 antigen, Stein (1985) defined a new entity of anaplastic large cell lymphoma [24]. Apart from our case, only four further cases of Ki-1 positive primary central nervous system lymphoma (PCNSL) have been reported in the literature to date. CASE REPORT: A 63-year-old man presented with two frontal and parietal mass lesions and one ring lesion on computed tomography scan. Clinically, no evidence of brain metastases or abscesses could be found. Immunohistochemical investigations of biopsy specimens revealed a large cell anaplastic T-cell lymphoma positive to Ki-1 antigen. In spite of all therapeutic efforts, the patient died less than 3 months after the onset of symptoms. DISCUSSION: In all cases the clinical course was very rapid, suggesting that Ki-1 positive PCNSL might form an aggressive subtype of lymphomas. Since the radiologic appearance was atypical and clinical diagnosis was not possible, diagnostic biopsy for immunohistochemical diagnosis should be performed.

Bilateral monitoring of CBF and tissue oxygen pressure in the penumbra of a focal mass lesion in rats.

The continuous monitoring of cerebral microcirculation is aimed at preventing secondary ischemic brain damage subsequent to severe head injury. Interrelations between bilateral changes of cortical Laser Doppler Flowmetry (LDF) and intraparenchymal, subcortical p(ti)O2 values were continuously monitored in the forebrain of rodents. A trauma group of 8 animals received an unilateral, focal parietal mass lesion by an expanding epidural balloon. 10 animals served as a sham group. In the sham-operated group the drift of median LDF values was 10.8% in the left and 9.6% in the right hemisphere. The absolute median p(ti)O2 showed values of 31.2 mm Hg (27.9-34.9) in the left and 30.1 mm Hg (27.5-31.7) in the right hemisphere. During maximum brain compression median LDF values decreased ipsilateral to 18.6% (13.3-24.4%) and contralateral to 23.4% (17.1-56.6%) of the baseline values. P(ti)O2 decreased ipsilateral to absolute values of 4.6 mm Hg (3.2-6.7 mm Hg) and contralateral to values of 7.1 mm Hg (6.1-8.5 mm Hg). After balloon deflation cortical LDF was restored much faster but did not reach baseline values [ipsilateral 55.2% (42.6-67.8%); contralateral 67% (53.4-82%) of baseline values]. The p(ti)O2 values reached ipsilateral 77.4% (72.0-93.3%) and contralateral 88.8% (86.0-97.4%) of baseline values. Both parameters showed a significant correlation (r = 0.57; p < 0.02). P(ti)O2 measurements supplement on-line cortical CBF monitoring and by far outscore discontinuous alternative measurement techniques in detecting hemodynamically relevant events. The small spatial resolution of the p(ti)O2 probes, however, which in the small animal model may be of negligible influence, does raise the question whether the values gained offer a general overview of the microcirculatory situation.

Application of minimal spanning trees in glioma grading--a CLIPPER program for the calculation and construction of minimal spanning trees.

We present a CLIPPER program for the calculation and graphical representation of minimal spanning trees (MST) which is available on request on diskette from the authors. The MST are a useful parameter for structural cluster detection. They can be applied to grading problems in tumour biology. We present and discuss the applicability of MST by an example from the field of astrocytoma grading.

Patients with recurrent glioblastoma multiforme. Initial experience with p-[(131)I]iodo-L-phenylalanine and external beam radiation therapy.

AIM: The objective of this study was to assess the feasibility, dosimetry, tolerability and efficacy of systemically administrated p-[(131)I]iodo-L-phenylalanine ((131)IPA) combined with hypo-fractionated external beam radiation therapy (EBRT) in patients with recurrent glioblastoma multiforme (GBM). PATIENTS, METHODS: Five patients (2 women, 3 men, aged 27-69) with recurrent GBM and exhaustion of regular therapy options were included. All had a positive O-(2-[(18)F]Fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) and pretherapeutic dosimetry was performed. Tumour targeting was verified by (131)IPA-SPECT up to six days after radiotracer administration. After (131)IPA therapy, patients were treated with hypo-fractionated EBRT in six fractions of 5 Gy (n = 4) or in eleven fractions of 2 Gy in one case. RESULTS: Based on the individual dosimetry, the patients received a single intravenous administration of 2 to 7 GBq of (131)IPA, resulting in radiation absorbed doses to the blood of 0.80-1.47 Gy. The treatment was well tolerated; only minor complaints of nausea and vomiting that responded to ondansetron and pantoprazol were noticed in the first two patients. After preventive medication, the last three patients had no complaints during therapy. In none of the patients a decrease of leukocyte or thrombocyte counts below the baseline level or the lower normal limit was observed. Tumour doses from (131)IPA were low (≤ 1 Gy) and all patients died three to eight (median 5.5) months after therapy. CONCLUSION: In this initial experience, treatment of GBM with (131)IPA in combination with EBRT was demonstrated to be safe and well tolerated, but less effective than suggested by the animal studies.

[Carbamazepine in treatment of alcohol withdrawal syndrome--an overview of current research]. / Carbamazepin in der Behandlung des Alkoholentzugssyndroms--Eine Ubersicht zum aktuellen Forschungsstand.

Originally only intended as an anti-epileptic carbamazepine has nowadays a multitude of applications in the treatment of neurological and psychiatric diseases. It is also being used for the treatment of alcohol withdrawal symptoms. Its pharmacological properties and side-effects are well known and very effective dosage schedules already exist. The exact physiological action of carbamazepine, however, as well as the pathophysiological basis of withdrawal itself have not been entirely discovered. Evidence exists that "anti-kindling-effects" are of particular importance. A number of controlled clinical studies were able to demonstrate the effectiveness of carbamazepine in the treatment of alcohol withdrawal symptoms and have also compared its properties to other substances such as clomethiazole and benzodiazepine. Due to its effectiveness and the lack of additive potential carbamazepine offers a useful alternative to conventional therapeutic approaches, especially in the treatment of mild and moderately severe alcohol withdrawal symptoms.

[Computer assisted grading of gliomas of the astrocytoma/glioblastoma groups]. / Computergestützte Graduierung von Gliomen der Astrocytom/Glioblastom-Gruppe.

For automated astrocytoma grading morphometric parameters are determined by means of an image analysis system and a special Ki-67(MIB1)/Feulgen-staining method allowing the quantification of the essential characteristics of malignant gliomas: growth pattern, cellularity, proliferation index and nucleus pleomorphism. Based upon a cluster analytical approach a grading scale resembling the WHO-scheme is established which is suitable for automatic glioma grading purposes (HOM-scale). For automatic glioma grading backpropagation neural networks are employed. The results are compared with those of a classical multivariate discriminant classificatory analysis. The presented approach can also be employed for automatic grading of other tumour entities.

Automated grading of astrocytomas based on histomorphometric analysis of Ki-67 and Feulgen stained paraffin sections. Classification results of neuronal networks and discriminant analysis.

In stereotactically obtained astrocytoma biopsies, four morphometric nuclear parameters were determined with the use of an image analysis system. A special Ki-67 (MIB1)/Feulgen stain made it possible to quantify the essential characteristics of gliomas of the astrocytoma/glioblastoma group: growth pattern, cellularity, proliferation tendency and nucleus pleomorphism. A grading scale based on a cluster analysis resembling the WHO-scheme, which is suitable for automated astrocytoma grading, was developed. Large back propagation neural networks were used and their results compared with those of a classical multivariate discriminant classification analysis. It is possible to show that the neural network technology is superior to the statistical approach for automated astrocytoma grading. Based on the results of our study we believe neural network technology to be useful for tumour grading problems. The presented approach can be generalized for the automated grading of other tumour entities.