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Although meningiomas are typically benign, they occasionally behave in an aggressive fashion and carry a less favorable prognosis. The aim of this study was to review the clinical, radiologic and histopathologic features of these aggressive variants as well as the outcome after multimodality therapy. 16 patients with atypical meningiomas (n = 11) and anaplastic meningiomas (n = 5) were treated in the Departments of Neurosurgery and Radiation Oncology at the University Hospital of Philipps University Marburg, Germany, between 1997 and 2003. Tumor grading was based on new WHO criteria. There were eleven men and five women with a mean age of 54 years. The median follow-up period was 34 months. A total of 24 surgical procedures were performed for these 16 patients. Only seven patients underwent postoperative fractionated stereotactic radiotherapy. Patients with atypical meningioma received radiotherapy only for the recurrent disease. Six patients (37.5%) experienced tumor recurrence after a mean period of 27.2 months in spite of gross total resection. Radiographic findings suggestive of aggressiveness were observed mostly with WHO grade III meningiomas. By comparing the proliferation rate in four cases with atypical meningioma operated twice, the recurrent tumor had a higher proliferation rate than the first tumor in three cases. A special proliferation pattern was noticed in MIB-1 with anaplastic meningiomas. The mean overall survival period was 66.5 months. There was no mortality among patients with atypical meningioma, while four out of five patients with anaplastic meningioma died during follow-up. Considering the higher rate of recurrence in aggressive meningiomas even after radical surgical excision and the possibility that the recurrent tumor is more aggressive than the original one, surgery should be combined with postoperative fractionated radiotherapy to improve local tumor control. The peculiar focal expression patterns of anaplastic meningioma in MIB-1 might be a marker of such malignant development.

Background. Argon plasma coagulation (APC) is based on the principle of ionised argon creating conductive plasma between an activating electrode and tissue surface and is used as an effective alternative coagulation technique in various surgical disciplines. This trial aims to compare thermal injury in rat brain caused by APC and conventional bipolar coagulation technique. Methods. A controlled study design with constant power setting and application time was established. Twenty rats were randomised into the APC and bipolar groups. Each group of ten rats had 20 treated lesions. Early and late histopathological changes, as well as maximum extent of the lesion after 48 hours (h) and 12 days were studied in overall 20 lesions. Findings. Although the maximum depth of the lesions was different in APC (2.2 mm) and bipolar (1.8 mm) groups after 48 h, this did not achieve statistical significance (p = 0.151). The superficially coagulated area was significantly larger after APC compared with the bipolar technique at the 48 h time point (p = 0.032). After twelve days there were no differences in penetration depth (p = 0.310) or coagulated area (p = 0.222). Conclusion. Tissue defects after APC application on rat brains were comparable to conventional bipolar technique in this trial. The results suggest that argon plasma coagulation (APC) is an effective coagulation technique.

✓ The authors present two cases in which enlarged Virchow—Robin spaces were located in the basal ganglia and the thalamomesencephalic region. The incidence of such huge cystic lesions is extremely rare. The expanding nature of these lesions, demonstrated by the patients' progressive symptoms due to compression of the adjacent brain parenchyma and obstructive hydrocephalus, mimicked that of brain tumors. The two patients were successfully treated by neuroendoscopic cystocisternostomy or ventriculocystostomy. To the authors' knowledge there have been only two published reports on expanding Virchow—Robin spaces that produced a compressive effect or consequent hydrocephalus and were directly fenestrated using neuroendoscopic techniques. Neuroendoscopy appears to offer an effective surgical option in the treatment of symptomatic Virchow—Robin spaces.

Klaus Joachim Zulch (1910-1988) since 1959 head of a department of the german Max-Planck-Society, deeply influenced the neurological sciences in post-war Germany. The department with the name Abteilung fur allgemeine Neurologie (i.e. department of general neurology) constituted a section of the renowned Max-Planck-Institut fur Hirnforschung (i.e. institute for brain research) and found its place in Cologne. At the same time he was in charge of the local neurology unit of the municipal Cologne hospital, on the right Rhine riverside in Koln (Cologne) Merheim. In this double position he was able to focus his work as a neurologist on the major issues of this specialty, that at this time were not in the center of neurological interest: The connection of basic science i.e. morphology with important themes such as raised intracranial pressure, brain swelling and edema, brain and spinal chord circulation disturbances, head injuries and - in the first line - tumors of the central nervous system. This broad approach to essential issues in the field was probably due to his upbringing in german neurological tradition. His first contact with this specialty took place in Otfrid Foersters neurological clinic in Breslau, today in Poland, before World War II. Otfrid Foerster, a neurological encyclopedist, exerted a deep influence upon Klaus Joachim Zulch lifelong. Here he also came in contact with Percieval Bailey with whom he shared the obsession to classify brain tumors since then. This preoccupation became fruitful when he started collaboration with Wilhelm Tonnis 1936 at the time still in Wurzburg. The collaboration continued, when Tonnis moved to Berlin, during and after World War II up to 1959, when Klaus Joachim Zulch became head of the mentioned department of the german Max-Planck-society. At this time, important contributions already existed concerning brain injuries, brain edema and tumor classification. The couple Wilhelm Tonnis and Klaus Joachim Zulch may well be compared to the team formed by Harvey Cushing and Percieval Bailey. Their respective philosophies were equally identical, namely to classify tumors of the central nervous system through a pragmatic approach that would facilitate the communication between neuropathologist, neurosurgeon, neurologist and of course be ultimately as helpful as possible to the patient. Since 1959 Zulchs research turned to the topics of brain hypoxia, circulatory disturbances and stroke, notwithstanding that his interest remained with the other items, whenever new or old questions came up. The occupation with tumors became even once more intense when the WHO installed a reference center for brain tumor classification at his place in Cologne. In the new field of brain circulation, Klaus Joachim Zulch tried once again to bring basic science and clinical practise together and to draw the neurologists attention upon these frequent and important conditions, a development that gained increasing importance under the heading of "stroke unit" in our days. Klaus Joachim Zulch therefore may be regarded as neurologist ahead of his time trying to cover the epidemiologically important and frequent themes and establishing equal partnership with neurosurgery The connection with the scientific basis, i.e. morphology in different variations at the time under a common roof was crucial in his understanding of the work as neurologist.

Antibodies against two major gangliosides detected in human brain and brain tumors--Glac2 (GD3) and Gtri2 (GD2)--were tested by immunohistochemistry in an unselected sample of intracranial tumors during the years 1986 through 1991. Two groups emerged as evaluable samples, namely gliomas of different grades and meningiomas. In a pilot series, it was shown that these gangliosides could be visualized in frozen sections of cells of gliomas and meningiomas (as well as neurinomas) and in some structures of the normal brain. It was however not possible in frozen sections to further analyze the cellular or subcellular expression pattern of the mentioned components and paraffin sections with conventional processing were only weakly and diffusely stained. A modified protocol therefore was created that replaced alcohol processing by acetone. With this protocol, interpretable results in paraffin sections were obtained. With this method, 133 single intracranial tumors were investigated as to their immunohistologically detectable ganglioside expression. The most consistent result was that the whole cytoplasm of highly fibrillary (gemistocytic) astrocytes in all grades of gliomas was stained by Gtri2 (GD2) and Glac2 (GD3) with high preponderance of Gtri2 (GD2) expression. In all meningiomas, Glac2 (GD3) had a higher expression than Gtri2. No constant pattern in the other entities emerged. By comparison with GFAP expression in gliomas and vimentin in meningiomas, the colocalisation of gangliosides and intermediary filament proteins is supposed.

In the present study we investigated the susceptibility of high passages of the rat glial transplantation tumour G-XIII to chemotherapy using nitrosourea compounds. We observed a significant increase in lifespan (ILS) of animals treated with BCNU (37%, p0.01) and CCNU (27%, p0.01). There were no difference in the efficiency between these two substances. Using a semi-quantitative score system no histopathological changes were observed which were associated with the response to therapy. The only predicative parameter in the present study was the quantitative DNA distribution pattern. There was a close correlation between treatment and the occurrence of unimodal DNA distribution patterns indicating clonal regrowth of recurrent tumours. Moreover, we also observed a correlation of the DNA distribution pattern of recurrent tumours with the result of experimental chemotherapy. Survival times of animals suffering from tumours containing unimodal DNA histogram was significantly longer than survival times of rats with multimodal DNA distribution, i.e. bimodal or broad DNA histograms. A unimodal, near-diploid stem line was only present in treated animals suggesting that these clones are more resistant against therapy using nitrosourea compounds. Our data indicate DNA cytophotometry as comprehensive tool for the monitoring of therapy response and the design of experimental chemotherapy using rat glial tumours.

Summary Malignant neurinomas can be induced in BD IX rats by transplacental application of ethylnitroso-urea during pregnancy. Tumors develop in the offspring in trigeminal and spinal nerves and can be easily transplanted upon rats of the same strain. During the first passages a considerable shortening of subsequent induction periods takes place. Concurrently, silver stained Nucleolar Organizer Regions (AgNORs) increase in number and other measured AgNOR parameters change in a similar way. The number of cells that express the proliferation marker PCNA equally becomes more frequent during the first subcutaneously transplanted generations. There is high correlation between AgNOR parameters, number of PCNA expressing cells, induction times and passage. It is concluded that the first generations of the transplantation model of these tumors can be used to test the validity of proliferation indicators. Our results show further that AgNORs in fact belong to the group of markers of proliferation.

Hintergrund: Die Autoimmunhepatitis ist eine seltene Form der nicht viral bedingten Hepatitis. Zwei Typen sind bisher beschrieben worden. Die klassische lupoide Hepatitis (Typ I) ist gekennzeichnet durch erhohte γ-Globuline und das Vorkommen von Antikorpern gegen glatte Muskelzellen und von antinuklearen Antikorpern (ANA). Die Autoimmunhepatitis Typ II, welche durch das Vorkommen von “Antiliver/Kidney Microsomal Antibodies” Typ 1 (LKM 1) gekennzeichnet ist, zeigt haufig einen aggressiveren klinischen Verlauf als die Autoimmunhepatitis Typ I und geht in 41% der Falle mit anderen Autoimmunkerkrankungen einher. Fallbericht: Wir berichten uber eine 56-jahrige Patientin mit Evans-Syndrom (autoimmune Thrombozytopenie und hamolytische Anamie) sowie einer Autoimmunhepatitis Typ II. Die Todesursache war eine fatale Kombination von Gerinnungsstorungen bei Leberzirrhose mit einer ausgepragten autoimmunen Thrombozytopenie. Auch die Splenektomie, welche aufgrund ungenugender Wirksamkeit der immunsuppresiven Therapie durchgefuhrt worden war, fuhrte nur zu einem vorubergehenden Anstieg der Thrombozytenzahl. Interessanterweise kommen einige Befunde dieses Falles, wie das vorgerucktes Lebensalter und der Nachweis von HLA-DR4 und von Antikorpern gegen glatte Muskelzellen, uberwiegend bei der Autoimmunhepatitis Typ I vor. Schlussfolgerung: Eine begleitende zweite Autoimmunerkrankung kann die Prognose der Autoimmunhepatitis Typ II entscheidend verschlechtern. Eine Therapie mit Azathioprin und Prednisolon ist bei einem aggressiven Verlauf der Autoimmunhepatitis nicht ausreichend. Alternativpraparate aus der Transplantationsmedizin konnen im Rahmen multizentrischer Studien eingesetzt werden.

Summary Two monoclonal antibodies (mabs) were raised against ganglioside GD2 (Gtri2) and tested on human intracranial tumors and normal brain by immunohistochemical methods both in frozen and paraffin embedded sections. In normal brain structures, astrocytes were visualized with both mabs (BW 625 and BW 704) almost exclusively in the subventricular and subpial layer. A minor amount of myelin sheaths in well defined localisation was only recognized in frozen sections. Consequently in astrocytic tumors of different grades of malignancy (WHO I–IV), astrocytes were depicted in their characteristic shape and arrangement around vessels. In addition, staining was observed in meningiomas and schwannomas, but not in pituitary adenomas or metastatic carcinomas. In meningioma und schwannoma the staining was restricted to the cellular periphery and was again present in frozen section material and absent in paraffin embedded tissue. In astrocytes, reactive and neoplastic, obviously fibrous processes and cytoplasm were distinctly stained both in frozen and paraffin embedded sections. It is concluded that some neuroectodermal derived cells as well as myelin of defined localisation express GD2 on the membrane surfaces and in the cytoplasm. The latter may primarily be the case in fibrous astrocytes, which were stained in reactive and pathologic conditions. The reaction can be used as diagnostic tool in astrocytic tumors; its positive therapeutic significance is hampered by the fact that (1) not all cells in heterogeneous tumor populations express the epitope and (2) there are normal structures which do so. *) Abbreviations of Gangliosides were performed using the Svennerholm notation ( Svennerholm 1988). The notation of Wiegandt (1984) are given in brackets.

Human meninges and 29 meningiomas were analyzed as to their glycosphingolipid composition. In the neutral fraction GSL, a mostly even distribution of mono-, di-, tri-and tetrahexoside was demonstrated. In the group of the gangliosides, Glac 1 in one broad band in chromatogramms occurred in almost all meningiomas; Glac 2 was present in 84% of tumours. Members of the Gtri-family were only found in a small minority of tumours while various Gtet-gangliosides were detectable in nearly half of them. No constant pattern or patterns emerged and no correlation to either morphological subtype or malignancy grade could be established. Immunohistochemistry revealed focal presence of Glac 2 in a pattern similar to that of vimentin expression. Semiquantitative evaluation showed good correlation between both parameters.

Summary Contradictory results have been reported claiming either none, partial or almost complete correlation between the complexity of GSL compound profiles and the assumed glial tumor differentiation. Therefore an attempt was made to compare GSL patterns with both the general (final) tumor diagnosis and malignancy grade (WHO) as well as the regional evaluation of the histology and the grading in the tumor tissue pieces directly subjected to biochemical analysis. Regional and general (final) diagnosis did not always correspond, especially when more than one tissue sample of a given tumor was analyzed. Four GSL component patterns were identified by TLC: GSL-type I with gangliosides primarily of the simple G lac -family lacking sulfatide and the more complex G tri - and G tet -gangliosides, GSL-type II with ganglioside of the G lac - and G tri -families, also without sulfatide, and GSL-type III, with more complex gangliosides of the G tri and G tet -families in addition to G lac -gangliosides and sul fatide, similar to the normal brain pattern, and the pattern of normal brain. There was only insufficient correlation between these GSL-type patterns and final diagnoses. However, between regional diagnosis of astrocytoma II and GSL-type III on the one hand and glioblastoma multiforme IV and GSL-type I on the other hand, a coincidence of more than 85% was found. In only 50% the intermediate GSL-type II and glioma III were associated. There was no relation between GFAP or vimentin expression and histology or GSL-type both with regard to final and regional diagnoses. Regional astrocytoma architectures exhibiting GSL-type III were mostly fibrillary, whilst glioblastomas with GSL component pattern I had often a giant cell make up. In conclusion regional biochemistry must be compared with the corresponding regional histology and grading, disregarding the overall (general or final) diagnosis, which reflects the most essential or malignant tumor part. Then ganglioside component patterns can be correlated to malignancy grades. This allows the consideration of gangliosides as candidates for malignancy markers in human gliomas.

Serially transplanted experimental tumors of the central and peripheral nervous system can be used as models to investigate open questions in human neurooncology. Altered susceptibility of higher passages to chemotherapy might be correlated with chromosome number and DNA-content variations which would be partly expressed as changes in proliferation behaviour. Karyotypes therefore were analysed in the 73rd to 90th generations of transplanted experimental gliomas. Wide variation of chromosome number was observed; 2 major types of distribution occurred, the one presenting with, the other without stemlines. Large chromosomes # 1 and # 4 were often monosomic, while small chromosomes of ## 8 to 20 were increased up to the fivefold. Lines with prominent and few markers were observed. On the whole, cells of the proliferating pool of the tumor had to be considered as hypotetraploid. Comparison of chromosome numbers and DNA content gave good correlation; differences between the 2 were explained by the fact that only the number of chromosomes was taken into account, regardless of whether small or large chromosomes were lacking or in excess. When intracerebrally transplanted tumors had been previously treated by administration of BCNU, the DNA content was altered, indicating an increased share of diploid cells in the proliferation pool. Results are at variance with earlier findings in tissue cultures of directly induced malignant gliomas and neurinomas in rats. The findings in transplanted tumors can be interpreted as a result of increased malignancy in transplantation tumors, documented by rapid growth in the animal and dedifferentiated histologic morphology.

The purpose of the present study was to test whether the anticonvulsant, memantine (1-amino-3,5-dimethyladamantane), can protect neurons against hypoxic or ischemic damage. To this end, we used a rat model of transient forebrain ischemia and cultured neurons from chick embryo cerebral hemispheres. Ischemia was induced for 10 min by clamping both carotid arteries and lowering the mean arterial blood pressure to 40 mm Hg; the rats were allowed to recover for 7 days. Cultured neurons were made hypoxic with 1 mmol/l NaCN added to the incubation medium for 30 min followed by a recovery period of 3 days. The possible effects of memantine were compared with those produced by a typical non-competitive NMDA antagonist, dizocilpine. Similar effects were obtained with both drugs. The drugs reduced the damage caused by transient ischemia to neurons of the hippocampal CA1 subfield. Memantine (10 and 20 mg/kg) had a dose-dependent effect when administered intraperitoneally to the rats 1 h before ischemia. Dizocilpine was active in this model at a dosage of 1 mg/kg. When administered after ischemia, 10 mg/kg memantine significantly protected CA1 neurons against ischemic damage. Furthermore, the drugs protected cultured neurons against hypoxic damage. The lowest effective concentration was 0.1 mumol/l for dizocilpine and 1 mumol/l for memantine. Thus, memantine possesses neuroprotective activity but is less potent than dizocilpine.

Summary 35 tumors of brain, spinal cord and cranial and peripheral nerves were induced with ENU (ethyl-nitrosourea) in the offspring of treated BD-IX pregnant rats. 36 tumors – 35 of the nervous system, one nephroblastoma — were observed in 14 rats. With these results, the number of experimental nervous system tumors of the own collection induced in BD-IX rats and classified next to the rules of human neurooncology, amounts to 2,216. All 35 tumors of the nervous system were treated by a panel of immunohistochemical reactions comprising antibodies against cytoskeleton intermediary filaments such as GFAP (glial fibrillary acid protein), neurofilament proteins, vimentin and cytokeratins and some nervous system antigens such as NSE (neuron specific enolase), MBP (myelin basic protein) and S-100 protein. In central tumors, considered to be malignant gliomas, focal reactivity against vimentin and GFAP was found. Expression of other tested markers was weak or absent. In neurinoma of trigeminal and peripheral nerves, reativity to S-100 antigen was lacking, whilst there was strong reaction to the vimentin antigen.

In neurooncology transplanting, tumors can be used for many purposes e.g. to solve questions concerning the etiology and pathogenesis of such tumors or their management. Experimentally induced and transplanted tumors of the nervous system become reproducible in their morphology and growth parameters after about 12 subsequent intracerebral passages. During the period from the first to the 12th intracerebral generations, a simplification of the histology and a reduction of the induction times take place. Nowadays the growth behavior of such tumors can be followed by imaging methods such as MRI if specially adapted to small animals. Our results are based on the investigation of over 2350 experimentally induced tumors of the central and peripheral nervous system that were diagnosed according to the rules of human and rodent brain tumor classification and various subgroups of this sample, analyzed by electron microscopy, postmortal angiography and MRI.

Secretory meningiomas constitute a relatively rare subtype of meningiomas, accounting for only 1.1% at our institution, with a 6:1 predominance of female patients. This study aimed to obtain more information about the immunohistochemical characteristics of this histological entity, and to analyse the effects of histological factors such as the presence of mast cells on the radiological evidence of surrounding tumour oedema that frequently occurred in this subtype of meningioma. Fourteen cases of secretory meningioma were examined. Relevant clinical information was obtained from the patient files. Peritumoural oedema was determined either by CT or MRI scans and graded as small, moderate and severe. In order to perform the quantitative evaluation of mast cells in secretory meningiomas in a comparison with other meningiomas, 14 non-secretory meningiomas were randomly selected and used as a control group. The immunohistochemical staining of carcinoembryonic antigen was positive within the secretory droplets and the cells surrounding them in all cases. Ki 67 (MIB 1) proliferative index mean values were 2.4%, indicating low expression in all secretory meningiomas. Moreover, from our statistical analysis, there is no clear-cut pattern of various types of cytokeratins emerging in secretory meningiomas. The secretory meningiomas were characterized by a significantly increased number of mast cells as compared with non-secretory meningiomas of different grades. As the present clinical findings and laboratory results could not confirm a correlation between mast cell density and radiological evidence of oedema, further studies of mediators are warranted.

BACKGROUND AND PURPOSE: : Primary glioblastomas (GBMs) are highly radioresistant, and in contrast to secondary GBMs, they bear wild-type (wt) p53 protein, which is stabilized in a proportion of these tumors. Therefore, it was investigated in vivo whether p53 expression has prognostic value in patients undergoing radiochemotherapy. Additionally, the authors tried to identify, in vitro, subgroups of primary GBM with different susceptibilities to irradiation, on the basis of their p53 and p21 responses to ionizing radiation. MATERIAL AND METHODS: : Tumor tissue samples from 31 patients suffering from primary GBM undergoing a combined radiochemotherapy with topotecan were investigated. The percentage of cells expressing p53 protein was determined immunohistochemically. Additionally, primary cultures from eleven primary GBMs were established and investigated. p53 and p21 expressions were evaluated before irradiation with 10 Gy and at 2 and 8 h after irradiation. p53 protein expression was measured by Western analysis and p21 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: : The percentage of p53-positive cells within the tumor specimens obtained from the 31 patients ranged from 0% to 28%, the median value being 4.3%. No significant correlation with disease-free survival or overall survival was found. In vitro, p53 protein was detected in seven of eleven cultures from primary GBM. After irradiation a decrease in p53 protein expression was seen in six of the seven p53-positive cultures. Half of the cultures (two of four) without basal p53 expression showed an increase in p53 expression after irradiation. Basal overexpression of p21 was detected in six of the eleven cultures; in four out of six irradiation led to a decrease in p21 expression. In all cell lines (five of eleven) initially showing absent p21 expression, irradiation induced p21 expression. Despite these responses, G1 arrest was not detectable in any of the GBM cultures. CONCLUSION: : p53 protein expression in vivo does not correlate with the outcome of patients with primary GBM. Therefore, p53 protein content per se does not appear to be a helpful prognostic factor for prognosis-adapted therapy in primary GBM. By contrast, primary GBM cells in vitro show different and independent responses in their p53 and p21 pathways to ionizing radiation. The failure of G1 arrest seems to be due to a functional defect in the p53 pathway, either because p21 was not induced or because of an unidentified defect downstream from p21.

STUDY DESIGN A retrospective case of an isolated paramedullary hemangioblastoma originating from the first cervical root is reported. OBJECTIVE To describe an uncommon type of spinal hemangioblastoma and its operative treatment. SUMMARY OF BACKGROUND DATA Spinal hemangioblastoma, rare finding accounting for approximately 1.5% to 2.5% of all spinal cord tumors, may have an intramedullary, extramedullary, or extradural location. Cervical hemangioblastomas occur in approximately 45% of the cases and are intramedullary in about 83% of the cases. METHODS A 59-year-old man presented with acute subarachnoid hemorrhage in the basal cisterns. Four-vessel angiography showed a highly vascular small tumor at the dorsolateral side of the cervicomedullary junction fed by a branch of the vertebral artery. The lesion was surgically removed. RESULTS Total removal of the lesion was achieved after identification of both the arterial feeder and the draining vein with the aid of microvascular Doppler sonography. There were no complications, and the patient did well after surgery. CONCLUSIONS Although hemangioblastomas occurring in the cervicomedullary area usually may cause progressive neural compression, occasionally they also can present clinically as acute subarachnoid hemorrhage. This situation requires urgent and adequate treatment as in the reported case.

Intercellular junctions morphologically identical to epithelial desmosomes are known structures in meningiomas and arachnoidal tissue. Desmoplakin as one of the desmosomal plaque components has proven to be a reliable marker for diagnosis of meningeal tumors. Here we demonstrate by immunofluorescence microscopy, immunoblot and reverse transcription-PCR reactions that cells of arachnoidal tissue, of diverse meningioma subtypes and of a meningioma-derived cell line contain the full complement of the typical desmosomal proteins desmoplakin (DP), plakophilin 2 (PP2), desmocollin 2 (Dsc2) and desmoglein 2 (Dsg2). Consequently, all these molecules are suitable for diagnostic applications of meningioma tumors. In addition to these constitutive desmosomal components, representative for single-layered (simple) epithelia, the dural border cells of the arachnoid and about 60% of the meningiomas tested were positive for desmocollin 3 (Dsc3), a protein in epithelia taken as an indicator for differentiation.

Plasma coagulation, used in some neurosurgical operative settings, is currently under experimental investigation for the precise assessment of the kind and extent of tissue damage. We established a standardised trial to investigate the effects of helium (argon) plasma coagulation - H(A)PC - on rat brain tissue. The tissue reactions were observed with common methods of morphology including immunohistology and electron microscopy. A time dependent profile of the tissue reactions was performed from day 1 after operation up to 6 weeks. The tissue reaction consisted of clearly demarcated concentric zones. The depth of the lesion was about 1 mm maximally, at the beginning. Reparative forces acted at variance both in the different layers and at the edges versus the center of the damage. A manifold but reproducible picture emerges in the various compartments allowing the study of different aspects of organisation and/or elimination of tissue components. This study has demonstrated that a defined circumscribed and reproducible small lesion can be performed with H(A)PC. As in other areas of surgery, this technique has proven to be minimally traumatic. Clinical application of this technique in neurosurgery is therefore promising. In addition, H(A)PC lesions are obviously best suited for morphological studies of early and late reparative reactions in cells and tissues.

We report here that angiomatous meningioma exhibit elevated numbers of mast cells within their tissue architecture compared to most other meningioma subgroups, but similar to the so-called secretory variety of this tumour type. This finding might help to understand the development of the vascular component of this neoplasm and might equally be helpful in diagnosing such tumours, since diagnostic criteria are by no means clear: The (WHO-) definition of the entity states, that angiomatous meningioma is a tumour that exhibits numerous blood vessels on the background of a typical meningioma. But the quantitative aspect i.e. the percentage of vasculature required for this diagnosis is not specified. Our analysis of 27 angiomatous meningiomas revealed a mast cell density of 0.32 % of all tumour cells. This is a significant increase (α = 0.05, U-test) compared to an unselected sample of meningiomas of various, mostly endotheliomatous specimens (0.13 %). This finding relates angiomatous meningiomas to the similarly highly vascular secretory variant, that presents with an even higher percentage of mast cells (1.11 %). This latter subgroup, however, is well defined by the occurrence of secretory products, whereas angiomatous meningioma in other and our samples present with at least two morphological types, microvascular and macrovascular. Single cases of angiomatous as well as secretory meningiomas may therefore produce abundant intracranial edema. The microvascular subtype of angiomatous meningioma is very similar to the so-called mircrocystic variety of meningeal tumors. Thus, the similarity between both on one side (general morphology) as well as the common occurrence of mast cells, prominent vasculature and increased edema formation in angiomatous and secretory meningiomas raises the question of the rationale of meningioma subtyping. In this respect, descriptive morphological analysis may yield significant results.

The high pressure neurological syndrome (HPNS), a neurological condition during elevated pressure especially in deep diving, has been simulated with experimental animals. Rats were subjected to 61 bars with slow pressure increase and one or two hours constant high pressure; subsequently the pressure was released to sea level within 20 seconds--leading to immediate oxygen depletion and death of animals--or with slow decompression rates allowing survival. In all animals, brains and partly other organs were investigated morphologically. In animals sacrificed immediately, subtle changes in different brain regions were found: symmetrical occurrence of dark neurons in the hippocampus formation, cortex and brain stem, reduced expression of tyrosin hydroxylase in the substantia nigra and enhanced expression of Bax protein in some of these regions. The dark neurons were only observed after aldehyde fixation, otherwise the brains were unaltered despite ultrarapid decrease of highly elevated pressure. In animals that were allowed to survive for different time periods, some of these subtle changes were equally noted by light and electron microscopy. Furthermore, the ventricles were enlarged, the astrocytic reaction in the hippocampus increased and some signs of the destruction of the adrenal gland were visible. We conclude, that HPNS leads to minimal changes within the nervous system. The behaviour of animals during pressure was slightly altered, the weights after the experiments reduced, but no lasting sequelae were noted. Since both in human and experimental deep diving conditions signs of psychosis were reported, this HPNS model must be considered as a tentative animal model of human psychosis.

Glyycosphingolipids seem to be ideal markers of cellular proliferation and differentiation. The purpose of this study was to evaluate the correlation between distinct glycosphingolipid (GSL)-component profiles of human gliomas with survival time and histopathological malignancy grading.

HPNS (high pressure neurological syndrome) is considered to be reversible condition of the nervous system caused by elevated (atmospheric) pressure. Clinical observations and experimental findings gave rise to the belief that this syndrome at least partly functions as a model of a dopamin dependent psychosis. Morphological alterations during or after HPNS in man and animals have not been reported so far. We treated rats for three hours with an increasing pressure of helium-oxygen mixture up to 61 ATA in a pressure chamber. This pressure was subsequently maintained for one hour and then released to zero within twenty seconds. The rats died within the first three seconds of pressure release due to complete deoxygenation. Brains were immediately removed and either cooled in liquid nitrogen or fixed in formalin. In both instances the central nervous tissue was excellently preserved. In paraffin embedded formalin fixed specimens, dark neurons in different brain regions were found, especially within parts of the dentate gyrus, the CA 4 subfield of the ammons horn, in dopaminergic brainstem nuclei and in some cortical pyramidal cells. In dopaminergic cells, tyrosine hydroxylase was found to be absent in cells transformed into dark neurons. These dark neurons which have long been recognized in neuropathology, probably represent reversibly damaged neurons transformed into the dark configuration by aldehyde fixation. They may correspond to early apoptosis or they may be the consequence of cytoskeletal disruption.

Intracranial tumor classification is paralleled by a grading system that empirically compares tumor entities with "progression stages" of supratentorial gliomas of the adult. This grading system is an integral part of the WHO classification. Glioma progression has originally been defined by descriptive morphology. In this respect, morphological key features of high-grade gliomas (WHO grades III and IV) are microvascular proliferation and the formation of tumor necroses. Glioma progression is now more accurately defined on the molecular genetic level by a stepwise accumulation of oncogene activation and/or tumor suppressor gene inactivation. Angiogenesis occurs during development and progression of glial tumors. Pathological vessels are a hallmark of malignant glioma and it has therefore been suggested that malignant glioma cells are able to induce neovascularization. Despite the exuberant neovascularisation, however, vascular supply may not be sufficient for tumor areas with high cell proliferation, and necroses may develop. Malignant transformation of blood vessel itself is a rare event but may be the underlying mechanism of gliosarcoma development. The recently purified vascular endothelial growth factor (VEGF) is at present the only mitogen known to selectively act on endothelial cells. Growing evidence suggests that VEGF is the key regulator of developmental and pathological angiogenesis. In vivo, VEGF mRNA is upregulated in a subpopulation of malignant glioma cells adjacent to necroses. Since VEGF is hypoxia-inducible, hypoxia may be an important regulator of VEGF mRNA expression and tumor angiogenesis in vivo. Two tyrosine kinase receptors for VEGF are expressed in vessels which invade the tumor, suggesting that tumor angiogenesis is regulated by a paracrine mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary A morphometric analysis of constituents of the rat hippocampus was performed in the different hippocampal regions that are known to be vulnerable in various degrees to experimental global ischemia. In the hippocampus formation of the normal Fisher rat the number and areas of neuronal nuclei and of their constituents, nucleoli and AgNOR particles, were counted and measured. Nuclear and nucleolar size were different in the various parts of the Ammon's formation. AgNORs, i.e. silver stainable proteins that represent actively rRNA transscribing genes, equally varied in number and extension in the different hippocampal subfields. In granule cells of the dentate gyrus and in pyramidal cells of CA 1, CA 3 and CA 4, AgNORs usually occupy half of the nucleolar area. Using the determined values an estimate of the length and volume of the neuronal layers within the different parts of the rats Ammon's horn was performed. After the development of delayed ischemia all measured structures were significantly smaller despite the fact that only nuclei with well preserved outlines could be analysed. They represent only 5–10 % of controls. Nuclear sizes were reduced between 20 and 55 %. The strongest reduction was observed in the transition zone between CA 1 and CA 3, the least in CA 3. Nucleoli and AgNORs equally were considerably smaller than in normal cells. For AgNORs a skewed distribution to the left resulted, whereas the nuclear size had normally distributed shape with peak at lower values. We conclude that an architecture of both nucleoli and AgNORs exists in the hippocampal subfields in addition to the known cytological architecture. Under ischemic conditions, even the healthy looking cells remain damaged to a variable extent in the different subfields corresponding to their selective vulnerability. There are some indications that damage to nucleoli and AgNORs is earlier and stronger than to nuclei. A time course of AgNOR damage can be constructed.

Summary The model of experimental tumors of the nervous system has greatly contributed to our understanding of growth and management of intracranial tumors, but has been somewhat neglected in the last years, because a wealth of new data concerning oncogenic action came from viral oncogenesis. These new issues led to a much better insight into human tumor induction and promotion. Yet one example of the impact of oncogenic transformation stems from the “neurooncogenic” model: the discovery of the neu oncogene and its product as a putative differentiation receptor in the cell membrane of experimental Schwann cell derived tumors. In the light of this unique finding the history of the “neurooncogenic” model and the morphological and “clinical” result of tumors produced within the model are reviewed. There is a large open field for future investigation both in basic and applied science.

Three types of glycosphingolipid (GSL) component profiles have been established for human intracranial gliomas. GSL-type I shows only Glac- and lacto-series-sialoglycolipids. Type II consist of Glac- and Gtri-gangliosides, whereas only GSL-type III contains sulphatide and, as a major neutral glycolipid, galactocerebroside, besides gangliosides of the Glac-, Gtri-, and Gtet-families. Whole gliomas of malignancy grading I/II, III and IV, display GSL-Types III, II, and I, respectively. Thus, the GSL component distribution of the samples taken after surgery from three individual gliomas and two biopsies correlate closely with the general diagnosis of these tumours. Arthrobacter ureafaciens sialidase was used for the characterization of gangliosides. GSL-type analysis of multiple regional samples, taken from necropsy and biopsy, were determined by microanalysis of microscopic cryostat section, and shown to be in good agreement with their histology. The results validate the relevance of tumour ganglioside analysis for the characterization and diagnosis of gliomas.

42 cadaver brains in situ were examined endoscopically to work out topographical anatomical landmarks for orientation. The endoscopic route from the chosen precoronal trepanation point to the defined ventricular landmarks has been measured in 22 cases. The identification and measurements of the anatomical landmarks are helpful for safe and atraumatic endoscopical navigation within the ventricular system. Furthermore this article describes and discusses cerebral lesions during ventriculoscopy.

Endoscopy of the intracranial space requires a new understanding of the anatomy and pathology of pertinent structures. This meets with the new development of imaging methods which equally require three dimensional interpretation of intracranial pathology. The stereological arrangement of intracranial lesions is examplified on three neuropathological conditions: brain tumours, territorial infarction and mass displacement.

The spectrum of glycosphingolipids (GSL*) to be found on the outer surface of essentially every animal cell is exquisitely sensitive to that cell’s general biological status; it reflects whether the cell: comes from an insect or a mammal from a brain or from the blood and whether that cell is benign or malignant (1). The neutral glycosphingolipids as well as their acidic counterparts, the sulfatides and the gangliosides, all contribute to the cell surface’s biological and immunological identity. In most of the papers included in this volume very specific questions have been asked of transformed cells. Issues such as to the presence or absence of growth factor receptors on cells as well as the kinetic parameters of such receptors are certainly of importance for an understanding of malignant growth. Our approach, however, has been of a more general nature. We have restated and refined the question of how the glycosphingolipid composition of nervous tissue changes as tumors develop (2), and in particular, whether these changes could be exploited to increase the accuracy in the histological diagnoses of stereotactically removed brain tumor biopsies weighing less than a milligram.

The purpose of the present study was to investigate the neuroprotective action of nimodipine. Furthermore, the influence of nimodipine on postischemic local CBF (LCBF) was examined. Forebrain ischemia of the rat was performed for 10 min by bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain an MABP of 40 mm Hg. LCBF was measured after 10 min of postischemic recirculation by injecting [14C]iodoantipyrine in saline solution. Nimodipine (0.1, 0.3, and 1.0 mg/kg) was suspended in miglyol oil and applied orally 60 min prior to ischemia. Histological evaluation was performed 7 days after ischemia. Hippocampal neuronal damage was determined as the percentage of necrotic neurons. After preischemic application of nimodipine, neuronal damage was significantly reduced in the hippocampal CA1 subfield. Postischemic LCBF was not affected by treatment with nimodipine. These findings show that nimodipine is able to protect neurons against ischemic damage. The neuroprotective effect of nimodipine was not mediated by a postischemic cerebral vasodilation, but by a direct action on the neurons.

We investigated the effect of the known antagonist of platelet-activating factor (PAF), ginkgolide B, on postischemic neuronal damage in the rat. Neuronal necroses were evaluated in the hippocampus 7 days after a 10-min forebrain ischemia. Preischemic application of ginkgolide B (50 mg/kg p.o.) significantly reduced neuronal damage. It is suggested that the antagonism of PAF is responsible for this beneficial effect of ginkgolide B.

The effects of naftidrofuryl on postischemic neuronal damage and on local cerebral blood flow (LCBF) were examined in a rat model of forebrain ischemia (occlusion of carotid arteries and hypotension). Ischemia was induced for 10 min. LCBF was measured after 2 and 10 min of recirculation. A histological evaluation of cell loss in the hippocampal areas was performed 7 days after ischemia. Naftidrofuryl (10 mg/kg) was administered intraperi-toneally 15 min before ischemia. The drug reduced the percentage of necrotic neurons in the CA 1 and CA4 sector of the hippocampus, while the LCBF of these hippocampal sections was not significantly altered. Thus, naftidrofuryl is suggested to protect hippocampal neurons against ischemic damage mainly by a direct effect on brain parenchyma.

"Olfactory neuroblastoma" covers several types of esthesioneurogenic tumors such as esthesioneuroepithelioma, esthesioneuroblastoma and others. They are thought to be of olfactory mucosal origin and present with typical light microscopical "neurogenic features" e.g. rosettes and/or axon production. Some cases have been analyzed ultrastructurally and contained membrane bound granula like others tumors of the APUD system, originating from the neural crest. Furthermore neuronal differentiation of various degrees has been described. The human case of this contribution did not contain rosettes, but axons could be demonstrated in considerable number by silver impregnation. Electron microscopy could demonstrate the presence of dendritic processes with microtubuli and filaments as well as abundance of secretory granules of 1800 A. The comparison with the up to now published findings shows that the production of dense core granules is the most constant ultrastructural feature in these tumors; however, additional ultrastructural features in typical human cases as here presented, earlier experimental results and few human descriptions show, that DCV production is not essential for olfactory neuroblastoma. This might shed new light on the histogenesis of these tumors.

In this report the effects of phencyclidine (PCP) on physiologic variables, local cerebral blood flow (LCBF), and on hippocampal cell damage were measured in a rat model of forebrain ischemia (2-vessel occlusion and hypotension). Ischemia was induced for 10 min. LCBF was determined after 2 min of recirculation, using the [14C]iodoantipyrine technique. Hippocampal cell loss was quantified histologically 7 days postischemia as the percentage of acidic stainable neurons. Intravenous application of PCP (2 mg/kg) at 15 min prior to ischemia left postischemic LCBF unchanged, but neuronal damage was significantly reduced in hippocampal CA1 sector from 46 to 15.7%. PCP is concluded to reduce ischemic damage of neurons mainly via a direct effect on brain tissue.

The most well known brain tumour models will be discussed. It is a series of animal experiments with an induced tumour and with heterologous and homologous transplantation. This work will deal especially with technical problems, which have not so far been satisfactorily resolved. With the aid of a stereotaxic operation method, the exactness of the technique of transplantation could be improved. The tumour contamination problem of the injection pathway as well as of the cerebral spinal fluid compartment is satisfactorily resolved. The authors have at their disposal a standardized cerebral glioma model in the rat in order to study the interstitial chemotherapy of brain tumours.

Summary Two models of experimental cerebral ischemia in rats were developed and used. The first model was permanent occlusion of both carotids up to 3 weeks, the second model the temporal occlusion of both carotids and systemic hypotension for 10 min. Rats treated by the first experimental set were investigated after one, 2 and 3 weeks. In all groups, about 40% of so treated animals had territorial infarcts, often more than one in the animal in question. These infarcts developed from necrotic, pale areas to ischemic cysts and this copied the evolution of human territorial infarction. Astroglial reaction was only seen in the border zone. In the second model, rats preferentially developed, as known, the so called delayed ganglion cell necrosis in the field CA 1 of the hippocampus. Cells were not altered on the second, but damaged on the sixth day after experimental ischemia. In both models the hippocampus was damaged, however in the first the damages were morphologically distinct from the damage in carotid occlusion in systemic hypotension. The first experimental model suits better for human territorial infarction, the second is highly reproducible and thus provides a much better experimental tool.

Summary Transplanted tumor lines are useful to study open questions in human pathology and clinical research, particularly with the evaluation of therapeutic measures. Transplantation tumor lines derived from neoplasms in the nervous system originally induced with resorptive carcinogens are considered to be useful for these purposes. In this study observations on the histological pattern of original and intracerebrally transplanted new induced spinal cord tumors, mainly in early passages, has been investigated with the aim to improve the usefulness of the experimental model.

Summary Tumors were induced in experimental animals in order to investigate early tumor growth with conventional histology and gliofibrillary acid protein (GFAP) demonstration with the peroxidase-antiperoxidase (PAP) method. In one experiment, the animals were killed after transplacental ENU administration, when microtumors were suspected; in the second experiment, the animals were followed up to their natural death and microtumors found at random were used for analysis. Conventional histology revealed 3 types of microtumors: growth restricted to the subventricular matrix, growth in the neighbourhood of the ventricles with obvious or probable connection to the ventricular zones and small tumors observed exclusively in the white matter. The latter tumors by conventional staining were composed of small round cells, considered to be oligodendrocytes. They did not contain GFA-protein positive cells within the tumor. The tumor in presumable and visible connection with the ventricular lining did contain GFAP-positive astrocytes. In the very small subventricular tumors, the small round cells (oligodendrocytes) were in continuous contact with the identical interfascicular glial cells, while GFAP positive astrocytes seemed to stem from the subventricular astrocytes (tanycytes, ependymoglia). The ependyma itself was always preserved. A twofold origin of these experimental tumors with probable development into one common cytological glial type is assumed.

In previous studies the calcium entry blocker flunarizine has been demonstrated to reduce hippocampal cell damage following forebrain ischemia in the rat (1–3). The purpose of the present investigation was to evaluate whether the phenylalkylamine derivative emopamil also could prevent neuronal cell loss following ischemia. A variety of calcium entry blockers including flunarizine and emopamil has on the other hand been shown to faster restore postischemic high-energy phosphate levels in the isolated perfused rat brain (4). The present study therefore aimed at evaluating whether cellular protection by calcium entry blockers might be associated with an improved energy metabolism during early recovery.

Tumors induced by transplacental action in the spinal cord of rats were transplanted into the brains of the same rat strain. They were followed up by electron microscopy during the first ten passages. Three architectural features were detected: First pure tumor parts, second myelin breakdown and phagocytosis, and third the resulting accumulation of resting macrophages. Architecture two and three were interpreted as result of considerable phagocytotic activity of tumor cells localized within the white substance of the brain and spinal cord. Only architecture one was considered to represent proper tumor. Since this was low differentiated and partial astrocytic differentiation only occurred around vessels to remarkable extent, the thesis is put forward that these transplacentally induced tumors correspond to human primitive neuroectodermal tumors.

The effects of the calcium entry blocker emopamil on physiological variables, local cerebral blood flow (LCBF) and on hippocampal cell damage were evaluated after 10 min of forebrain ischemia in the rat. LCBF was determined with the 14C-iodoantipyrine technique after 2, 10, and 60 min of postischemic recirculation. Histological evaluation was performed 7 days after ischemia in cortical and hippocampal tissue by determination of the percentage of necrotic neurons. Preischemic application of emopamil [4 mg/kg racemate or 2 mg/kg (S)-emopamil; i.v.] caused increases in LCBF in cortical areas but did not alter blood flow in the hippocampus at 2 min of recirculation. After 10 and 30 min of flow resumption no differences in LCBF between drug-treated and control animals were observed. In the histological series (S)-emopamil was applied at doses of 2, 4 or 6 mg/kg before the induction of ischemia. After 7 days of postischemic recovery, neuronal damage was significantly reduced by the calcium antagonist in hippocampal CA 1 sector at all doses tested, the most prominent effects being observed with the lowest dose. At this dose cell loss in the Ca3 sector was also reduced. In cortical tissue the number of necrotic cells remained unchanged by emopamil treatment. It is concluded that the calcium antagonist emopamil can reduce ischemia-induced neuronal cell damage. The compound improves circulation in cortical tissue only during early recovery but not at later phases of reflow, i.e. the period of delayed hypoperfusion. These increases in blood flow are not of crucial importance for ultimate neuronal death in this area. The ameliorative action of emopamil on the survival of hippocampal neurons is not associated with blood flow changes and therefore seems to reflect a direct effect on cerebral parenchyma.

It has been pointed out in numerous papers [4, 6, 7,18,19] that the disturbed calcium homeostasis plays a pivotal role in the pathogenesis of neuronal cell damage caused by ischemia. Calcium ions can fulfill their function as second messengers only when the cytosolic concentration of free Ca2+ is maintained at a level of approximately 10−7mol/l whereas the extracellular concentration of Ca2+ is around 10−3 mol/l.

The effects of vinpocetine on hippocampal cell damage and local cerebral blood flow (LCBF) were measured in a rat model of forebrain ischemia (2-vessel occlusion and hypotension). Duration of ischemia was 10 min. LCBF was determined after 2 min of recirculation using the 14C-iodoantipyrine technique. Hippocampal cell loss was quantified histologically 7 days post-ischemia. Intraperitoneal application of vinpocetine (10 mg/kg) 15 min prior to ischemia significantly reduced neuronal cell loss in hippocampal CA 1 sector from 60% to 28%. The drug led to a marked increase in blood flow in cortical areas, whereas LCBF remained unchanged in hippocampus and all other structures measured. It is suggested that the protective effect of vinpocetine does not depend on increased postischemic blood flow.