Search

Risk factors for prediction of prognosis in meningiomas derivable from routine preoperative magnetic resonance imaging (pMRI) remain elusive. Correlations of tumor and edema volume, disruption of the arachnoid layer, heterogeneity of contrast enhancement, enhancement of the capsule, T2-intensity, tumor shape, and calcifications on pMRI with tumor recurrence and high-grade (WHO grade II/III) histology were analyzed in 565 patients who underwent surgery for WHO grade I (N = 516, 91%) or II/III (high-grade histology, N = 49, 9%) meningioma between 1991 and 2018. Edema volume (OR, 1.00; p = 0.003), heterogeneous contrast enhancement (OR, 3.10; p < 0.001), and an irregular shape (OR, 2.16; p = 0.015) were associated with high-grade histology. Multivariate analyses confirmed edema volume (OR, 1.00; p = 0.037) and heterogeneous contrast enhancement (OR, 2.51; p = 0.014) as risk factors for high-grade histology. Tumor volume (HR, 1.01; p = 0.045), disruption of the arachnoid layer (HR, 2.50; p = 0.003), heterogeneous contrast enhancement (HR, 2.05; p = 0.007), and an irregular tumor shape (HR, 2.57; p = 0.001) were correlated with recurrence. Multivariate analyses confirmed tumor volume (HR, 1.01; p = 0.032) and disruption of the arachnoid layer (HR, 2.44; p = 0.013) as risk factors for recurrence, independent of histology. Subgroup analyses revealed disruption of the arachnoid layer (HR, 9.41; p < 0.001) as a stronger risk factor for recurrence than high-grade histology (HR, 5.15; p = 0.001). Routine pMRI contains relevant information about the risk of recurrence or high-grade histology of meningioma patients. Loss of integrity of the arachnoid layer on MRI had a higher prognostic value than the WHO grading, and underlying histological or molecular alterations remain to be determined.

Telomerase activity and (human) Telomerase Reverse Transcriptase (hTERT) expression are considered hallmarks in oncogenesis of neoplasms and are upregulated by alterations of the hTERT promoter. In meningiomas, numerous studies investigated hTERT expression, telomerase activity, promoter mutations, and methylations. Moreover, reports about hTERT-targeted chemotherapy in meningiomas have recently been published. We provide a systematic review of the literature about the role of hTERT in meningiomas. TERT expression and telomerase activity is found in benign and high-grade meningiomas and increase with WHO grade. Remarkably, rates of TERT expression/telomerase activity usually exceed mutation frequency and both telomerase activity and TERT expression have also been found in hTERT promoter wildtype meningiomas, indicating further mechanisms of TERT upregulation. Although hTERT promoter methylation has been reported in the vast majority of meningiomas, correlation with TERT expression remains controversial. Rates of promoter mutations, and methylation were shown to increase with rising WHO grade. Moreover, promoter methylation and mutations strongly correlate with prognosis. Although mutations predicted malignant progression, de novo mutations in high-grade recurrences of former benign lesions were also observed. Retroviral transduction of the TERT gene enabled immortalization in several grade I-III meningioma cell lines. In vitro analyses revealed significant effects on viability in hTERT-mutated meningioma cells after targeted treatment. Alternative mechanisms of telomere lengthening are usually absent in meningiomas. TERT and hTERT promoter alterations play a major role during oncogenesis of meningiomas with implications for prognosis and potentially treatment.

Brain invasion (BI) is a new criterion for atypia in meningiomas and therefore potentially impacts adjuvant treatment. However, it remains unclear whether surgical practice and specimen characteristics influence histopathological analyses and the accuracy of detecting BI. Tumor location, specimen characteristics, and rates of BI were compared in meningioma samples obtained from 2938 surgeries in different neurosurgical departments but diagnosed in a single neuropathological institute. Non-skull base tumor location was associated with CNS tissue on the microscopic slides (OR 1.45; p < .001), increasing specimen weight (OR 1.01; p < .001), and remaining tissue not subjected to neuropathological analyses (OR 2.18; p < .001) but not with BI (OR 1.29; p = .199). Specimen weight, rates of residual tissue not subjected to histopathological analyses, of BI and of brain tissue, on the microscopic slides differed among the neurosurgical centers (p < .001, each). Frequency of BI was increased in one department (OR 2.07; p = .002) and tended to be lower in another (OR .61; p = .088). The same centers displayed the highest and lowest rates of brain tissue in the specimen, respectively (p < .001). Moreover, the correlation of BI with the neurosurgical center was not confirmed when only analyzing specimen with evidence of brain tissue in microscopic analyses (p = .223). Detection of BI was not correlated with the intraoperative use of CUSA in subgroup analyses. Rates of brain invasion in neuropathological analyses are not associated with tumor location but differ among some neurosurgical centers. Evidence raises that surgical nuances impact specimen characteristics and therefore the accuracy of the detection of BI.

Background: Approximately 20% of low-grade gliomas (LGG) display visible protoporphyrin fluorescence during surgery after 5-aminolevulinic acid (5-ALA) administration., Objective: To determine if fluorescence represents a prognostic marker in LGG., Methods: Seventy-four consecutive patients with LGG (World Health Organization 2016) were operated on with 5-ALA. Fluorescent tissue was specifically biopsied. Tumor size, age, Karnofsky index, contrast-enhancement, fluorescence, and molecular factors (IDH1/IDH2-mutations, Ki67/MIB1 Index, 1p19q codeletions, ATRX, EGFR, p53 expression, and O6-methylguanine DNA methyltransferase promotor methylation), were related to progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS)., Results: Sixteen of seventy-four LGGs (21.6%) fluoresced. Fluorescence was partially related to weak enhancement on magnetic resonance imaging and increased (positron emission tomography)PET-FET uptake, but not to Karnofsky Performance Score, tumor size, or age. Regarding molecular markers, only EGFR expression differed marginally (fluorescing vs nonfluorescing: 19% vs 5%; P = .057). Median follow-up was 46.4 mo (95% confidence interval [CI]: 41.8-51.1). PFS, MTFS, and OS were shorter in fluorescing tumors (PFS: median 9.8 mo, 95% CI: 1.00-27.7 vs 45.8, 31.9-59.7, MTFS: 43.0 [27.5-58.5] vs 64.6 [57.7-71.5], median not reached, P = .015; OS: 51.6, [34.8-68.3] vs [68.2, 62.7-73.8], P = .002). IDH mutations significantly predicted PFS, MTFS, and OS. In multivariate analysis IDH status and fluorescence both independently predicted MTFS and OS. PFS was not independently predicted by fluorescence., Conclusion: This is the first report investigating the role of ALA-induced fluorescence in histologically confirmed LGG. Fluorescence appeared to be a marker for inherent malignant transformation and OS, independently of known prognostic markers. Fluorescence in LGG might be taken into account when deciding on adjuvant therapies., (© Congress of Neurological Surgeons 2018.)

Objective: Identification of risk factors for perioperative epilepsy remains crucial in the care of patients with meningioma. Moreover, associations of brain invasion with clinical and radiological variables have been largely unexplored. The authors hypothesized that invasion of the cortex and subsequent increased edema facilitate seizures, and they compared radiological data and perioperative seizures in patients with brain-invasive or noninvasive meningioma., Methods: Correlations of brain invasion with tumor and edema volumes and preoperative and postoperative seizures were analyzed in univariate and multivariate analyses., Results: Totals of 108 (61%) females and 68 (39%) males with a median age of 60 years and harboring totals of 92 (52%) grade I, 79 (45%) grade II, and 5 (3%) grade III tumors were included. Brain invasion was found in 38 (22%) patients and was absent in 138 (78%) patients. The tumors were located at the convexity in 72 (41%) patients, at the falx cerebri in 26 (15%), at the skull base in 69 (39%), in the posterior fossa in 7 (4%), and in the ventricle in 2 (1%); the median tumor and edema volumes were 13.73 cm3 (range 0.81-162.22 cm3) and 1.38 cm3 (range 0.00-355.80 cm3), respectively. As expected, edema volume increased with rising tumor volume (p < 0.001). Brain invasion was independent of tumor volume (p = 0.176) but strongly correlated with edema volume (p < 0.001). The mean edema volume in noninvasive tumors was 33.0 cm3, but in invasive tumors, it was 130.7 cm3 (p = 0.008). The frequency of preoperative seizures was independent of the patients' age, sex, and tumor location; however, the frequency was 32% (n = 12) in patients with invasive meningioma and 15% (n = 21) in those with noninvasive meningioma (p = 0.033). In contrast, the probability of detecting brain invasion microscopically was increased more than 2-fold in patients with a history of preoperative seizures (OR 2.57, 95% CI 1.13-5.88; p = 0.025). In univariate analyses, the rate of preoperative seizures correlated slightly with tumor volume (p = 0.049) but strongly with edema volume (p = 0.014), whereas seizure semiology was found to be independent of brain invasion (p = 0.211). In multivariate analyses adjusted for age, sex, tumor location, tumor and edema volumes, and WHO grade, rising tumor volume (OR 1.02, 95% CI 1.00-1.03; p = 0.042) and especially brain invasion (OR 5.26, 95% CI 1.52-18.15; p = 0.009) were identified as independent predictors of preoperative seizures. Nine (5%) patients developed new seizures within a median follow-up time of 15 months after surgery. Development of postoperative epilepsy was independent of all clinical variables, including Simpson grade (p = 0.133), tumor location (p = 0.936), brain invasion (p = 0.408), and preoperative edema volume (p = 0.081), but was correlated with increasing preoperative tumor volume (p = 0.004). Postoperative seizure-free rates were similar among patients with invasive and those with noninvasive meningioma (p = 0.372)., Conclusions: Brain invasion was identified as a new and strong predictor for preoperative, but not postoperative, seizures. Although also associated with increased peritumoral edema, seizures in patients with invasive meningioma might be facilitated substantially by cortical invasion itself. Consideration of seizures in consultations between the neurosurgeon and neuropathologist can improve the microscopic detection of brain invasion.

Background: The aim of the study was to determine pre-operative factors associated with adverse events occurring within 30 days after neurosurgical tumor treatment in a German center, adjusting for their incidence in order to prospectively compare different centers., Methods: Adult patients that were hospitalized due to a benign or malignant brain were retrospectively assessed for quality indicators and adverse events. Analyses were performed in order to determine risk factors for adverse events and reasons for readmission and reoperation., Results: A total of 2511 cases were enrolled. The 30 days unplanned readmission rate to the same hospital was 5.7%. The main reason for readmission was tumor progression. Every 10th patient had an unplanned reoperation. The incidence of surgical revisions due to infections was 2.3%. Taking together all monitored adverse events, male patients had a higher risk for any of these complications (OR 1.236, 95%CI 1.025-1.490, p = 0.027). Age, sex, and histological diagnosis were predictors of experiencing any complication. Adjusted by incidence, the increased risk ratios greater than 10.0% were found for male sex, age, metastatic tumor, and hemiplegia for various quality indicators., Conclusions: We found that most predictors of outcome rates are based on preoperative underlying medical conditions and are not modifiable by the surgeon. Comparing our results to the literature, we conclude that differences in readmission and reoperation rates are strongly influenced by standards in decision making and that comparison of outcome rates between different health-care providers on an international basis is challenging. Each health-care system has to develop own metrics for risk adjustment that require regular reassessment.

OBJECTIVEAwake craniotomies have become a feasible tool over time to treat brain tumors located in eloquent regions. Different techniques have been applied in neurooncology centers. Both "asleep-awake-asleep" (asleep) and "conscious sedation" were used subsequently at the authors' neurosurgical department. Since 2013, the authors have only performed conscious sedation surgeries, predominantly using the α2-receptor agonist dexmedetomidine as the anesthetic drug. The aim of this study was to compare both mentioned techniques and evaluate the clinical use of dexmedetomidine in the setting of awake craniotomies for glioma surgery.METHODSThe authors retrospectively analyzed patients who underwent operations either under the asleep condition using propofol-remifentanil or under conscious sedation conditions using dexmedetomidine infusions. In the asleep group patients were intubated with a laryngeal mask and extubated for the assessment period. Adverse events, as well as applied drugs with doses and frequency of usage, were recorded.RESULTSFrom 224 awake surgeries between 2009 and 2015, 180 were performed for the resection of gliomas and included in the study. In the conscious sedation group (n = 75) significantly fewer opiates (p < 0.001) and vasoactive (p < 0.001) and antihypertensive (p < 0.001) drugs were used in comparison with the asleep group (n = 105). Furthermore, the postoperative length of stay (p < 0.001) and the surgical duration (p < 0.001) were significantly lower in the conscious sedation group.CONCLUSIONSUse of dexmedetomidine creates excellent conditions for awake surgeries. It sedates moderately and acts as an anxiolytic. Thus, after ceasing infusion it enables quick and reliable clinical neurological assessment of patients. This might lead to reducing the amount of administered antihypertensive and vasoactive drugs as well as the length of hospitalization, while likely ensuring more rapid surgery.

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

OBJECTIVE Fluorescence guidance with 5-aminolevulinic acid (5-ALA) helps improve resections of malignant gliomas. However, one limitation is the low intensity of blue light for background illumination. Fluorescein has recently been reintroduced into neurosurgery, and novel microscope systems are available for visualizing this fluorochrome, which highlights all perfused tissues but has limited selectivity for tumor detection. Here, the authors investigate a combination of both fluorochromes: 5-ALA for distinguishing tumor and fluorescein for providing tissue fluorescence of adjacent brain tissue. METHODS The authors evaluated 6 patients who harbored cerebral lesions suggestive of high-grade glioma. Patients received 5-ALA (20 mg/kg) orally 4 hours before induction of anesthesia. Low-dose fluorescein (3 mg/kg intravenous) was injected immediately after anesthesia induction. Pentero microscopes (equipped either with Yellow 560 or Blue 400 filters) were used to visualize fluorescence. To simultaneously visualize both fluorochromes, the Yellow 560 module was combined with external blue light illumination (D-light C System). RESULTS Fluorescein-induced fluorescence created a useful background for protoporphyrin IX (PPIX) fluorescence, which appeared orange to red, surrounded by greenly fluorescent normal brain and edematous tissue. Green brain-tissue fluorescence was helpful in augmenting background. Levels of blue illumination that were too strong obscured PPIX fluorescence. Unspecific extravasation of fluorescein was noted at resection margins, which did not interfere with PPIX fluorescence detection. CONCLUSIONS Dual labeling with both PPIX and fluorescein fluorescence is feasible and gives superior background information during fluorescence-guided resections. The authors believe that this technique carries potential as a next step in fluorescence-guided resections if it is completely integrated into the surgical microscope.

With the release of the 2016 edition of the World Health Organization (WHO) Classification of Central Nervous System Tumors, brain invasion in meningiomas has been added as a stand-alone criterion for atypia and can therefore impact grading and indirectly adjuvant therapy. Regarding this rising clinical importance, we have reviewed the current knowledge about brain invasion with emphasis on its implications on current and future clinical practice. We found various definitions of brain invasion and approaches for evaluation in surgically obtained specimens described over the past decades. This heterogeneity is reflected by weak correlation with prognosis and remains controversial. Similarly, associated clinical factors are largely unknown. Preoperative, imaging-guided detection of brain invasion is unspecific, and intraoperative assessment using standard and new high-magnification microscopic techniques remains imprecise. Despite the increasing knowledge about molecular alterations of the tumor/ brain surface, pharmacotherapeutic options targeting brain invasive meningiomas are lacking. Finally, we summarize the impact of brain invasion on histopathological grading in the WHO classifications of brain tumors since 1979.In conclusion, standardized neurosurgical sampling and neuropathological analyses could improve diagnostic reliability and reproducibility of future studies. Further research is needed to improve pre- and intraoperative visualization of brain invasion and to develop adjuvant, targeted therapies., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite considerable advances in preoperative and intraoperative imaging and neuronavigation, resection of thalamic gliomas remains challenging. Although both endoscopic biopsy and third ventriculostomy (ETV) for the treatment of secondary hydrocephalus are commonly performed, endoscopic resection of thalamic gliomas has been very sparsely described., Method: We report and illustrate the surgical procedure and patient's outcome after full endoscopic resection of a thalamic glioma and to discuss this approach as an alternative to open microsurgery., Results: In 2016, a 56-year-old woman presented with disorientation, dysphasia and right facial hypaesthesia in our department. Cranial magnetic resonance imaging revealed a left thalamic lesion and subsequent hydrocephalus. Initially, hydrocephalus was treated by ETV but forceps biopsy was not diagnostic. However, metabolism in 18 F-fluoroethyl-L-tyrosine positron emission tomography indicated glioma. Subsequently, endoscopic and neuronavigation-guided tumour resection was performed using a <1 cm 2 , trans-sulcal approach through the left posterior horn of the lateral ventricle. While visibility was poor using the intraoperative microscope, neuroendoscopy provided excellent visualisation and allowed safe tumour debulking. Neither haemorrhage from the tumour or collapse of the cavity compromised endoscopic resection., Conclusions: In accordance with one previously published case of endoscopic resection of a thalamic glioma, no surgery-related complications were observed. Although this remains to be determined in larger series, endoscopic resection of these lesions might be a safe and feasible alternative to biopsy or open surgery. Future studies should also aim to identify patients specifically eligible for these approaches.

Objective: In meningioma, correlation of brain invasion with prognosis and clinical variables remains controversial., Methods: Correlation of brain invasion with clinical and histopathologic variables was investigated in 467 patients with primary intracranial meningioma., Results: Diffuse (n = 3; 10%), clusterlike (n = 11; 34%) or fingerlike (n = 18; 56%) invasion was detected in 32 patients (7%). Brain invasion was more common in males than in females (13% vs. 5%; odds ratio, 2.75; 95% confidence interval, 1.29-5.89; P = 0.009) and pattern of invasion differed between genders (P = 0.037). Brain invasion was absent in 401 benign meningiomas and present in 48% of 60 atypical (n = 29) and 50% of 6 anaplastic (n = 3) meningiomas (P < 0.001) but was independent of tumor location and extent of resection. Progression occurred in 11% and was more frequent (31% vs. 15%; P = 0.036) in invasive than in noninvasive tumors, but only after gross total resection and in univariate analyses, and independent of invasion pattern. In atypical meningiomas, frequency of adjuvant irradiation was similar comparing invasive and noninvasive tumors and grading solely based on brain invasion (n = 20; 33%), other World Health Organization (WHO) criteria (n = 31; 52%) or a combination of both (n = 9; 15%). Risk of recurrence was lower (hazard ratio, 0.258, 95% confidence interval, 0.09-0.734; P = 0.011) when grading exclusively based on brain invasion than when further WHO criteria were in addition present and the progression-free interval among the first was similar to benign tumors., Conclusions: Brain invasion and its patterns are correlated to gender. In contrast to the current WHO classification, invasion was associated with recurrence only after gross total resection and not independent of further histopathologic criteria of atypia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Fluorescent agents, e.g. 5-aminolevulinic acid (5-ALA), fluorescein and indocyanine green (ICG) are in common use in neurosurgery for tumor resection and neurovascular surgery. Protoporphyrine IX (PPIX) as major metabolite of 5-ALA is a strong fluorescent substance accumulated within malignant glioma tissue and a very sensitive and specific tool for visualizing high grade glioma tissue during surgery. Furthermore, 5-ALA or rather PPIX also offers an intratumoral therapeutic option stimulated by laser light in specific wavelength. Fluorescein was demonstrated to show similar fluorescent reactions in neurosurgery, but is controversial in its use, especially in high grade tumor surgery. Intraoperative angiography during resection of arterio-venous malformations, extracranial-intracranial-bypass or aneurysm surgery is supported by ICG fluorescence. Generally ICG will provide beneficial information for both, exposure of the pathology and illustration of healthy structures. This manuscript shows an overview of the literature focussing fluorescence in neurosurgery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Ultrasonic aspiration is widely used in the resection of brain tumors. Nevertheless, tumor tissue fragments obtained by ultrasonic aspiration are usually discarded. In this study, we demonstrate that these fragments are possible sources of material for histopathological study and tissue culture and compare their microscopic features and viability in tissue culture of cavitron ultrasonic surgical aspirator tissue fragments., Methods: Brain tumor tissue collected by ultrasonic aspiration (CUSA EXcel®; Integra Radionics Inc.) in a simple sterile suction trap during resection was processed for primary cell culture. Cell viability and immunohistological markers were measured by the WST-1 test, microscopy and immunofluorescent evaluation., Results: Six gliomas are presented to demonstrate that these tissue fragments show good preservation of histological detail and tissue viability in culture., Conclusion: Utilization of this material may facilitate pathological interpretation by providing a more representative sample of tumor histology as well as an adequate and sterile biosource of material for tissue culture studies.

Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.

Aims: WHO grade III meningiomas are malignant neoplasms for which new and more targeted treatment strategies are urgently needed. Although clinical trials investigating anti-angiogenic vascular endothelial growth factor (VEGF) targeted therapies are currently recruiting, knowledge about the expression of VEGF and VEGF receptors remains to be determined., Methods: We investigated the expression of VEGF and its receptors VEGFR1 and VEGFR2 in 32 WHO grade III meningioma samples by immunohistochemistry. Furthermore, we performed in-situ hybridisation for VEGF., Results: We found low VEGF expression in tumor and endothelial cells. Highest VEGF expression levels were seen in peri-necrotic tumor cells potentially suffering from hypoxia. VEGFR1 and 2 were virtually absent on tumor cells, although endothelial cells displayed significantly higher levels reaching stronger expression for VEGFR2 than VEGFR1., Conclusions: Our findings showing constant expression levels of VEGFR2 in endothelial cells serve as a first indication that the use of small tyrosine kinase inhibitors such as Sunitinib directly targeting the VEGF-receptors might be worth testing, also in the clinical context in cases of therapy-refractory meningiomas. Further investigations are needed to study the response to drugs targeting the VEGF pathway in relation to the expression profile of VEGF and its receptors in high grade meningiomas.

Glioblastoma may develop rapidly without evidence for precursor lesions (primary glioblastomas), or progress from diffuse or anaplastic astrocytomas (secondary glioblastomas). Despite having distinct genetic profiles, these glioblastoma subtypes have similar histological features. We hypothesized that the highly malignant phenotype of glioblastoma may be attributable to genetic alterations that are common to both glioblastoma subtypes. In the present study, we first searched for commonly (>35%) amplified genes in glioblastomas with IDH1 mutation (a hallmark of secondary glioblastoma) and those without IDH1 mutation (typical for primary glioblastoma) in data from The Cancer Genome Atlas (TCGA). A total of 25 genes were identified, of which 21 were located at 7q31-34. We then screened 264 gliomas (70 glioblastomas, 112 diffuse astrocytomas, 82 oligodendrogliomas) for gain of the MET at 7q31.2 with quantitative polymerase chain reaction (PCR). MET gain was detected in primary glioblastomas (47%) and secondary glioblastomas (44%), suggesting that this genetic alteration plays a role in the pathogenesis of both glioblastoma subtypes. MET gain was also common in diffuse astrocytomas (38%), but less frequent in oligodendrogliomas (16%). MET gain in diffuse astrocytomas was associated with shorter survival (median, 43.0 vs. 70.7 months; P = 0.004), suggesting that MET gain is a useful prognostic marker for diffuse astrocytomas., (© 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.)

Glioblastomas with a proneural expression signature are characterized by frequent IDH1 mutations (i.e. genetic hallmarks of secondary glioblastomas) and PDGFRA (platelet-derived growth factor receptor-α) amplification. Mutations in IDH1/2 are frequent and early genetic events in diffuse astrocytomas (World Health Organization grade II), precursor to secondary glioblastomas, but little is known about the role and timing of PDGFRA amplification in these tumors. We assessed PDGFRA gain in 342 low-grade diffuse gliomas by quantitative polymerase chain reaction. Gain in PDGFRA was detected in 27 (16.3%) of 166 diffuse astrocytomas, significantly more frequent than in oligodendrogliomas (3 [2.6%] of 115, p < 0.0001). Analyses using previously published data from our laboratory showed an inverse correlation between PDGFRA gain and IDH1/2 mutations (p = 0.018) or 1p/19q loss (p < 0.0001). The vast majority of diffuse astrocytomas showed IDH1/2 mutations and/or PDGFRA gain (154 [93%] of 166). Mean survival of diffuse astrocytoma patients with PDGFRA gain was 8.8 ± 1.6 years, similar to that with IDH1/2 mutations (7.8 ± 0.5 years) or TP53 mutations (7.6 ± 0.6 years) but significantly longer than those with MET gain (4.4 ± 0.7 years). Dual-color fluorescence in situ hybridization in 6 diffuse astrocytomas with PDGFRA/MET co-gain identified by quantitative polymerase chain reaction revealed that PDGFRA and MET were typically amplified in different tumor cell populations. Tumor cells with coamplification were also focally observed, suggesting intratumoral heterogeneity, even in diffuse astrocytomas.

Chromosomal 7q34 duplication and BRAF-KIAA1549 fusion is a characteristic genetic alteration in pilocytic astrocytomas. 7q34 gain appears to be common in diffuse astrocytomas, but its significance is unclear. We assessed BRAF gain and BRAF mutations in 123 low-grade diffuse gliomas, including 55 diffuse astrocytomas, 18 oligoastrocytomas and 50 oligodendrogliomas. Quantitative polymerase chain reaction (PCR) revealed BRAF gain in 17/50 (34%) oligodendrogliomas, a significantly higher frequency than in diffuse astrocytomas (7/55; 13%; P = 0.0112). BRAF gain was common in low-grade diffuse gliomas with 1p/19q loss (39%) and those lacking any of the genetic alterations analyzed (31%), but was rare in those with TP53 mutations (2%). Logistic regression analysis showed a significant positive association between 1p/19q loss and BRAF gain (P = 0.0032) and a significant negative association between TP53 mutations and BRAF gain (P = 0.0042). Fluorescence in situ hybridization (FISH) analysis of 26 low-grade diffuse gliomas with BRAF gain additionally revealed BRAF-KIAA1549 fusion in one oligodendroglioma. Sequencing of cDNA in 17 low-grade diffuse gliomas showed BRAF-KIAA1549 fusion in another oligodendroglioma. A BRAF(V600E) mutation was also detected in one oligodendroglioma, and a BRAF(A598V) in one diffuse astrocytoma. These results suggest that low-grade diffuse gliomas with 1p/19q loss have frequent BRAF gains, and a small fraction of oligodendrogliomas may show BRAF-KIAA1549 fusion., (© 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.)

Gliosarcoma is a rare variant of glioblastoma characterized by a biphasic pattern of glial and mesenchymal differentiation. It is unclear whether mesenchymal differentiation in gliosarcomas is because of extensive genomic instability and/or to a mechanism similar to epithelial-mesenchymal transition (EMT). In the present study, we assessed 40 gliosarcomas for immunoreactivity of Slug, Twist, matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which are involved in EMT in epithelial tumors. Nuclear Slug expression was observed in >50% of neoplastic cells in mesenchymal tumor areas of 33 (83%) gliosarcomas, but not in glial areas (P < 0.0001). Nuclear Twist expression was observed in >50% of neoplastic cells in mesenchymal tumor areas of 35 (88%) gliosarcomas, but glial tumor areas were largely negative except in four cases (P < 0.0001). Expression of MMP-2 and MMP-9 was also significantly more extensive in mesenchymal than in glial tumor areas. None of 20 ordinary glioblastomas showed Slug or Twist expression in >10% neoplastic cells. Thus, expression of Slug, Twist, MMP-2 and MMP-9 was characteristic of mesenchymal tumor areas of gliosarcomas, suggesting that mechanisms involved in the EMT in epithelial neoplasms may play roles in mesenchymal differentiation in gliosarcomas., (© 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.)

Primary glioblastomas develop with a short clinical history, without evidence for less malignant precursor lesions, while secondary glioblastomas slowly develop via progression from diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time until progression and the clinical outcome of diffuse astrocytomas vary significantly. We have shown that IDH1 mutations reliably distinguish between primary glioblastomas (without IDH1 mutations) and secondary glioblastomas (with IDH1 mutations). The most frequent genetic alteration shared by primary and secondary glioblastomas is loss of heterozygosity at 10q (up to 60% of cases). Here, we first assessed The Cancer Genome Atlas data to identify gene loss at 10q in glioblastomas with or without IDH1 mutations. Using log-ratio thresholds of -1.0, 10 genes were identified; with the log-ratio thresholds of -2.0, only the DMBT1 (deleted in malignant brain tumor 1) gene at 10q26.13 remained as a deleted gene in glioblastomas with or without IDH1 mutations (12.5% vs 8.0%). We then analyzed a total of 404 gliomas by differential polymerase chain reaction and found a DMBT1 homozygous deletion at a similar frequency in primary and secondary glioblastomas (19.6% vs 20.8%). A fraction (11.3%) of diffuse astrocytomas showed a DMBT1 homozygous deletion that was significantly associated with a shorter overall survival (52.8 vs 84.0 months; p = 0.003). These results indicate that a DMBT1 homozygous deletion is present in a fraction of diffuse astrocytomas and that it is associated with an unfavorable clinical outcome.

We recently reported that the vast majority (>90%) of low-grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple-negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14(ARF) , p15(INK4b) , p16(INK4a) loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple-negative cases as well as a total of 160 non-triple-negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15(INK4b) , p16(INK4a) and RB1 genes) were significantly more frequent in triple-negative (26%) than in non-triple-negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low-grade diffuse glioma [hazard ratio, 3.024 (1.279-6.631); P = 0.0057]. These results suggest that a fraction of low-grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell-cycle control regulated by the RB1 pathway., (© 2011 The Authors; Brain Pathology © 2011 International Society of Neuropathology.)

Intramedullary spinal cord metastases (ISCM) are rare spinal cord neoplasms associated with severe neurological deterioration and poor life expectancy. However, their incidence is expected to increase as a result of advances in diagnostic techniques and longer survival of patients with cancer due to improvements in cancer therapy. Reports on ISCM from primary urothelial carcinoma are virtually non existent. We report a 74-year-old male patient with a significant history of a high-grade urothelial carcinoma who presented with progressive back pain and concomitant weakness, grade 3-4/5 proximally and 0-1/5 distally, and distal hyperesthesia and hyperalgesia, particularly of the left lower limb. MRI revealed a contrast-enhancing intramedullary lesion at Th11/Th12. Laminectomies of Th11/Th12 and lesion resection were performed. Postoperative histopathological examinations confirmed the metastatic nature of the lesion. Subsequently the patient developed multiple brain metastases. Radiation therapy was refused by the patient. We conclude that ISCM are devastating complications of systemic cancer. Early and thorough diagnosis, as well as carefully considered and prompt therapy, is important for minimizing the patient's functional deficit, thus improving quality of life., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma.