Koray Özduman

Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Genetic Clues to Meningioma Meningiomas are the most common primary brain tumors in adults. Located within the layer of tissue covering the brain, these tumors are usually slow-growing and benign but can cause serious neurological complications. About half of these tumors have mutations in the neurofibromin 2 gene (NF2). To identify other genes that contribute to meningioma pathogenesis, Clark et al. (p. 1077, published online 24 January) performed genome sequence analysis on 300 tumors. Meningiomas fell into two general classes: benign tumors located at the skull base—which tend to harbor mutations in the TRAF7, KLF4, AKT1, and SMO genes—and higher-grade tumors located in the cerebral and cerebellar hemispheres harbor mutations in NF2. The mutational profiles of meningiomas, a common type of brain tumor, correlate with their anatomical location and clinical status. We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Hypertension, Age, and Location Predict Rupture of Small Intracranial Aneurysms

BACKGROUND:Although current guidelines for the management of unruptured intracranial aneurysms (IAs) suggest aneurysms larger than 7 mm should be considered for treatment, a significant number of subarachnoid hemorrhages are caused by IAs 7 mm or smaller. Thus, we sought to identify risk factors associated with the rupture of IAs 7 mm or smaller. METHODS:We identified 100 patients with subarachnoid hemorrhage resulting from IAs 7 mm or smaller between January 2001 and 2004. Patients were compared with controls (n = 51) with unruptured IAs 7 mm or smaller, diagnosed by conventional angiography or three-dimensional computerized angiography, with respect to aneurysm characteristics (size, location, and age of presentation) and risk factors (hypertension, smoking, cocaine use, and family history). RESULTS:Hypertensive patients with IAs 7 mm or smaller were 2.6 times more likely to experience rupture (P = 0.01; 95% confidence interval, 1.21–5.53) than patients with normal blood pressure. Posterior circulation aneurysms were 3.5 times more likely to rupture than anterior circulation aneurysms (P = 0.048; 95% confidence interval, 0.95–19.4). After adjustment for location and hypertension, the age of patient on presentation was associated with a trend toward inverse correlation with aneurysmal rupture risk (P = 0.07). Hypertension and posterior location remained significant independent predictors in the logistic regression model. CONCLUSION:Among patients with small aneurysms (≤7 mm), hypertension, relatively young age, and posterior circulation were significant risk factors for rupture. Given the minimal long-term morbidity and mortality of treatment of unruptured aneurysms in large, tertiary medical centers, management of unruptured aneurysms 7 mm or smaller should be governed by factors other than size, specifically age, history of hypertension, and location.

Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates.

AbstractTwenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding—more than 20 viruses have been recognized as potential oncolytic viruses—new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme. So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against glioblastoma multiforme. In this review, we present an overview of viruses that have been developed or considered for glioblastoma multiforme treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of oncolytic virus application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results; next-generation oncolytic viruses that are either “armed” with therapeutic genes or embedded in a multimodality treatment regimen should enhance the clinical results.

Integrated genomic characterization of IDH1-mutant glioma malignant progression

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Systemic Vesicular Stomatitis Virus Selectively Destroys Multifocal Glioma and Metastatic Carcinoma in Brain

Metastatic tumors and malignant gliomas make up the majority of cancers in the brain. They are invariably fatal and there is currently no cure. From in vitro comparisons of a number of viruses, we selected one that appeared the best in selectively killing glioblastoma cells. This replication-competent virus, the glioma-adapted vesicular stomatis virus strain VSVrp30a, was used for in vivo tests with the underlying view that infection of tumor cells will lead to an increase in the number of viruses subsequently released to kill additional tumor cells. Intravenous injection of VSVrp30a expressing a green fluorescent protein reporter, rapidly targeted and destroyed multiple types of human and mouse tumors implanted in the mouse brain, including glioblastoma and mammary tumors. When tumors were implanted both in the brain and peripherally, emulating systemic cancer metastasis, tumors inside and outside the brain were simultaneously infected. Intranasal inoculation, leading to olfactory nerve transport of the virus into the brain, selectively infected and killed olfactory bulb tumors. Neither control cortical wounds nor transplanted normal mouse or human cells were targeted, indicating viral tumor selectivity. Control viruses, including pseudorabies, adeno-associated, or replication-deficient VSV, did not infect the brain tumor. Confocal laser time-lapse imaging through a cranial window showed that intravenous VSV infects the tumor at multiple sites and kills migrating tumor cells. Disrupted tumor vasculature, suggested by dye leakage, may be the port of entry for intravenously delivered VSV. Quantitative PCR analysis of how VSVrp30a selectively infected tumor cells suggested multiple mechanisms, including cell surface binding and internalization.

First intraoperative, shared-resource, ultrahigh-field 3-Tesla magnetic resonance imaging system and its application in low-grade glioma resection

OBJECT The authors describe the first shared-resource, 3-T intraoperative MR (ioMR) imaging system and analyze its impact on low-grade glioma (LGG) resection with an emphasis on the use of intraoperative proton MR spectroscopy. METHODS The Acibadem University ioMR imaging facility houses a 3-T Siemens Trio system and consists of interconnected but independent MR imaging and surgical suites. Neurosurgery is performed using regular ferromagnetic equipment, and a patient can be transferred to the ioMR imaging system within 1.5 minutes by using a floating table. The ioMR imaging protocol takes < 10 minutes including the transfer, and the authors obtain very high-resolution T2-weighted MR images without the use of intravenous contrast. Functional sequences are performed when needed. A new 5-pin headrest-head coil combination and floating transfer table were specifically designed for this system. RESULTS Since the facility became operational in June 2004, 56 LGG resections have been performed using ioMR imaging, and > 19,000 outpatient MR imaging procedures have been conducted. First-look MR imaging studies led to further resection attempts in 37.5% of cases as well as a 32.3% increase in the number of gross-total resections. Intraoperative ultrasonography detected 16% of the tumor remnants. Intraoperative proton MR spectroscopy and diffusion weighted MR imaging were used to differentiate residual tumor tissue from peritumoral parenchymal changes. Functional and diffusion tensor MR imaging sequences were used both pre- and postoperatively but not intraoperatively. No infections or other procedure-related complications were encountered. CONCLUSIONS This novel, shared-resource, ultrahigh-field, 3-T ioMR imaging system is a cost-effective means of affording a highly capable ioMR imaging system and increases the efficiency of LGG resections.

Outcome determinants of pterional surgery for tuberculum sellae meningiomas

SummaryBackground. Current literature on tuberculum sellae meningiomas is very heterogenous due to wide variation in nomenclature, diagnostic and operative techniques. The aim of this study is specifically to analyze the results of pterional craniotomy for tuberculum sellae meningiomas. A homogenous cohort of 42 consecutively operated tuberculum sellae meningioma cases are reviewed with special emphasis on the effects of pterional microsurgery on visual outcome. Methods. This is a retrospective clinical analysis. 42 consecutive patients operated upon during the period of 15 years in a single institution using standard imaging protocols and pterional microsurgery are presented and effect of various variables on visual outcome analysed. Findings. 81% of the patients presented with visual symptoms. The mean duration of symptoms was 12 months. Tumour volumes ranged from 7.5 to 210 mm3. A right sided pterional microsurgery was used in all patients. Complete resection rate was 81%. Vision improved in 58%, worsened in 14%. Non-visual morbidity was 7.1% and mortality was 2.4%. The follow up period of patients ranged from 3 to 192 months (median: 30 months). The mean was 37.5 months (SD = ±36.7 months) and a recurrence rate of 2.4% was observed. Conclusions. A standard pterional craniotomy using microsurgical technique provides the necessary exposure enabling total removal while keeping the complications to a minimum. Upon analysis of our findings we found that patient age of more than 60, duration of visual symptoms longer than 1 year, severe visual symptomatology, predominantly vertical growth, presence of significant peri-tumoural oedema, absence of an intact arachnoid plane and subtotal removal were correlated with a dismal visual outcome.

Spinal hydatid disease.

Study design: Review article on spinal involvement of hydatid disease.Objectives: A better understanding of this rare but clinically challenging disease is intended. An overview of the epidemiology, pathogenesis, presentation and diagnosis of spinal hydatid disease is provided. Management problems and frequent pitfalls are discussed as well as current therapeutic options, results and outcome.Methods: Thirty-seven reports of spinal hydatid disease published between 1964 and 2000 were reviewed.Results: Most of the reported cases of spinal hydatid disease presented with spinal cord compression syndrome. Due to the relative rarity of the problem the diagnosis was frequently made during surgery. Surgical intervention by decompressive laminectomy was the most frequent first management. Reports of anterior procedures as well as spinal stabilization exist. Intraoperative prophylaxis to reduce spillage as well as pharmacotherapy were usually instituted. Results of surgery were generally reported to be poor. Progressive neurological and mechanical deterioration over the years was the most frequently reported disease course. Anecdotal reports of alternative management strategies exist.Conclusion: Spinal hydatid disease should be considered in the differential diagnosis of spinal cord compression syndrome in endemic countries and sought after with imaging and serology. Treatment is based on surgical decompression. Despite therapy the disease frequently relapses with progressive destruction of the vertebral column and neurological deterioration. Retention of spinal stability is the major long term concern. Overall outcome is poor with few reports of disease-free long term survival.

Experience of a single institution treating foramen magnum meningiomas

Despite the introduction of skull base approaches, there is still controversy in the optimum surgical management of foramen magnum meningiomas. Between January 1990 and January 2003, 22 patients underwent 23 surgical procedures with a diagnosis of foramen magnum meningioma at Marmara University, Department of Neurosurgery. The suboccipital approach was used for 2 posteriorly located tumors with radiological total removal. The paramedian suboccipital approach was replaced by the far-lateral modification in the treatment of ventral meningiomas. 1 of the 20 ventral tumors was operated twice. The classical suboccipital approach was followed by the far-lateral modification. A gross-total removal was achieved in 21 patients. The overall morbidity was 32%. No specific and clinically significant complications attributable to the far-lateral modification were observed. The far-lateral approach has improved the success of surgery in ventrally located lesions. The posterior suboccipital approach is still indicated in the removal of lesions placed posterior to the dentate ligament.

Tenascin in meningioma: Expression is correlated with anaplasia, vascular endothelial growth factor expression, and peritumoral edema but not with tumor border shape

OBJECTIVE : Tenascin is an extracellular matrix glycoprotein that is expressed during embryogenesis, inflammation, angiogenesis, and carcinogenesis. The aim of this study was to investigate how tenascin expression relates to histological grade, angiogenesis, and radiological findings in meningiomas. Methods: Twenty typical, 20 atypical, and 5 malignant meningiomas were studied retrospectively. Tenascin expression and vascular endothelial growth factor (VEGF) expression in the tumor tissue were investigated by immunohistochemistry. Tenascin messenger ribonucleic acid expression was also studied by comparative reverse transciptase-polymerase chain reaction. Magnetic resonance images from each case were assessed for peritumoral edema and tumor border shape. Results: The atypical and malignant meningiomas showed higher levels of tenascin expression than the typical meningiomas. The more sensitive messenger ribonucleic acid-based methods confirmed this finding. Tenascin expression was correlated with peritumoral edema and VEGF expression byt not with tumor border shape. In the 13 tumors with marked tenascin expression, peritumoral edema was Grade 0 in one, Grade 1 in three, and Grade 2 in nine specimens. In the same 13 tumors, VEGF expression was Grade 1 in five and Grade 2 in eight specimens, and the findings for tumor border shape were Grade 0 in seven, Grade 1 in four, and Grade 2 in two speciemens. Conclusion: In meningiomas, tenascin expression is correlated with anaplasia, tumor-associated edema, and VEGF expression but not with tumor border shape. This protein may play a role in the neoplastic and/or angiogenic processes in atypical and malignant meningiomas and may thus be a potential target for meningioma therapy.