Araştırma Çıktıları
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Item Oligosarcomas, IDH-mutant are distinct and aggressive(SPRINGER, 2022-01-01) Suwala, Abigail K.; Felix, Marius; Friedel, Dennis; Stichel, Damian; Schrimpf, Daniel; Hinz, Felix; Hewer, Ekkehard; Schweizer, Leonille; Dohmen, Hildegard; Pohl, Ute; Staszewski, Ori; Korshunov, Andrey; Stein, Marco; Wongsurawat, Thidathip; Cheunsuacchon, Pornsuk; Sathornsumetee, Sith; Koelsche, Christian; Turner, Clinton; Le Rhun, Emilie; Muhlebner, Angelika; Schucht, Philippe; Ozduman, Koray; Ono, Takahiro; Shimizu, Hiroaki; Prinz, Marco; Acker, Till; Herold-Mende, Christel; Kessler, Tobias; Wick, Wolfgang; Capper, David; Wesseling, Pieter; Sahm, Felix; von Deimling, Andreas; Hartmann, Christian; Reuss, David E.Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.Item Longitudinal analysis of treatment-induced genomic alterations in gliomas(BIOMED CENTRAL LTD, 2017-01-01) Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bulent; Harmanci, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Li, Jie; Ozduman, Koray; Carrion-Grant, Geneive; Clark, Victoria E.; Caglar, Caner; Bakircioglu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer; Gunel, MuratBackground: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapyItem Oncolytic Virus Therapy for Glioblastoma Multiforme Concepts and Candidates(LIPPINCOTT WILLIAMS \& WILKINS, 2012-01-01) Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N.Twenty 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 resultsItem Correlation of anatomical involvement patterns of insular gliomas with subnetworks of the limbic system(AMER ASSOC NEUROLOGICAL SURGEONS, 2022-01-01) Ulgen, Ege; Aras, Fuat Kaan; Cosgun, Erdal; Ersen-Danyeli, Ayca; Dincer, Alp; Usseli, M. Imre; Ozduman, Koray; Pamir, M. NecmettinOBJECTIVE Gliomas frequently involve the insula both primarily and secondarily by invasion. Despite the high connectivity of the human insula, gliomas do not spread randomly to or from the insula but follow stereotypical anatomical involvement patterns. In the majority of cases, these patterns correspond to the intrinsic connectivity of the limbic system, except for tumors with aggressive biology. On the basis of these observations, the authors hypothesized that these different involvement patterns may be correlated with distinct outcomes and analyzed these correlations in an institutional cohort. METHODS Fifty-nine patients who had undergone surgery for insular diffuse gliomas and had complete demographic, pre- and postoperative imaging, pathology, molecular genetics, and clinical follow-up data were included in the analysis (median age 37 years, range 21-71 years, M/F ratio 1.68). Patients with gliomatosis and those with only minor involvement of the insula were excluded. The presence of T2-hyperintense tumor infiltration was evaluated in 12 anatomical structures. Hierarchical biclustering was used to identify co-involved structures, and the findings were correlated with established functional anatomy knowledge. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazards regression analysis (17 parameters). RESULTS The tumors involved the anterior insula (98.3\%), posterior insula (67.8\%), temporal operculum (47.5\%), amygdala (42.4\%), frontal operculum (40.7\%), temporal pole (39\%), parolfactory area (35.6\%), hypothalamus (23.7\%), hippocampus (16.9\%), thalamus (6.8\%), striatum (5.1\%), and cingulate gyrus (3.4\%). A mean 4.2 +/- 2.6 structures were involved. On the basis of hierarchical biclustering, 7 involvement patterns were identified and correlated with cortical functional anatomy (pure insular {[}11.9\%], olfactocentric {[}15.3\%], olfactoopercular {[}33.9\%], operculoinsular {[}15.3\%], striatoinsular {[}3.4\%], translimbic {[}11.9\%], and multifocal {[}8.5\%] patterns). Cox regression identified hippocampal involvement (p = 0.006) and postoperative tumor volume (p = 0.027) as significant negative independent prognosticators of overall survival and extent of resection (p = 0.015) as a significant positive independent prognosticator. CONCLUSIONS The study findings indicate that insular gliomas primarily involve the olfactocentric limbic girdle and that involvement in the hippocampocentric limbic girdle is associated with a worse prognosis.