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Treatment of meningiomas refractory to surgery and irradiation is challenging and effective chemotherapies are still lacking. Recently, in vitro analyses revealed decitabine (DCT, 5-aza-2’–deoxycytidine) to be effective in high-grade meningiomas and, moreover, to induce hypomethylation of distinct oncogenes only sparsely described in meningiomas in vivo yet.Expression of the corresponding onco- and tumor suppressor genes TRIM58, FAM84B, ELOVL2, MAL2, LMO3, and DIO3 were analyzed and scored by immunohistochemical staining and RT-PCR in samples of 111 meningioma patients. Correlations with clinical and histological variables and prognosis were analyzed in uni- and multivariate analyses.All analyzed oncogenes were highly expressed in meningiomas. Expression scores of TRIM58 tended to be higher in benign than in high-grade tumors 20 vs 16 (p = .002) and all 9 samples lacking TRIM58 expression displayed WHO grade II/III histology. In contrast, median expression scores for both FAM84B (6 vs 4, p ≤ .001) and ELOVL2 (9 vs 6, p DIO3 expression was distinctly higher in all analyzed samples as compared to the reference decitabine-resistant Ben-Men 1 cell line. Increased ELOVL2 expression (score ≥ 8) correlated with tumor relapse in both uni- (HR: 2.42, 95%CI 1.18–4.94; p = .015) and multivariate (HR: 2.09, 95%CI 1.01–4.44; p = .046) analyses.All oncogenes involved in DCT efficacy in vitro are also widely expressed in vivo, and expression is partially associated with histology and prognosis. These results strongly encourage further analyses of DCT efficiency in meningiomas in vitro and in situ.

Synchronous or metachronous growth of multiple tumors (≥ 2) is found in up to 20% of meningioma patients. However, biological as well as histological features and prognosis are largely unexplored. Clinical and histological characteristics were retrospectively investigated in 95 patients harboring 226 multiple meningiomas (MMs) and compared with 135 cases of singular meningiomas (SM) using uni- and multivariate analyses. In MM, tumors occurred synchronously and metachronously in 62% and 38%, respectively. WHO grade was intra-individually constant in all but two MMs, and histological subtype varied in 13% of grade 1 tumors. MM occurred more commonly in convexity/parasagittal locations, while SM were more frequent at the skull base (p p = .014) and high-grade histology in MM were associated with a prolonged time to progression (p p ≥ .05, each). Multivariate analyses showed synchronous/metachronous meningioma growth (HR 4.50, 95% CI 2.26–8.96; p p = .224), but exponentially raised in patients with 3–4 (HR 3.25, 1.22–1.62; p = .018) and ≥ 5 tumors (HR 13.80, 4.06–46.96; p

Risk factors to predict late-onset tumor recurrence in meningioma patients are urgently needed to schedule control intervals during long-term follow-up. We therefore analyzed the value of established risk factors for postoperative meningioma recurrence for the prediction of long-term prognosis. Correlations of clinical and histopathological variables with tumor relapse after 3, 5, and 10 years following microsurgery were analyzed in uni- and multivariate analyses, and compared to findings in the entire cohort. In the entire cohort (N = 1218), skull base location (HR: 1.51, 95%CI 1.05–2.16; p = .026), Simpson ≥ IV resections (HR: 2.41, 95%CI 1.52–3.84; p p p = .042) were independent risk factors for recurrence. Skull base location (HR: 1.92, 95%CI 1.17–3.17; p = .010 and HR: 2.02, 95%CI 1.04–3.95; p = .038) and high-grade histology (HR: 1.87, 95%CI 1.04–3.38; p = .038 and HR: 2.29, 95%CI 1.07–4.01; p = .034) but not subtotal resection (HR: 1.53, 95%CI .68–3.45; p = .303 and HR: 1.75, 95%CI .52–5.96; p = .369) remained correlated with recurrence after a recurrence-free follow-up of ≥ 3 and ≥ 5 years, respectively. Postoperative tumor volume was related with recurrence in general (p p > .05). In 147 patients with a follow-up of ≥ 10 years, ten recurrences occurred and were not correlated with any of the analyzed variables. Skull base tumor location and high-grade histology but not the extent of resection should be considered when scheduling the long-term follow-up after meningioma surgery. Recurrences ≥ 10 years after surgery are rare, and predictors are lacking.

The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent potentially previously misclassified adenoid cystic carcinomas. Our findings can aid in improving the diagnostic classification of sinonasal tumors and could help to change the current perception of SNUCs.

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E−10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E−7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.

Exact histological clot composition remains unknown. The purpose of this study was to identify the best imaging variables to be extrapolated on clot composition and clarify variability in the imaging of thrombi by non-contrast CT. Using a CT-phantom and covering a wide range of histologies, we analyzed 80 clot analogs with respect to X-ray attenuation at 24 and 48 h after production. The mean, maximum, and minimum HU values for the axial and coronal reconstructions were recorded. Each thrombus underwent a corresponding histological analysis, together with a laboratory analysis of water and iron contents. Decision trees, a type of supervised machine learning, were used to select the primary variable altering attenuation and the best parameter for predicting histology. The decision trees selected red blood cells (RBCs) for correlation with all attenuation parameters (p

Atypical teratoid/rhabdoid tumors (ATRT) are highly malignant brain tumors arising in young children. The majority of ATRT is characterized by inactivation of the chromatin remodeling complex member SMARCB1 (INI1/hSNF5). Little is known, however, on downstream pathways involved in the detrimental effects of SMARCB1 deficiency which might also represent targets for treatment. Using Drosophila melanogaster and the Gal4-UAS system, modifier screens were performed in order to identify the role of SMAD dependent signaling in the lethal phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. Expression and functional role of human homologs was next investigated in ATRT tumor samples and SMARCB1-deficient rhabdoid tumor cells. The lethal phenotype associated with snr1 knockdown in Drosophila melanogaster could be shifted to later stages of development upon additional knockdown of several decapentaplegic pathway members including Smox, and Med. Similarly, the transforming growth factor beta (TGFbeta) receptor type I kinase inhibitor SB431542 ameliorated the detrimental effect of snr1 knockdown in the fruit fly. Examination of homologs of candidate decapentaplegic pathway members in human SMARCB1-deficent ATRT samples revealed SMAD3 and SMAD6 to be over-expressed. In SMARCB1-deficent rhabdoid tumor cells, siRNA-mediated silencing of SMAD3 or SMAD6 expression reduced TGFbeta signaling activity and resulted in decreased proliferation. Similar results were obtained upon pharmacological inhibition of TGFbeta signaling using SB431542. Our data suggest that SMAD dependent signaling is involved in the detrimental effects of SMARCB1-deficiency and provide a rationale for the investigation of TGFbeta targeted treatments in ATRT.

The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade MPNST, three malignant Triton tumors, six low-grade MPNST, four epithelioid MPNST, 33 neurofibromas (15 dermal, 8 intraneural, 10 plexiform), six atypical neurofibromas, 43 schwannomas (including 5 NF2 and 5 schwannomatosis associated cases), 11 cellular schwannomas, 10 melanotic schwannomas, 7 neurofibroma/schwannoma hybrid tumors, 10 nerve sheath myxomas and 10 ganglioneuromas. Schwannomas formed different epigenomic subgroups including a vestibular schwannoma subgroup. Cellular schwannomas were not distinct from conventional schwannomas. Nerve sheath myxomas and neurofibroma/schwannoma hybrid tumors were most similar to schwannomas. Dermal, intraneural and plexiform neurofibromas as well as ganglioneuromas all showed distinct methylation profiles. Atypical neurofibromas and low-grade MPNST were indistinguishable with a common methylation profile and frequent losses of CDKN2A. Epigenomic analysis finds two groups of conventional high-grade MPNST sharing a frequent loss of neurofibromin. The larger of the two groups shows an additional loss of trimethylation of histone H3 at lysine 27 (H3K27me3). The smaller one retains H3K27me3 and is found in spinal locations. Sporadic MPNST with retained neurofibromin expression did not form an epigenetic group and most cases could be reclassified as cellular schwannomas or soft tissue sarcomas. Widespread immunohistochemical loss of H3K27me3 was exclusively seen in MPNST of the main methylation cluster, which defines it as an additional useful marker for the differentiation of cellular schwannoma and MPNST.

IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional glioblastoma (GBM), and 15/160 (9 %) as GBM-H3F3A mutated (GBM-H3). 13/160 (8 %) exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78 %) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse. Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. The diagnosis of IDHwt diffuse astrocytoma or anaplastic astrocytoma should be used with caution.

Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations, while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in situ hybridization addressing surrogates for the molecular genetic markers IDH1R132H, TP53, ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co-deletion. In 31/43 OA, only alterations typical for oligodendroglioma were observed, while in 11/43 OA, only indicators for mutations typical for astrocytomas were detected. A single case exhibited a distinct pattern, nuclear expression of p53, ATRX loss, IDH1 mutation and partial 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly contributing to the acquisition of this uncommon combination. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive, while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic. These data provide strong evidence against the existence of an independent OA entity.

The differential diagnosis of lymphoid lesions in the central nervous system covers a broad spectrum of neoplastic and inflammatory disorders. Complex cases benefit from the combined expertise in the fields of hematopoietic and neuroepithelial tumors as well as neuroimmunology. The Network Lymphomas and Lymphomatoid Lesions in the Nervous System (NLLLN) recommends performing a biopsy prior to any therapeutic intervention as a precise diagnosis was impossible in approximately 50 % of patients pretreated with corticosteroids. This is based on the analysis of approximately 1,000 cases in the past 4 years. In addition to total NLLLN experiences the characteristics, pathogenesis and differential diagnosis of primary lymphoma of the central nervous system are discussed.

Choroid plexus carcinomas are malignant brain tumors predominantly arising in young children. Because a prognostic role of p53 alterations has been demonstrated, further research into potential underlying mechanisms is essential. Our objective was, therefore, to investigate the role of p53 in the growth-inhibitory potential of a variety of anticancer agents in the rodent choroid plexus epithelial cell line Z310. Furthermore, association of p53 alterations with proliferative activity (Ki67/MIB1) in choroid plexus carcinoma samples (N = 20) was examined by use of immunohistochemistry. Silencing of TP53 expression did not significantly alter metabolic activity in Z310 cells and p53 protein expression status was not associated with increased proliferative activity in choroid plexus carcinomas. However, the growth-inhibitory activity of vincristine, doxorubicin, carboplatin, etoposide, and temozolomide was significantly impaired by silencing of TP53. In conclusion, these results indicate a potential predictive role of p53 in choroid plexus carcinomas. Alterations of p53 should be taken into account when evaluating the effect of anticancer agents in future clinical trials.

Professor Kurt Jellinger is, without any doubt, one of the most eminent neuropathologists of our current times. Born in Vienna, Austria, on May 28, 1931 to Rosa and Alois Jellinger (Fig. 1), he studied medicine at the Medical Faculty of the University of Vienna and received his promotion to Dr. med. univ. ‘‘sub auspiciis praesidentis’’ in April 1956. His primary medical training was in clinical neurology to become a board-certified neurologist in 1963. In parallel, he was trained in neuropathology at the Neurological Institute of the University of Vienna (Fig. 2) under the guidance of Franz Seitelberger. Following his promotion to reader for Neurology, Neuropathology and Neuroanatomy at the University of Vienna in 1967, he became Head of the Neuropathological Department of the Neurological Institute and a.o. University Professor for Neuropathology in 1973. His high international reputation resulted in several international offers to take over full Professorships in Germany (Dusseldorf) and the United States (Miami, Cleveland), which he all declined. Instead, he decided to accept the position as Head of the Department of Neurology at the Viennese Municipal Hospital Lainz in 1976 and the Directorship of the Ludwig Boltzmann Institute for Clinical Neurobiology, located in the same building (1977). He held both positions until his retirement in the 1990s. Kurt Jellinger is an outstanding member of many scientific societies and he continues to be among the most active participants of important scientific meetings (Fig. 3). He co-organized the First European Congress of Neuropathology in Vienna in 1980 and the 9th International Congress of Neuropathology in Vienna in 1982, serving as Vice President of the International Society of Neuropathology from 1981 to 1984. Being highly respected in both neuropathology and neurology, he was President of the Austrian Society of Neurology and Psychiatry (1990–1992) and President of the Austrian Society of Neuropathology (1994–1998). Needless to say that Kurt Jellinger has been elected an honorary member of several national and international societies. Kurt Jellinger’s contributions to neuropathological science are enormous. The ISI Web of Knowledge reports 698 papers with an h-index of 71 and an average number of citations of 32.5, 50 of his publications being citation classics receiving more than 100 citations so far, the most prominent ones being related to Alzheimer’s and Parkinson’s diseases. This is supplemented by a large number of additional publications in conference proceedings and book chapters. Thus, his predominant focus of research is in the area of neurodegenerative diseases. However, this gives only an incomplete impression of his scientific activity. There is virtually no field of neuropathology that is not covered by fundamental publications of Kurt Jellinger, including neuroanatomy, neurotraumatology, vascular diseases, infectious diseases of the nervous system, multiple sclerosis, developmental disorders of the brain, and H. Lassmann Center for Brain Research, Medical University of Vienna, Vienna, Austria

Overexpression of MET and polysomy 7 was formerly demonstrated in chordomas. We investigated mesenchymal-epithelial transition factor (MET) protein expression and copy numbers of chromosome 7 in human chordomas. Furthermore, tumors were screened for gene fusions (PAX3-FKHR, ASPL-TFE3, and SYT-SSX) previously shown to be associated with MET activation in sarcomas. Tissue microarrays (TMAs) were constructed from 66 chordoma samples. MET protein expression was assessed by immunohistochemistry using an immunoreactive score (IRS, scores 0-12). fluorescence in situ hybridization (FISH) with a dual-color DNA probe (7q31) for MET amplification was performed on TMA sections and RT-PCR for PAX3-FKHR, ASPL-TFE3 (type 1 + 2), and SYT-SSX (type 1 + 2) gene fusions on punch biopsies. All tumors (n = 66) expressed MET protein. FISH analysis of 33 tumors lacked MET gene amplification but showed polysomy of chromosome 7 in 15 (45.5%) tumors (13 low and two high polysomies). Although, polysomy 7 showed an increasing incidence with escalating MET IRS, this finding was not statistically significant. PAX3-FKHR, ASPL-TFE3, or SYT-SSX gene fusions were not demonstrable (n = 52). We found MET protein expression in all chordomas. A clear influence of polysomy 7 on MET protein expression could not be statistically demonstrated for this cohort. Moreover, gene fusions with the ability to cause MET overexpression do not occur in chordomas.

Glioma-cell migration is usually assessed in dissociated cell cultures, spheroid cultures, acute brain slices and intracranial implantation models. However, the interactions between migrating glioma cells and neuronal tracts remain poorly understood. We describe here a protocol for the coculture of glioma cells with myelinated axons in vitro. Unlike other methods, this protocol allows the creation of in vitro conditions that largely mimic the complex in vivo environment. First, long retinal axons from embryonic chicken are formed in an organotypic culture. Glioma cells are then positioned in the vicinity of the explants to allow them to contact the axons, interact with them and eventually migrate along them. High-resolution video microscopy and confocal microscopy can be used to monitor the migratory behavior. This protocol, which takes about 5 days to complete, could be applied to different types of tumor cells that interact with neurites, and is suitable for pharmacological and genetic approaches aimed at elucidating mechanisms underlying tumor migration.

Brain tumors account for approximately 20% of all childhood cancers, and are the leading cause of cancer morbidity and mortality among children. Although numerous demographic, clinical and therapeutic parameters have been identified over the past few years that have significant prognostic bearing for some pediatric brain tumors, predicting the clinical course and outcome among children with central nervous system tumors is still difficult. A survey of publications on prognosis-related histopathological and immunohistochemical features among pediatric brain tumors revealed 172 series, of which 91 presented statistically significant outcome-associated parameters as defined by a P value of less than 0.05. Most investigations revealing significant prognosis-related markers were performed on medulloblastomas (30 publications), ependymomas (25) and astrocytic tumors (18). In total, 16 cohorts consisted of more than 100 cases (5 on ependymomas, 3 each on medulloblastomas and astrocytic tumors). On the other hand, there were also 13 series with fewer than 20 cases (5 on medulloblastomas). Potentially prognostic histopathological markers vary among different entities and consist of assessment of necroses, mitoses, differentiation, vascular proliferation, and growth pattern, whereas immunohistochemical features include proliferation markers (Ki-67, MIB-1), expression of oncogenes/tumor suppressor genes and their proteins (TP53, c-erbB2), growth factor and hormonal receptors (VEGF, EGFR, HER2, HER4, ErbB-2), cell cycle genes (p27, p14ARF) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the prognostic potential of histopathological and immunohistochemical markers that can be investigated by the practicing neuropathologist as part of the routine diagnostic workload, and scrutinizes their benefit for predicting therapy response and patient outcome among children with brain tumors.

The blood-brain barrier (BBB), mediated by endothelial tight junctions, is defective in malignant gliomas such as glioblastoma, resulting in cerebral edema and contrast enhancement upon neuroradiological examination. The mechanisms underlying BBB breakdown are essentially unknown. Since non-neoplastic astrocytes are required to induce BBB features of cerebral endothelial cells, it is conceivable that malignant astrocytes have lost this ability due to dedifferentiation. Alternatively, glioma cells might actively degrade previously intact BBB tight junctions. To examine the latter hypothesis, we have employed a transepithelial electrical resistance breakdown assay using monolayers of the C7 subclone of Madin-Darby canine kidney (MDCK-C7) cells forming tight junctions similar to those of BBB endothelial cells. We found that glioblastoma primary cells co-cultured with the MDCK-C7 monolayer (without direct contact of the two cell types) resulted in marked breakdown of electrical resistance, whereas primary cultures derived from low-grade gliomas (fibrillary astrocytoma, oligoastrocytoma) showed delayed or no effects. These results suggest that malignant gliomas have acquired the ability to actively degrade tight junctions by secreting soluble factors, eventually leading to BBB disruption within invaded brain tissue.

Despite a decline in the overall rate of sudden infant death syndrome (SIDS), it remains the leading cause of postneonatal infant mortality. Research into underlying mechanisms of SIDS has still not yielded a morphological, histopathological correlate explaining aetiology and pathophysiology of an infant's sudden death. Of particular interest would be elucidating pathophysiological and molecular events immediately preceding the infant's sudden death. C-jun is an immediate early gene with a physiological role in orchestrating cellular responses following injury including a role in cell death. It is also one of the earliest and most consistent markers for neurons undergoing stress, degeneration and survival. We investigated the immunohistochemical expression of the acute phase protein c-jun within 47 separate cerebral regions of interest in the brains of 23 SIDS and 7 control cases for evidence of acute neuronal injury immediately preceding sudden death and to assess the distribution of cellular damage suggestive of pathophysiologically sensitive or critical cerebral regions. Dividing SIDS-cases and controls into subgroups with (1) no neuronal expression of c-jun at all or (2) some c-jun expression, a statistically significant higher c-jun expression for SIDS compared with control cases was established for the inferior colliculi ( P=0.008), the spinal trigeminal nuclei ( P=0.046) and the premotoric cortex layers II and IV ( P=0.029). The increased expression of c-jun in these areas might be directly related to the pathogenesis of sudden death, or may represent a secondary marker of neuronal injury with the primary event/injury being elsewhere in critical cardioventilatory circuits.

Case report. We present the first application of comparative genomic hybridisation (CGH) in fetal brain tumours in the case of a fetal immature teratoma. The tumour was discovered in a female fetus at 22 weeks gestation after presentation with significant craniomegaly of such degree that the head size measured by sonography was found to correspond to a gestational age of 37 weeks, and the pregnancy was terminated. Results. Neuropathological examination showed an immature teratoma measuring 1.7×1.6×0.5 cm and containing tissue from all three germinal layers. CGH was successfully performed and, in contrast to earlier results in both cerebral and extracerebral teratomas also investigated with the same technique, it revealed no chromosomal imbalances. Conclusion. This indicates that mono- or trisomies did not have a role in the pathogenesis in this particular case and that a fetal immature teratoma may contain aberrations smaller than the detection threshold of CGH. However, it remains to be seen in larger cohorts whether fetal teratomas follow a different pathogenetic pathway and may be triggered by different molecular events than teratomas occurring in later life.

We present the case of a 10-year-old girl with cardiomyopathy who received a heart transplant. Due to organ rejection, the dosage of immunosuppressive agents was increased postoperatively. The patient complained of intermittent headaches in the following days and developed a haemorrhagic necrosis of the left thalamus. A week later, an oral dose of cyclosporin A was accidentally given intravenously, and 2 weeks later a recurrent subarachnoid haemorrhage of unknown origin was diagnosed. The clinical course was then characterised by progressive deterioration resulting in coma, fluctuating brain stem symptoms and the development of a massive cerebral oedema with subsequent brain death. A coroner's autopsy was instigated to investigate a claim of medical misadventure. Neuropathological investigations found a focal infiltration of fungal hyphae in the left posterior cerebral artery resulting in necrosis of the vascular wall and thus explaining the source of the recurrent subarachnoid haemorrhage which eventually resulted in the girl's death. Medical misadventure due to the administration of cyclosporin was not directly responsible for the death of this patient. This case illustrates that it is of paramount importance to copiously sample and investigate the basal cerebral arteries in cases of subarachnoid haemorrhage of unknown origin, in particular in a medico-legal context.

Seven granular cell tumours (GCT) were studied by comparative genomic hybridisation. These consisted of two cerebral and one pituitary GCT as well as four other central nervous system tumours predominantly composed of granular cells (one glioblastoma, meningioma, ganglioglioma and neurinoma each). DNA copy number changes were found in four of seven tumours. Overall, losses (mean: 1.0 per tumour) were more frequent than gains (mean: 0.6 per tumour) and no high-level gains were found. The only DNA copy number change found in two tumours (both cerebral GCT) was loss of 13q21, while the other nine aberrations were only encountered once each: the granular cells of one cerebral GCT additionally showed +1p32-pter, +9q33-qter, +20q, -4, and -18q, of the glioblastoma +7 and -10, and of the meningioma -1p and -22q, while the pituitary GCT, the ganglioglioma and the neurinoma showed no imbalances. Our data suggest that a variety of genetic changes are associated with granular cell formation and support the notion that GCT are not a distinct tumour entity characterised by specific chromosomal imbalances but rather a degenerative phenomenon of cells of various origin showing DNA copy number changes akin to the underlying tumour.

Meningeal melanocytoma is a rare benign neoplasm of the central nervous system. Approximately 50% of the tumors are located intracranially with a preference for posterior fossa. We report a new case of intracranial suprasellar melanocytoma in a 57-year-old male patient treated with primary high-dose conformal radiotherapy to 50.4 Gy. Fourty-two months subsequent to treatment the tumor is well under control without neither deterioration of clinical symptoms nor progression of gross tumor volume on MR imaging. No late sequelae of treatment have been observed. A review of the literature is presented indicating that resection of melanocytoma is the treatment of first choice hampered by a relapse rate of approximately 30% depending on resection status. The role of adjuvant radiotherapy in patiens with complete resection of melanocytoma has not yet been defined. These patients carry a risk of relapse of approximately 15%, and adjuvant irradiation is currently not recommended. Primary high-dose radiotherapy has been shown to be effective in long-term control of the neoplasm in patients where no resection of the tumor could be accomplished. In case of incomplete resection of melanocytoma, data of the literature indicate that adjuvant radiotherapy may in fact increase long-term local control of the tumor. Requirements for optimal treatment results of radiotherapy are sufficiently high doses of, at least, 50 Gy for intracranial lesions and three-dimensional treatment planning guaranting precise targeting of the tumor volume with only a low-risk of late sequalae to the surrounding tissues.

Background Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients. Methods Using a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences. Results Increasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis. Conclusions Even taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation. peerReviewed

We present three cases of Raine syndrome occurring in siblings of consanguineous parents. Raine syndrome is characterised by generalised osteosclerosis with craniofacial anomalies and intracranial calcifications. So far, only nine cases have been reported, and no evaluation of the distribution and extent of the cerebral mineralisations, as well as their impact on the surrounding tissue, has been undertaken yet. In our cases, calcifications were unevenly distributed throughout the central nervous system, not associated with neuronal loss or dystrophic events and appeared mostly as single calcospherites within the neuropil with occasional confluent deposits at advanced gestational age. There was intense perifocal microgliosis around single immature calcospherites, as well as mild astrogliosis around and within the confluent lesions, in which occasional macrophages could be found. Rarely, mineralisations occurred in blood-vessel walls, mainly affecting basal ganglia. Preferential sites of calcification were parietal and occipital periventricular white matter and corpus callosum, while frontal lobes were mildly affected. The cortex, temporal lobes as well as internal capsule, brain stem, cerebellum, leptomeninges, pituitary gland and choroid plexus were devoid of mineralisations. The subcortical grey matter was moderately involved in the putamen and pallidum, mildly in the caudate nucleus and subependymal germ cell matrix and not at all in the thalamus, Ammon's horn, amygdala and substantia nigra. The distribution of mineral deposits was thus inversely correlated to regional blood circulation and capillary density, with calcifications being concentrated in more sparsely perfused areas but lacking in highly vascularised tissue. This inverse relationship between mineralisation and regional blood flow was reflected in the varying distribution of calcospherites in grey and white matter as well as in the white matter of different lobes.

We present the case of an 80-year-old malnourished and non-alcoholic woman who died from neglect-associated Marchiafava-Bignami disease, an illness usually almost exclusively occurring in male alcoholics. The patient had been bedridden for several months and had been looked after by her son. The patient was admitted to hospital in an extremely poor care condition suffering from severe exsiccosis, pressure sores and marasmus and died shortly afterwards. The initial post-mortem examination could not establish a definite cause of death, however, upon neuropathological examination a necrotising cystic lesion in the left cingulate gyrus as well as a central necrosis in the corpus callosum indicative of Marchiafava-Bignami disease were revealed. This is the first known case of Marchiafava-Bignami disease in a non-alcoholic woman and the first case in the forensic setting of neglect.

Eight pituitary adenomas (four gonadotroph cell adenomas, three prolactin cell adenomas, one null cell adenoma) and their respective recurrences in the same patients were studied by comparative genomic hybridization. Chromosomal imbalances were found in seven of eight patients affecting two of eight primary and seven of eight recurrent tumors. Overall, pituitary adenomas showed an average of 1.6 chromosomal imbalances per primary and 3.4 per recurrent tumor (P

Four pituitary carcinoma metastases [two adrenocorticotropic hormone (ACTH) and prolactin cell tumors each] were studied by comparative genomic hybridization. Chromosomal gains were found in all four carcinoma metastases, but losses only in the two prolactin cell carcinoma metastases. Overall, pituitary carcinoma metastases showed an average of 8.3 chromosomal imbalances per tumor (7 gains vs 1.3 losses), 10 in prolactin cell carcinoma metastases (7.5 gains vs 2.5 losses) and 6.5 in ACTH cell carcinoma metastases (6.5 gains vs 0 loss). The most common changes were gains of chromosome 5, 7p, and 14q (in three tumors each). High-level gains were found on 13q22-qter and 14q (two cases each) and on 1q, 3p, 7, 8, 9p, and 21q (one case each). To date, gains of chromosome 14q have not been reported among pituitary tumors. It remains to be shown whether gain of 14q is associated with malignant progression and metastatic dissemination of pituitary carcinomas.

We present four cases of sudden unexpected death in young adults with chronic hydrocephalus. The patients were between 20 and 28 years of age and had suffered from aqueduct stenosis (two patients), spina bifida in combination with Arnold-Chiari malformation (type II) and fragile X-syndrome. The patients suddenly collapsed with cardiorespiratory failure and could not be resuscitated and none had a history of headache or seizures. The post-mortem examinations revealed no unusual findings and a definite cause of death could not be established. Neuropathological examination revealed chronically hydrocephalic brains without any signs of uncal or tonsillar herniation. We hypothesise that a sudden pressure-induced decompensation of cerebral neuronal pathways involving insular and limbic cortex, hypothalamus and brain stem nuclei, may have caused disturbances of the cardiopulmonary control centres in the reticular formation of the brain stem, which in turn may have led to instantaneous cardiorespiratory arrest resulting in sudden "neurogenic" cardiac death.

Single crystals of Li-aegirine LiFe3+Si2O6 were synthesized at 1573 K and 3 GPa, and a polycrystalline sample suitable for neutron diffraction was produced by ceramic sintering at 1223 K. LiFe3+Si2O6 is monoclinic, space group C2/c, a=9.6641(2) A, b= 8.6612(3) A, c=5.2924(2) A, β=110.12(1)∘ at 300 K as refined from powder neutron data. At 229 K Li-aegirine undergoes a phase transition from C2/c to P21 /c. This is indicated by strong discontinuities in the temperature variation of the lattice parameters, especially for the monoclinic angle β and by the appearance of Bragg reflections (hkl) with h+k≠2n. In the low-temperature form two non-equivalent Si-sites with 〈SiA–O〉=1.622 A and 〈SiB–O〉=1.624 A at 100 K are present. The bridging angles of the SiO4 tetrahedra O3–O3–O3 are 192.55(8)° and 160.02(9)° at 100 K in the two independent tetrahedral chains in space group P21 /c, whereas it is 180.83(9)° at 300 K in the high-temperature C2/c phase, i.e. the chains are nearly fully expanded. Upon the phase transition the Li-coordination changes from six to five. At 100 K four Li–O bond lengths lie within 2.072(4)–2.172(3) A, the fifth Li–O bond length is 2.356(4) A, whereas the Li–O3 A bond lengths amount to 2.796(4) A. From 57Fe Mossbauer spectroscopic measurements between 80 and 500 K the structural phase transition is characterized by a small discontinuity of the quadrupole splitting. Temperature-dependent neutron powder diffraction experiments show first occurrence of magnetic reflections at 16.5 K in good agreement with the point of inflection in the temperature-dependent magnetization of LiFe3+Si2O6. Distinct preordering phenomena can be observed up to 35 K. At the magnetic phase transition the unit cell parameters exhibit a pronounced magneto-striction of the lattice. Below T N Li-aegirine shows a collinear antiferromagnetic structure. From our neutron powder diffraction experiments we extract a collinear antiferromagnetic spin arrangement within the a–c plane.

Glioneuronal tumors with neuropil-like islands (rosetted glioneuronal tumors) were recently reported as a novel brain tumor entity with characteristic clinicopathological features (Am J Surg Pathol 23: 502, 1999). Here we describe the clinical, histological and genetic features of another case arising in the parietal lobe of a 43-year-old man suffering from focal motor epilepsy. Histologically, nodules of small neuronal tumor cells immunoreactive for synaptophysin and NeuN were embedded within a diffuse astrocytoma. Remarkably, highest proliferative activity was observed within the neuronal nodules. Comparative genomic hybridization revealed a gain of chromosome 7q and a loss on chromosome 9p.

Wahrend die Bedeutung der MR-Spektroskopie, Volumetrie und T2-Relaxometrie fur die praoperative Lokalisation durch verschiedene Studien belegt ist, stellt sich die Frage, inwieweit die einzelnen Verfahren fur die postoperative Anfallsprognose geeignet sind. In einer prospektiven Vergleichsstudie wurden 26 Patienten praoperativ mit Hilfe eines 1,5 T-Ganzkorpertomographen (Siemens-Magnetom-Vision) untersucht. Die MR-Spektroskopie (MRS) erfolgte durch hochauflosende 1-H-Protonen-Spektroskopie. Die Volumetrie mit Hilfe einer M-P-Rage-Technik. Das postoperative Outcome wurde nach der Klassifikation von Engel festgelegt. Unsere Ergebnisse zeigen, dass die MR-spektroskopischen Befunde in 3 Gruppen aufgeteilt werden konnen: unilateral, gering bilateral oder schwer bilateral bis kontralateral metabolische Veranderungen. Bei bilateralen Veranderungen war die Schwere der metabolischen Veranderungen der nichtoperierten, also kontralateralen Seite fur das spatere Outcome entscheidend. Die Ergebnisse der Volumetrie korrelierten nicht mit dem postoperativen Outcome.

Transcription control systems enable experimental regulation of transgene expression in eukaryotic cells by application of specific repressors or inducers. Currently used inducible systems include tetracycline (tet-off), dimerizer and ecdysone systems. While numerous studies have utilized a single system, their comparative performance under identical conditions remains unclear. We therefore compared the efficiency of these three systems in C6 glioma cells by using transient transfection and the lacZ reporter gene. Highest induced activity was found with the ecdysone system, followed by tet-off and dimerizer systems. Both lowest repressed activity and highest regulation were revealed with the dimerizer system, followed by ecdysone and tet-off systems. Our data suggest that the most appropriate system depends on the experimental procedures, the application and the gene to be regulated.

Experimental investigation of glioma biology and therapy requires a representative model and a convenient technique for regulating gene expression. We have established an in vivo model in which genetically modified rat C6 glioma cells (C6TL cells) are transplanted into nude mice brain, followed by specific transcriptional control of a transgene. Histologically, the tumors exhibit an astrocytic phenotype and closely resemble human malignant gliomas including diffuse brain invasion. Due to a stably integrated lacZ gene, individual tumor cells can be unequivocally identified in tissue sections by histochemistry for beta-galactosidase. Since C6TL cells carry the tet transactivator (tTA) gene, any additional gene under control of a tetracycline/tTA-responsive promoter can be transcriptionally regulated by the concentration of tetracycline. C6TL cells stably transfected with a tetracycline/tTA-responsive luciferase reporter gene showed 23-fold regulation of luciferase activity in vitro. After intracerebral transplantation a regulation of 4.5- to 8.3-fold was obtained, dependent on the concentration and the type of tetracycline in the drinking water. This model should be useful for studying the functional role of candidate genes in tumor biology as well as for experimental gene therapy studies.

To assess treatment outcome and prognostic factors following postoperative external radiotherapy in 77 patients with low-grade glioma. Patients and Methods: Between 1977 and 1996, 45 patients with astrocytoma, 14 with oligodendroglioma and 18 with mixed glioma received postoperative radiotherapy with a median total dose of 52 Gy (range, 45 to 61 Gy). Sixty-seven patients were treated immediately following surgery, 10 patients with tumor progression. The influence of various factors including histology, gender, age, seizures, duration of symptoms (≤ 6 weeks vs > 6 weeks), CT pattern (enhancement vs no enhancement), type of surgery, total radiotherapy dose and timing of radiotherapy on relapse-free survival and overall survival was investigated. Results: The median overall survival time was 81 month, the 5- and 10-year survival rates were 54% and 31%, respectively. The median time to progression was 56 months, while the 5- and 10-year progression-free survival rates were 45% and 24%. Univariate analyses identified the total radiotherapy dose (p = 0.01), duration of symptoms (p = 0.05), the presence of seizures (p = 0.04), and the CT pattern following intravenous contrast (p = 0.005) as significant prognostic factors for overall survival. Progression-free survival rates were influenced by the total dose (p = 0.04), the duration of symptoms (p = 0.01) and CT pattern (p = 0.006). On multivariate analysis, only the CT pattern (enhancement vs no enhancement) remained as independent prognostic factors for both progression-free survival and overall survival. Conclusion: A minimum total dose of 52 Gy is recommended for the postoperative radiotherapy in low-grade glioma. Tumors with CT enhancement seem to need further intensification of treatment.

Both thallium-201 and iodine-123 alpha-methyltyrosine (123I-IMT) have been shown to be useful in the diagnostic evaluation of brain tumours. The aim of this study was to investigate the respective contributions of 201Tl and 123I-IMT single-photon emission tomography (SPET) in the non-invasive evaluation of intracerebral tumours. We analysed 65 patients with the following brain tumours: 8 non-neoplastic lesions, 4 meningiomas, 12 low-grade gliomas, 28 high-grade gliomas, 11 metastases and 2 high-grade lymphomas. 201Tl SPET and 123I-IMT SPET were performed [start of 201Tl SPET: 15 min p.i. (early) and 180 min p.i. (delayed); start of 123I-IMT SPET: 15 min p.i.]. The intensity of uptake was quantified as the ratio between tracer accumulation in the tumour and in the contralateral hemisphere. None of the non-neoplastic lesions or low-grade gliomas expressed marked 201Tl uptake. All malignant tumours except one small metastasis and all meningiomas except one small, cystic and degenerated lesion showed significant 201Tl accumulation [Tl(15')2.0]; 123I-IMT uptake was either absent or intermediate in non-malignant lesions except in two low-grade gliomas; the highest levels were observed in high-grade gliomas followed by metastases and lymphomas (mean IMT: 2.7 vs. 2.1 vs. 1.8), with metastases showing a high variability in 123I-IMT uptake (range: 0.8-3.6). Using 201Tl to distinguish non-neoplastic lesions from malignant tumours and meningiomas, 63 of 65 patients were characterised correctly. In the latter group, high-grade gliomas were correctly identified in 27 of 28 cases by their amino acid uptake. It is concluded that the combination of 201Tl and 123I-IMT surpasses the accuracy of each single test in the differentiation of space-occupying lesions of the brain. Based on these preliminary results, a sequential strategy is proposed involving an initial 201Tl SPET study and an additional 123I-IMT SPET study in the event of positive 201Tl uptake.

Single photon emission computed tomography (SPECT) with 201T1 and 123I-α-methyl tyrosine (123I-IMT) are routine methods for the evaluation of brain tumors. 123-I-IMT transport across the blood brain barrier is mediated by an amino acid carrier, 201T1 accumulation is analogous to cerebral potassium uptake. Patients and Methods: To determine the differences in glioma extension as shown by the 2 methods, 17 patients with malignant gliomas were included in this comparative imaging study: astrocytoma III: n = 6, ependymoma III: n = 1, oligodendroglioma III: n = 1, glioblastoma IV: n = 9. The tomographic image sets were matched anatomically and the slices showing maximal tumor extension were identified in both image sets respectively. Tumor spread was compared visually and the tumor extension was quantified. Results: In gliomas WHO III tumor extension was delineated significantly larger by 123I-IMT-SPECT than by 201T1-SPECT (mean ± SD: 816 ± 281 pixels vs 600 ± 220 pixels, n = 8, p < 0.05). The size of glioblastomas was shown in a comparable manner by the 2 methods (977 ± 571 vs 1,051 ± 588, n = 9, ns, p = 0.57), but there were considerable regional differences between the area of 201T1 uptake and amino acid retention. In the whole group a weak but significant negative correlation between intensity of 201T1 uptake on the one hand and a ratio of the area as depicted by 123I-IMT vs area as depicted by 201T1 on the other hand, was found (n = 17, r = 0.49, p < 0.05). Thus the differences in the delineation of areas became smaller with increasing 201T1 uptake. Conclusions: These preliminary data indicate that the extension of gliomas is depicted differently by the 2 methods. 123I-IMT-SPECT shows a larger tumor extension especially in gliomas WHO III. Since 201T1 uptake has previously been shown to correlate with disruption of the blood brain barrier, 123I-IMT-SPECT may delineate tumor parts without endothelial leakage. This additional information may be helpful in planning surgical or radiation therapy. The advantages of 123I-IMT in this respect decrease with increasing 201T1 uptake and with increasing malignancy.

Xanthogranulomatous change of craniopharyngioma, consisting of cholesterol clefts, macrophages, chronic inflammatory infiltrates, necrotic debris and hemosiderin deposits, has been traditionally considered a hallmark of the adamantinomatous variant, even in the absence of epithelium. Based on a series of 110 craniopharyngioma patients undergoing primary surgery, we found 37 specimens with a predominating xanthogranulomatous component. Only 3 of these cases (8%) exhibited additional histological features of adamantinomatous craniopharyngioma, while 13 cases (35%) contained non-adamantinomatous epithelium composed of squamous or ciliated cuboidal cells. Subsequent clinical analysis revealed that these 37 xanthogranulomatous lesions differed from 59 classical adamantinomatous craniopharyngiomas with respect to preferential occurrence in adolescents and young adults (mean age 27 years), predominant intrasellar location, smaller tumor size, more severe endocrinological deficits, longer preoperative history, lower frequency of calcification and visual disturbances, better resectability, and a more favorable outcome. On the other hand, xanthogranulomatous and adamantinomatous lesions did not differ with respect to sex, amount of cystic components, or the intraoperative aspect, considered by the neurosurgeon as being typical for craniopharyngioma in all cases. We suggest that xanthogranuloma (cholesterol granuloma) of the sellar region is clinically and pathologically distinct from the classical adamantinomatous craniopharyngioma.

A mixed lymphoblastic T cell lymphoma and gonadotroph cell pituitary adenoma occurred 25 years after first resection of the adenoma. Within 1 year the lymphoma overgrew the adenoma, but was still restricted to the sellar region. Histologically, lymphoma and adenoma components were tightly admixed. Possible pathogenetic pathways for intra-adenomatous lymphoma development include monoclonal expansion of T cell infiltrates, expression of adhesion molecules specific for adenoma endothelium, and production of mitogenic pituitary hormones.

We present a patient harboring a large squamous papillary craniopharyngioma. The diagnosis was confirmed by a stereotactic biopsy. Because of vegetative symptoms indicating hypothalamic derangement, we were reluctant to perform surgical resection. Following fractionated megavoltage radiotherapy, MR imaging and CT demonstrated complete regression of the craniopharyngioma and the patient recovered from endocrine deficiency, chiasmal syndrome and vegetative hypothalamic symptoms.

Ecchordosis physaliphora (EP) is a rare intracranial mass derived from ectopic notochordal tissue. It is usually a fortuitous finding at autopsy or by computed tomography/magnetic resonance imaging. Very few authors have described an EP-associated symptomatology. In this study, we report a case of the sudden and unexpected death of a 48-year-old woman. At autopsy, the cause of death was subarachnoid bleeding, the origin of which was identified as a gelatinous mass stemming from the dura mater and occupying the prepontine space. Further histological and immunohistochemical investigations allowed the diagnosis of EP.

The communication between tumor cells and extracellular matrix (ECM) is responsible for clinically important features of malignant gliomas, such as cerebral invasion and leptomeningeal spread. The synthesis of ECM components, ECM-degrading activities and ECM receptors as well as the interaction between ECM components and their receptors represents the molecular basis for these processes. Recent studies have shown that proteases and integrins, the major group of ECM receptors, may be over-expressed by astrocytic tumor cells. Furthermore, integrins and the hyaluronate receptor CD44 have been found to be involved in adhesion and basement membrane invasion of glioma cells. Critical issues which are poorly understood so far include the ECM composition of the normal human brain and of brain tumors, the function of individual ECM components and receptors in a neuro-oncological context, and the molecular processes mediating the diffuse invasion of glioma cells into the brain.