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Item Associations of meningioma molecular subgroup and tumor recurrence(OXFORD UNIV PRESS INC, 2021-01-01) Youngblood, Mark W.; Miyagishima, Danielle F.; Jin, Lan; Gupte, Trisha; Li, Chang; Duran, Daniel; Montejo, Julio D.; Zhao, Amy; Sheth, Amar; Tyrtova, Evgeniya; Ozduman, Koray; Iacoangeli, Francesco; Peyre, Matthieu; Boetto, Julien; Pease, Matthew; Avsar, Timucin; Huttner, Anita; Bilguvar, Kaya; Kilic, Turker; Pamir, M. Necmettin; Amankulor, Nduka; Kalamarides, Michel; Erson-Omay, E. Zeynep; Gunel, Murat; Moliterno, JenniferBackground. We and others have identified mutually exclusive molecular subgroups of meningiomasItem Information theory approaches to improve glioma diagnostic workflows in surgical neuropathology(WILEY, 2022-01-01) Cevik, Lokman; Landrove, Marilyn Vazquez; Aslan, Mehmet Tahir; Khammad, Vasilii; Garagorry Guerra, Francisco Jose; Cabello-Izquierdo, Yolanda; Wang, Wesley; Zhao, Jing; Becker, Aline Paixao; Czeisler, Catherine; Rendeiro, Anne Costa; Sousa Veras, Lucas Luis; Zanon, Maicon Fernando; Reis, Rui Manuel; Matsushita, Marcus de Medeiros; Ozduman, Koray; Pamir, M. Necmettin; Danyeli, Ayca Ersen; Pearce, Thomas; Felicella, Michelle; Eschbacher, Jennifer; Arakaki, Naomi; Martinetto, Horacio; Parwani, Anil; Thomas, Diana L.; Otero, Jose JavierAims Resource-strained healthcare ecosystems often struggle with the adoption of the World Health Organization (WHO) recommendations for the classification of central nervous system (CNS) tumors. The generation of robust clinical diagnostic aids and the advancement of simple solutions to inform investment strategies in surgical neuropathology would improve patient care in these settings. Methods We used simple information theory calculations on a brain cancer simulation model and real-world data sets to compare contributions of clinical, histologic, immunohistochemical, and molecular information. An image noise assay was generated to compare the efficiencies of different image segmentation methods in H\&E and Olig2 stained images obtained from digital slides. An auto-adjustable image analysis workflow was generated and compared with neuropathologists for p53 positivity quantification. Finally, the density of extracted features of the nuclei, p53 positivity quantification, and combined ATRX/age feature was used to generate a predictive model for 1p/19q codeletion in IDH-mutant tumors. Results Information theory calculations can be performed on open access platforms and provide significant insight into linear and nonlinear associations between diagnostic biomarkers. Age, p53, and ATRX status have significant information for the diagnosis of IDH-mutant tumors. The predictive models may facilitate the reduction of false-positive 1p/19q codeletion by fluorescence in situ hybridization (FISH) testing. Conclusions We posit that this approach provides an improvement on the cIMPACT-NOW workflow recommendations for IDH-mutant tumors and a framework for future resource and testing allocation.Item IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation(NATURE PUBLISHING GROUP, 2016-01-01) Oktay, Yavuz; Ulgen, Ege; Can, Ozge; Akyerli, Cemaliye B.; Yuksel, Sirin; Erdemgil, Yigit; Durasi, I. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Sevin; Ozpinar, Aysel; Huse, Jason T.; Sav, M. Aydin; Flanagan, Adrienne; Gunel, Murat; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, KorayThe single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52Item Integrated genomic characterization of IDH1-mutant glioma malignant progression(NATURE PUBLISHING GROUP, 2016-01-01) Bai, Hanwen; Harmanci, Akdes Serin; Erson-Omay, E. Zeynep; Li, Jie; Coskun, Sueleyman; Simon, Matthias; Krischek, Boris; Ozduman, Koray; Omay, S. Buelent; Sorensen, Eric A.; Turcan, Sevin; Bakirciglu, Mehmet; Carrion-Grant, Geneive; Murray, Phillip B.; Clark, Victoria E.; Ercan-Sencicek, A. Gulhan; Knight, James; Sencar, Leman; Altinok, Selin; Kaulen, Leon D.; Guelez, Burcu; Timmer, Marco; Schramm, Johannes; Mishra-Gorur, Ketu; Henegariu, Octavian; Moliterno, Jennifer; Louvi, Angeliki; Chan, Timothy A.; Tannheimer, Stacey L.; Pamir, M. Necmettin; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; Guenel, MuratGliomas represent approximately 30\% of all central nervous system tumors and 80\% of malignant brain tumors(1). 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.Item Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms(MDPI, 2020-01-01) Ulgen, Ege; Karacan, Sila; Gerlevik, Umut; Can, Ozge; Bilguvar, Kaya; Oktay, Yavuz; B. Akyerli, Cemaliye; K. Yuksel, Sirin; E. Danyeli, Ayca; Tihan, Tarik; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, KorayLittle is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and ``Others{''} differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.Item Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis(OXFORD UNIV PRESS INC, 2015-01-01) Erson-Omay, E. Zeynep; Caglayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bulent; Ozduman, Koray; Koksal, Yavuz; Li, Jie; Harmanci, Akdes Serin; Clark, Victoria; Carrion-Grant, Geneive; Baranoski, Jacob; Caglar, Caner; Barak, Tanyeri; Coskun, Suleyman; Baran, Burcin; Kose, Dogan; Sun, Jia; Bakircioglu, Mehmet; Gunel, Jennifer Moliterno; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J.; Sander, Chris; Gunel, MuratBackground. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these ``ultramutated{''} tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.Item Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma(BMC, 2021-01-01) Ulgen, Ege; Can, Ozge; Bilguvar, Kaya; Boylu, Cemaliye Akyerli; Yuksel, Sirin Kilicturgay; Danyeli, Ayca Ersen; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, KorayBackground In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. Methods The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. Results The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14-33) variants per patient was reported. There was a median of 6 (0-590) reported somatic short variants per tumor. A median of 19 (0-94) broad SCNAs and a median of 6 (0-12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38\%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9\%). Conclusions We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.Item The effect of tumor shape irregularity on Gamma Knife treatment plan quality and treatment outcome: an analysis of 234 vestibular schwannomas(NATURE PORTFOLIO, 2022-01-01) Sumer, Esra; Tek, Ece; Ture, O. Artunc; Sengoz, Meric; Dincer, Alp; Ozcan, Alpay; Pamir, M. Necmettin; Ozduman, Koray; Ozturk-Isik, EsinThe primary aim of Gamma Knife (GK) radiosurgery is to deliver high-dose radiation precisely to a target while conforming to the target shape. In this study, the effects of tumor shape irregularity (TSI) on GK dose-plan quality and treatment outcomes were analyzed in 234 vestibular schwannomas. TSI was quantified using seven different metrics including volumetric index of sphericity (VioS). GK treatment plans were created on a single GK-Perfexion/ICON platform. The plan quality was measured using selectivity index (SI), gradient index (GI), Paddick's conformity index (PCI), and efficiency index (EI). Correlation and linear regression analyses were conducted between shape irregularity features and dose plan indices. Machine learning was employed to identify the shape feature that predicted dose plan quality most effectively. The treatment outcome analysis including tumor growth control and serviceable hearing preservation at 2 years, were conducted using Cox regression analyses. All TSI features correlated significantly with the dose plan indices (P < 0.0012). With increasing tumor volume, vestibular schwannomas became more spherical (P < 0.05) and the dose plan indices varied significantly between tumor volume subgroups (P < 0.001 and P < 0.01). VioS was the most effective predictor of GK indices (P < 0.001) and we obtained 89.36\% accuracy (79.17\% sensitivity and 100\% specificity) for predicting PCI. Our results indicated that TSI had significant effects on the plan quality however did not adversely affect treatment outcomes.Item The Carotid Endarterectomy Cadaveric Investigation for Cranial Nerve Injuries: Anatomical Study(MDPI, 2021-01-01) Cevik, Orhun Mete; Usseli, Murat Imre; Babur, Mert; Unal, Cansu; Eksi, Murat Sakir; Guduk, Mustafa; Ovalioglu, Talat Cem; Aksoy, Mehmet Emin; Pamir, M. Necmettin; Bozkurt, BaranCerebral stroke continues to be one of the leading causes of mortality and long-term morbidityItem Pterional and Unifrontal Approaches for the Microsurgical Resection of Olfactory Groove Meningiomas: Experience with 61 Consecutive Patients(TURKISH NEUROSURGICAL SOC, 2017-01-01) Guduk, Mustafa; Yener, Ulas; Sun, Halil Ibrahim; Hacihanefioglu, Mehmet; Ozduman, Koray; Pamir, M. NecmettinAIM: Olfactory groove meningiomas make up 4 to 13\% of meningiomas. The first line treatment of meningiomas is surgery, but the extent and types of approaches advised for olfactory groove meningiomas are diverse, from aggressive skull base approaches to standard or minimally invasive craniotomies and endoscopic approaches. We retrospectively reviewed our series of olfactory groove meningiomas that were operated microsurgically by standard pterional or unifrontal approaches. MATERIAL and METHODS: Our series of 61 olfactory groove meningioma patients operated through pterional or unifrontal approaches between March 1987 and September 2015 was reviewed and the clinical data, radiological findings, surgical treatment and clinical outcomes of the patients were retrospectively analyzed. RESULTS: Sixty-three craniotomies were performed in total. Pterional and unifrontal approaches were used in 38 (60.3\%) and 25 (39.7\%) surgical procedures, respectively. Overall, gross total tumor resection was achieved in 59 (93.7\%) cases. Complications were seen in 8 cases, and 2 of these patients underwent reoperation. Three of the 4 patients where only subtotal resection could be achieved underwent gamma knife radiosurgery. CONCLUSION: Pterional and unifrontal approaches, which are familiar and standard for neurosurgeons, can accomplish high rates of total resection with acceptable complication and recurrence rates for the treatment of olfactory groove meningiomas.