17. NOA Tagung 2015 in Heidelberg

Transkript

1 17. NOA Tagung 2015 in Heidelberg

2 Liebe Kolleginnen, liebe Kollegen, EINLADUNG ZUR NOA NACH HEIDELBERG wir laden Sie im Namen des NOA-Vorstands sehr herzlich zur 17. NOA-Tagung ein. Am 18. und 19. Juni 2015 werden wir erneut den aktuellen Stand der klinisch relevanten Grundlagenforschung und der klinischen Forschung bei primären Hirntumoren diskutieren. Schwerpunkte der diesjährigen Tagung sind ein Überblick über die molekularen Biomarker, Gliomtherapien, patientenzentrierte Studienendpunkte und Vorträge mit Tumorboardelementen. Am 18. Juni werden wir abends in der Kulturbrauerei neben der Verleihung des Assmus-Preises für Neuroonkologie Gelegenheit zu weiterführenden Diskussionen haben. Aufgrund der geänderten Finanzierungsoptionen und aus Compliancegründen müssen wir einen Kostenbeitrag von 50 von Ihnen erheben, den Sie bitte mit der Anmeldung auf das unten angegebene Konto überweisen. Wir laden zur Einreichung von Abstracts für Posterbeiträge, die während der gesamten Tagung ausgestellt werden, ein. Abstractautoren müssen keinen Kostenbeitrag leisten. Außerdem wählen wir aus den Abstracts im NOA-Vorstand einige freie Vorträge aus. Zimmer können Sie aus dem reichhaltigen Angebot der Stadt buchen. Wir haben Zimmerkontingente zu Sonderpreisen im HIP-Hotel ( Buchungsoption bis ) und im Parkhotel Atlantic ( Buchungsoptionen bis ) für Sie reserviert. Bitte geben Sie bei der Buchung das Stichwort NOA-Tagung 2015 an. Des Weiteren stehen in der Umgebung Unterkünfte in verschiedenen Preiskategorien zur Verfügung. Wir freuen uns darauf, Sie in Heidelberg begrüßen zu dürfen. Herzlichst Ihr Prof. Dr. Wolfgang Wick Sprecher der NOA 2

3 17. NOA Tagung 2015 Ort: Molkenkur, Heidelberg, Klingenteichstrasse 31, Heidelberg Programm (Version 3, ) Donnerstag, 18. Juni :00 h Vorstandssitzung (bis 11:00 h) ab 11:00 h Akkreditierung und Imbiss 12:00 h Begrüßung W. Wick (Heidelberg) h Aktueller Stand und Neuigkeiten der NOA Studien und der NOAassoziierten Studien Vorsitz: J.P. Steinbach, Frankfurt & S.E. Combs, München NOA-04 NOA-07 NOA-09/CeTeG NOA-10 NOA-11/PDT NOA-12/NONK-3 NOA-14/Hipporad NOA-16/NONK-6 W. Wick (Heidelberg) P. Hau (Regensburg) M. Glas (Bonn) A. Grosu (Freiburg) W. Stummer (Münster) M. Platten (Heidelberg) A. Grosu (Freiburg) M. Platten (Heidelberg) h Kaffeepause 14:30 h Neues aus der Grundlagenwissenschaft Vorsitz: G. Tabatabai (Tübingen) & P. Vajkoczy (Berlin) Gliome: eine Netzwerkerkrankung F. Winkler 15 min (Heidelberg) Die hypoxische Nische und hallmarks of cancer T. Acker 15 min (Giessen) Heterogenität bei Gliomen M. Glas 15 min (Bonn) Stammzellen bei Gliomen G. 15 min Niedermann (Freiburg) Vier freie Vorträge à 8 min ErbB2/HER2-targeted NK cells display potent activity against glioblastoma and enhance survival M. Burger (Frankfurt) 3

4 Synergie von Strahlentherapie und Antigen-spezifischer Vakzinierung in der Behandlung maligner Gliome K. Ochs (Heidelberg) ZEB1 is ubiquitously expressed across subtypes in human glioblastoma and a surrogate marker of tumor purity P. Euskirchen (Berlin) Über die parakrinen immunmodulatorischen Effekte des Onkometaboliten 2- Hydroxyglutarat im Gliommikromilieu T. Schumacher (Heidelberg) 16:00 h Kaffeepause 16:15 h Fokus: Kontroverse Themen der Neuroonkologie Vorsitz: J.-C. Tonn & F. Schmidt (München) Ependymome: Standardtherapie J. Boström 15 min im TuBo Stil (Bonn) Ependymome: Entwicklungen J.-C. Tonn 15 min im TuBo Stil (München) Primärtherapie bei PZNSL A. Korfel 15 min (Berlin) Rezidivtherapie bei PZNSL U. Schlegel 15 min (Bochum) Zerebrale Oligomestatasierung in das ZNS: Relevanz W. Stummer 15 min (Münster) Therapiekonzepte aus Sicht der Radioonkologie S. Combs 15 min (München) 17:45 h Entwicklungen in der Rezidivtherapie von Gliomen Vorsitz: W. Stummer (Münster) & C. Herold-Mende (Heidelberg) Rezidivoperation: wer, wann, warum? (Re-Surge) Temozolomid, Lomustin, Rebestrahlung, und nun? Im TuBo Stil A. Raabe (Bern) J.P. Steinbach (Frankfurt) 18:15 h Keynote Lecture: Immuntherapie für Gliome M. Platten Vorsitz: Wolfgang Wick (Heidelberg) (Heidelberg) 19:00 h Mitgliederversammlung der NOA ab 20:00 Gesellschaftsabend mit Verleihung des Assmus-Preises für Neuroonkologie 4

5 Freitag, 19. Juni :15 h Studien der EORTC Hirntumorgruppe M. Weller (Zürich) 08:30 h Molekulare Neuroonkologie Vorsitz: C. Hartmann (Hannover) & D. Capper (Heidelberg) Grading in der WHO Klassifikation: fact or fiction A. von 15 min Deimling (Heidelberg) Methylierungsplattform: Neuropathologe 2.0 D. Jones 15 min (Heidelberg) Biomarker für Therapieentscheidungen M. Weller 15 min Im TuBo Stil (Zürich) INFORM Register für kindliche Tumoren O. Witt 10 min (Heidelberg) NCT Neuro Master Match (N 2 M 2 ) W. Wick 10 min (Heidelberg) Drei freie Vorträge à 8 min ATF4 as a mediator of resistance to targeted therapy in high-grade gliomas S. Moeckel (Regensburg) Prognostic value of the extent of resection and IDH1 mutation status in WHO grade II astrocytomas C. Jungk (Heidelberg) Next-Generation-Sequencing in routine neuropathology diagnostics F. Sahm (Heidelberg) 10:00 h Kaffeepause 10:30 h Fokus: Patientenzentrierung alternative Endpunkte Vorsitz: A. Wick & A. Unterberg (Heidelberg) Psychoonkologie D. Wiewrodt 15 min (Münster) Cognitive Function M. Klein 15 min (Amsterdam) Supportivtherapie Palliation J. Rieger 15 min (Frankfurt) Immunmonitoring für Gliomstudien M. Platten 10 min (Heidelberg) 5

6 Alternative Studienendpunkte W. Wick 10 min (Heidelberg) 3 freie Vorträge MRI tumor progression patterns in the GLARIUS trial S. Kebir (Bonn) Resection of prerolandic motor areas defined by ntms motor evoked potentials correlates with postoperative motor function S.M. Krieg (München) Supportive care in patients with high-grade gliomas how to integrate clinical assessment in daily routine? Results of a prospective multicentric trial ERASMUS in 175 patients. M. Renonvanz (Mainz) 12:00 h Bildgebung: Wissenschaft, Surrogat, Klinik Vorsitz: E. Hattingen (Bonn) & M. Bendszus (Heidelberg) Internationales MRT Standardprotokoll Advanced Imaging mittels MRT: Bonner Sicht Advanced Imaging mittels MRT: Heidelberger Sicht PET zur RT Planung und Verlaufskontrolle M. Bendszus (Heidelberg) E. Hattingen (Bonn) A. Radbruch (Heidelberg) A. Grosu (Freiburg) 13:15 h Mittagspause PET zur Differenzierung von strahlenbedingten Veränderungen N. Galldiks, Köln 14:00 h Entwicklungen in der Primärtherapie von Gliomen Vorsitz: P. Hau (Regensburg) & A. Weyerbrock (Freiburg) Frühe aggressive Therapie von WHO Grad II Gliomen pro R. 15 min Goldbrunner (Köln) Frühe aggressive Therapie von WHO Grad II Gliomen contra U. Schlegel 15 min (Bochum) Standard und neue Fragen für 1p/19q kodeletierte Gliome U. Herrlinger 15 min Im TuBo Stil (Bonn) NOVO TTF: Ergebnisse der Primärtherapiestudie bei Patienten A. Hottinger mit neu diagnostiziertem Glioblastom (Genf) 20 min Immuntherapie: 6

7 fact? O. Grauer 10 min (Münster) fiction? P. Roth 10 min (Zürich) 15:30 h Keynote Lecture: WHO Classification of Brain Tumors Vorsitz: G. Reifenberger (Düsseldorf) WHO Classification of Brain Tumors David Louis (Boston) 16:15 h Kaffepause 7

8 Informationen Anmeldung: über die NOA-Homepage Kosten: 50 Baden-Württembergische Bank Stuttgart BLZ Kto.Nr IBAN DE Stichwort: NOA-Tagung, D Webseite: CME Punkte: 18 (beantragt) Tagungsort: Molkenkur, Klingenteichstrasse 31, Heidelberg Sponsoren: Gold: Silber: Bronze: 8

9 Abstracts der 17. NOA-Tagung *Kurzvorträge sind markiert Stereotactic fractionated radiotherapy of the resection cavity in patients with one to three brain metastases A. Bilger, Milanovic, Lorenz, A.-L. Grosu Dept. Of Radiation Oncology, University Clinic Freiburg In patients undergoing surgical resection of brain metastasis local recurrence is about 60%. Whole brain Radiation Therapy (WBRT) can significantly reduce the risk of local relapse but fails to improve overall survival. The most important side effects of WBRT are neurocognitive deficits, which can reduce quality of life. Stereotactic fractionated radiotherapy (SFRT) of the resection cavity could be an alternative to WBRT in patients with a limited number of brain metastasis. The goal of this study is to evaluate the role of SFRT of the resection cavity in patients with 1 to 3 brain metastases after surgical resection. From November 2009 to August resection cavities of 60 patients were treated by SFRT. All patients had 3 brain metastasis. The total irradiation dose was 30 Gy in 5 Gy/d, 5x/week after complete macroscopical resection and 35 Gy (5Gy/d) in patients with macroscopic residual tumor after surgery. The gross tumor volume (GTV) encompasses the residual tumor delineated on the contrast-enhanced T1- MRI, the clinical target volume (CTV) encompasses the surgical cavity plus 1 mm and the planning target volume (PTV) the CTV plus 2 mm. In 52 patients there was a follow-up with MRI to evaluate local and distant intracranial tumor control. There were 6/52 (11.54%) local failures and 29/52 (55.77%) distant failures. Local control was correlated with age (p=0.046). 37/60 (61.6%) patients died during follow-up. Median follow-up was 8 months. Median Overall survival was 15 months. Survival was correlated with KPS score 70% and PTV (ccm). No severe side effects were seen. SFRT of the resection cavity could be an alternative to WBRT after surgical resection of 3 brain metastasis. Prospective studies are warranted. *ErbB2/HER2-targeted NK cells display potent activity against glioblastoma and enhance survival Michael Burger 1,2, Congcong Zhang 2,3, Iris Mildenberger 1,2, Lukas Jennewein 4, Sabrina Genßler 3, Kurt Schönfeld 3, Pia Zeiner 4, Elke Hattingen 5, Patrick N. Harter 4, Michel Mittelbronn 4, Torsten Tonn 6, Winfried S. Wels 2,3, Joachim P. Steinbach 1,2 1 Institute for Neurooncology, Goethe University, Frankfurt am Main, Germany. 2 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. 3 Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany. 4 Edinger Institute, Goethe University, Frankfurt am Main, Germany. 5 Institute of Neuroradiology, Goethe University, Frankfurt am Main, Germany. 6 Institute for Transfusion Medicine, German 9

10 Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany. Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and is currently incurable. Recent studies suggest that natural killer (NK) cells have potential for adoptive immunotherapy of GBM if consistent activation of their cytolytic activity is maintained in the tumor microenvironment. To specifically target NK cell activity to GBM, we employed NK-92/5.28.z cells which are continuously expanding human NK cells that carry an ErbB2-specific second generation chimeric antigen receptor (CAR). The cells were previously derived from the clinically applicable NK- 92 cell line under GMP conditions by transduction with a lentiviral CAR vector. In immunohistochemical analysis we found elevated ErbB2 protein expression in >20% of primary GBM samples and in the majority of GBM cell lines analyzed. In in vitro cell killing assays, NK-92/5.28.z in contrast to untargeted NK-92 cells lysed all ErbB2- positive established and primary GBM cells tested, with cell killing kinetics correlating with the degree of NK cell activation upon contact with tumor cells. Potent in vivo antitumor activity of NK-92/5.28.z cells was observed in different orthotopic GBM xenograft models in NSG mice, resulting in inhibition of tumor growth and marked extension of symptom-free survival upon repeated stereotactic injection of the CAR NK cells into the tumor area. Our data demonstrate the potential of ErbB2-specific NK-92/5.28.z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2-positive GBM in clinical studies. *ZEB1 is ubiquitously expressed across subtypes in human glioblastoma and a surrogate marker of tumor purity Philipp Euskirchen 1, Josefine Radke 2, Marc Sören Schmidt 1, Eva Schulze Heuling 1, Eric Kadikowski 1, Meron Maricos 1, Felix Knab 1, Jun Cheng 3, Peter Hufnagl 4, Marcus Czabanka 5, Christoph Dieterich 3, Hrvoje Miletic 6,7, Sverre Mørk 7, Arend Koch 2, Matthias Endres 1 and Christoph Harms 1 1 Dept. of Neurology, Charité Universitätsmedizin Berlin 2 Dept. of Neuropathology, Charité Universitätsmedizin Berlin 3 Max-Planck-Institute for the Biology of Ageing, Cologne 4 Dept. of Pathology, Charité Universitätsmedizin Berlin 5 Dept. of Neurosurgery, Charité Universitätsmedizin Berlin 6 Dept. of Biomedicine, University of Bergen, Norway 7 Department of Pathology, Haukeland University Hospital, Norway The transcription factor ZEB1 has gained attention in tumor biology of epithelial cancers because of its suggested roles in epithelial-mesenchymal transition, DNA repair, mediation of stem cell properties and tumor-induced immunosuppresion, but its role in CNS tumors, especially glioblastoma multiforme is not well understood. We comprehensively characterized ZEB1 expression at single cell level in biopsy samples from 273 human astroglial tumors. Interaction of ZEB1 and EGFR signalling was interrogated in vitro by realtime quantitative PCR and immunocytochemistry in glioma stem cell lines from subtype-stratified parental tumors based on RNAseq transcriptomic gene expression profiles. 10

11 ZEB1 is expressed in nearly all examined tumors but in highly variable fraction of cells. Co-staining of reactive CNS cell types in non-tumor tissue show that besides bona fide tumor cells, only reactive astrocytes but not leucocytes, microglia and macrophages contribute to the ZEB1 positive population. In GBM, ZEB1 labelling index correlates with EGFR amplification and IDH1 mutation, but EGFR modulation by cetuximab treatment did not alter ZEB1 expression in vitro. ZEB1 is expressed ubiquitously and across molecularily defined subtypes in glioblastoma multiforme as well as in non-gbm astroglial tumors. ZEB1 labelling varies across GBM subtypes, but a causal link remains questionable. We speculate that ZEB1 is a pan-astroglial tumor marker that reflects tumor purity. *Prognostic value of the extent of resection and IDH1 mutation status in WHO grade II astrocytomas Christine Jungk 1, Moritz Scherer 1, Andreas Mock 1, David Capper 2, Alexander Radbruch 3, Andreas v. Deimling 2, Christel Herold-Mende 1, Andreas Unterberg 1 1 Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany 2 Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany 3 Division of Neuroradiology, Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany Current evidence is in favour of a maximized extent of resection (EOR) in low-grade gliomas (LGG). However, conclusions were drawn from pooled cohorts of astrocytic and oligodendroglial histology, underrating the fact that histologic subtypes and molecular markers like mutations in the isocitrate dehydrogenase (IDH)1 entail divergent outcomes. We therefore evaluated the prognostic impact of extensive surgery in pure astrocytic LGGs stratified for IDH1 mutation status. Forty-six consecutive cases of 1 st resections for WHO grade II astrocytoma with known IDH1 mutation status were analysed. Pre-, postoperative and follow-up tumour volumes were calculated on FLAIR images. Cases with EOR 40% (n=39) were analysed separately. Analysis for overall (OS), progression-free (PFS), malignant progression-free (MPFS) survival and time to reintervention (TTR) was conducted with uni- (uv) and multivariate (mv) regression models. Analysing the complete cohort, a median final EOR of 90.4% (range %) was achieved at follow-up MRI, corresponding to a median residual tumour volume of 4.09 cm 3. EOR did not impact on OS but was significantly associated with PFS (HR 0.23; p=0.04) and TTR (HR=0.23; p=0.04; uv). IDH1 was the only independent prognosticator for OS (HR 0.04; p=0.002; mv). When restricting survival analysis to cases with EOR 40%, both initial and residual tumour volumes were predictive of OS (HR >1, p<0.01 and HR>1, p<0.05, respectively; uv), even after adjustment for IDH1. No significant correlation between EOR and neurologic morbidity was observed (p=0.73). In this histology-adjusted cohort, a greater EOR significantly delayed tumour progression, malignisation and TTR without causing additional neurologic morbidity. OS was predominantly determined by the presence of IDH1 mutations. Noteworthy, in IDH1-mutated, EOR 40% cases, extensive surgery was predictive of OS as well. 11

12 Our approach illustrates the diverse impact of biological and surgical factors upon outcome, underscoring the need to strive for maximized and safe resections. *MRI tumor progression patterns in the GLARIUS trial Sied Kebir 1,2, Nina Junold 1, Elke Hattingen 3, Christina Schaub 1, Niklas Schäfer 1,2, Joachim P. Steinbach, 4 Astrid Weyerbrock, 5 Peter Hau, 6 Roland Goldbrunner, 7 Michael Niessen 1, Frederic Mack 1, Moritz Stuplich 1, Theophilos Tzaridis 1, Oliver Bähr, Martin Proescholdt, 8 Martin Glas 1,2,9, Ulrich Herrlinger 1 1 Division of Clinical Neurooncology, Dept. of Neurology; University of Bonn, 2 Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 3 Divison of Neuroradiology; Department of Radiology, University of Bonn, 4 Dr. Senckenberg Institute of Neurooncology, University of Frankfurt, 5 Department of Neurosurgery, University of Freiburg, 6 Department of Neurology and Wilhelm Sander NeuroOncology Unit, University of Regensburg, 7 Department of Neurosurgery, University of Cologne, 8 Department of Neurosurgery, University of Regensburg, 9 Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik, Bonn, Germany We evaluated patterns of tumor progression in patients with primary glioblastoma who were assigned to undergo treatment with bevacizumab/irinotecan (BEV/IRI) versus standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. In 160 patients (106 BEV/IRI, 54 TMZ), we reviewed MRI scans at baseline and tumor progression. Based on contrast-enhanced T1-weighted and FLAIR images we assessed tumor patterns and invasiveness. Tumor patterns were classified as either multifocal or local at baseline and progression; at progression, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations were calculated using Fisher s exact test. At baseline, 118 of 160 evaluable patients (73,8%) had a locally confined tumor. In the BEV/IRI arm 10% and in the TMZ arm 8% of patients with an initially local tumor growth changed to a multifocal pattern (p=0.78); distant lesions were found in 24% in the BEV/IRI arm and 19% in the TMZ arm (p=0.55). Eight percent of patients in the BEV/IRI arm and 11% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p=0.58). The tumor progression and invasiveness patterns do not differ between BEV/IRI and TMZ-treated patients in the GLARIUS trial. BEV/IRI did not increase the rate of multifocal, distant or highly invasive tumors at the time of progression. Cerebrale Ischämie unter Glioblastom-Rezidiv-Therapie mit Bevacizumab Koeppen S 1, Hense J 2 1 Klinik für Neurologie, 2 Westdeutsches Tumorzentrum, Universitätsklinikum Essen Bevacizumab, ein humanisierter monoklonaler Antikörper gegen zirkulierenden Vascular Endothelial Growth Factor (VEGF), findet insbesondere in Kombination mit 12

13 Lomustin breite Anwendung in der Rezidivbehandlung des Glioblastoms (GBM). Gliom-Patienten haben bereits therapieunabhängig ein erhöhtes Risiko, einen ischämischen Hirninfarkt oder eine intrakranielle Blutung zu erleiden. Unter antiangiogener Therapie lag die Inzidenz für ischämische Schlaganfälle und intrakranielle Hämatome in einer auf Patientendaten aus 4 Phase I- bzw. Phase II- Studien im Zeitraum basierenden retrospektiven Analyse des National Cancer Institute bei jeweils 1.9%. Eine 50-jährige Patientin, bei der 2/2014 ein links frontales GBM mit negativem Methylierungsstatus teilreseziert und anschließend eine standardmäßige Radio- Chemotherapie mit konkomitanter und adjuvanter Temozolomid-Gabe durchgeführt worden war, unterzog sich 6/2014 wegen Tumorprogress einer Navigations- und 5- Aminolävulinsäure (ALA)-gestützten Wachkraniotomie, erhielt 7/2014 eine Lumbaldrainage aufgrund eines Liquorkissens links frontal, wurde dann mit Irinotecan ± Temsirolimus im Rahmen einer unizentrischen Phase I-Studie (TEMIR) behandelt und ab 11/2014 mit Bevacizumab wegen erneuten Tumorwachstums, welches sich im weiteren Verlauf regredient zeigte. 3/2015 traten subakut holocephale Kopfschmerzen, eine fluktuierende expressive Aphasie mit phonematischen und semantischen Paraphasien, eine Dysphagie, Dyslexie, leichtgradige zentrale Facialisparese rechts und ein Babinski-Phänomen links auf. Im MRT stellten sich hämorrhagische, gering Kontrastmittel (KM)-anreichernde Areale in der Umgebung der Resektionshöhle, ventral in den Stammganglien, links insulär und rechts frontal dar neben Tumoranteilen ohne KM-Enhancement links, zusätzlich akute ischämische Areale links temporo-parietal und bds. ventral in den Stammganglien. Doppler-/duplexsonographisch fand sich extra- und transcraniell keine Stenose / Occlusion der hirnversorgenden Arterien. Unter Ischämieprophylaxe mit Acetylsalicylsäure (ASS) 100mg/d und Enoxaparin 60mg/d war die neurologische Symptomatik innerhalb von 4 Tagen partiell rückläufig bei gleichzeitiger antiödematöser Therapie mit Dexamethason 8mg/d. 9 Tage später erfolgte allerdings eine notfallmäßige stationäre Aufnahme der Patientin wegen Diplopie, Schwindel und ausgeprägter Fatigue. Während es sich bei den bisher beschriebenen mit anti-angiogener Therapie assoziierten cerebralen Ischämien in 50% der Fälle um lakunäre Durchblutungsstörungen handelte, die sich mit einer medianen Latenz von 16.2 Monaten nach Therapiebeginn entwickelten, kam es im vorliegenden Fall unter Monotherapie mit Bevacizumab bereits nach 4 Monaten zu einer territorialen Ischämie im Arteria cerebri media Areal links, die unter Thrombozytenaggregationshemmung mit ASS partiell reversibel war. Die rasch nachfolgende Verschlechterung des Allgemeinzustandes und Zunahme der neurologischen Symptomatik ließ sich einer Tumorprogression nach Absetzen von Bevacizumab zuordnen. Venous thromboembolism in human glioblastoma: The journey from patients symptoms to tumor biology and back to a clinical trial from Trousseau Syndrome to CoaGlio IV Susanne A. Kuhn 1, Tobias Kratzsch 2, Linn Handel 3, Rolf Kalff 3, Uwe-Karsten Hanisch( ) 4,5, Peter Vajkoczy 2 1 Hospital Ernst von Bergmann, Department of Neurosurgery, Potsdam, Germany 13

14 2 Charité-Universitätsmedizin Berlin, Department of Neurosurgery, Berlin, Germany 3 Medical Center of Jena University, Department of Neurosurgery, Jena, Germany 4 Universitätsmedizin Göttingen, Institute for Neuropathology, Göttingen, Germany 5 Paul-Flechsing-Institut, Universität Leipzig, Germany Venous thromboembolism (VTE) is a largely preventable, often fatal complication in cancer patients. Multiple anticoagulants are widely and affordably available, but unfortunately VTE is often not prevented and represents the second most frequent death cause in cancer patients. Further, the annual average total costs for cancer patients with VTE were found to be almost 50% higher than that of cancer patients without VTE. Additionally, growing evidence shows VTE as paraneoplastic syndrome, acting as external monitor of highly coagulation-active tumors that use the coagulation system for supporting their own aggressive malignancy. VTE events in malignant tumors will harm patients and recur, unless the tumors coagulative activity isn t blocked. Currently, no guidelines can recommend long-term prophylactic anticoagulation, as there exists not any officially approved anticoagulant drug, neither subcutaneously nor orally to administer, that was tested for its VTE prophylactic power in a patient population of solely cancer patients. This study aims at pathway, target, and drug identification and the generation of a clinical trial for providing a rationale for consequent VTE prophylaxis. Clinical file review, prospective cohort study (n=41), glioblastoma (GBM) sample immunochemistry (n=112), cell line assays (n>450) and animal models (n=20) were performed. Target for VTE prevention and experimental drug was identified. Clinical study for VTE prophylaxis was developed as randomized, controlled, triple-blind, multinational clinical phase III trial CoaGlio IV. GBM patients experience clinically evident VTE in one third of all cases; silent events are even more common. As they show pathologically activated coagulation factors (FII-FXII) in their systemic coagulation, those with VTE display significant correlation with coagulation factor activation (p=0.018). Further, patients with preoperative, protective co-activation of antithrombin III experience longer survival times, whereas patients with preoperative, normal or low antithrombin III survive shorter. Not enough the coagulation activation in the periphery, glioblastoma tissue pathologically expresses all coagulation factors of the intrinsic pathway as well as the common final pathway (FII, FIX, FX, FXI, FXII, p<0.05), and the coagulation factor receptors PAR-1 and PAR-4 (p<0.05). The activation of receptors with coagulation factors increases cellular DNA synthesis (p<0.01), proliferation (p<0.01), and migration (p<0.05). Consequently, VTE prophylaxis by low molecular weight heparins reduces size of established human glioblastomas in xenografts (p<0.05), mitotic activity within xenografts and tumor angiogenesis. Taken together and reflected against the background of other human cancers, clinical trials for VTE prophylaxis are urgently needed. Therefore, the controlled, triple-blind, multinational phase III study (CoaGlio IV) was created to randomize 530 patients in a 1:1 fashion to receive either international first line standard therapy after surgery (radiochemotherapy with temozolomide + adjuvant temozolomide) and placebo or consequent postoperative prophylactic anticoagulation with oral factor Xa blocker apixaban over a 12-monthperiod. The power calculation is a 10% difference in overall survival, power at 80%, and two-sided alpha level of The primary endpoint is overall survival. Trial will activate at more than 20 centers in Germany, Austria, Switzerland, and the United States. Trial is registered at European Clinical Trials Database: Finally, factor Xa inhibition not only should prevent VTE frequency, severity, as well as related deaths in the short time, but also should improve the long-term prognosis 14

15 by active inhibition of tumor biology. Transfer of clinical problems into the lab as well as translation of results into a clinical study protocol is necessary, as VTE is a dangerous complication, and glioblastoma is still a deadly disease. Ibuprofen and diclofenac inhibit migration and proliferation of human glioma cell lines in vitro Verena Leidgens 1, Corinna Seliger 1, Petra Leukel 1, Arabel Vollmann-Zwerenz 1, Lisa Rauer 1, Ulrich Bogdahn 1, Marina Kreutz 2, Paul Sander 3, Oliver M. Grauer 1,4, Peter Hau 1 1 Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University of Regensburg, Regensburg, Germany, 2 Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany, 3 Institute of Biophysics and Physical Biochemistry, University of Regensburg, Regensburg, Germany, 4 Department of Neurology, University Hospital Münster, Münster, Germany Hallmarked by infiltrating tumor cells, Glioblastoma (GBM) are characterized as highly malignant brain tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been described to inhibit tumor cell proliferation as well as to induce tumor cell apoptosis in a Cox-independent way. The current study was designed to evaluate the effects of the NSAIDs diclofenac and ibuprofen (in concentrations achievable in patients) on proliferation, migration and lactate formation in several human glioma cells. Significantly decreased migration and proliferation was observed with diclofenac or ibuprofen, whereas ASA had negligible effects. Additionally, diclofenac and ibuprofen proved to affect cell proliferation as ibuprofen caused cell cycle arrest in G1 whereas cells treated with higher diclofenac concentrations arrest at the G2/M checkpoint. Both drugs lead to a decrease of lactate and pstat3 levels. To further investigate STAT3 effects, the specific inhibitor STATTIC preventing STAT3 phosphorylation was used, revealing a comparable effect on cell proliferation and migration supporting the substantial role of STAT3 in this regulation cascade. In summary, this study shows an in vitro treatment advantage of diclofenac or ibuprofen over ASA. Thus both NSAIDs may be suited to augment GBM treatment in patients, due to their migration and proliferation inhibiting effects. Consequential further comparative studies with different NSAIDs and in vivo studies are necessary to affirm the positive effects of diclofenac and ibuprofen in glioma patient treatment. *ATF4 as a mediator of resistance to targeted therapy in high-grade gliomas Sylvia Moeckel 1, Bart Neyns 2, Edward Pan 3, Markus J. Riemenschneider 4, Anja- Katrin Bosserhoff 5, Arabel Vollmann-Zwerenz 1, Katharina Meyer 6, Rainer Spang 6, Peter Hau 1 1 Wilhelm Sander-NeuroOncology Unit and Department of Neurology, 4 Department of Neuropathology, Regensburg University Hospital, 6 Institute of Functional Genomics, University of Regensburg, Regensburg, Germany 5 Institute of Biochemistry, Emil-FischerCenter, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany 15

16 2 Medical Oncology, UZ Brussel, Brussel, Belgium, 3 Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA Small molecule inhibitors have been investigated in a large set of clinical trials in high-grade gliomas (HGG). Despite promising preclinical studies, results of pilot trials have been generally disappointing. A deeper understanding of the complex biology of malignant glioma cells, and their adaptation to targeted agents is therefore critical for further therapy development. We performed microarray analysis in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Based on the observation of gene network analysis we hypothesize that the central mediator of the integrated stress response ATF4 (activating transcription factor 4) plays an important role in the regulation of the Sunitinib induced expression profiles and probably in the adaptation to treatment conditions. ATF4 is involved in metabolism and nutrient uptake, antioxidation, and regulation of apoptosis and autophagy. Of note, ATF4 has been associated with multidrug resistance in different cancer models. We analyzed the expression of ATF4 in paraffin embedded tissue blocks from HGG patients treated with Sunitinib by immunohistochemistry. Interestingly, ATF4 significantly correlated with shorter overall survival from the beginning of Sunitinib treatment. In vitro studies confirmed a dose dependent induction of ATF4 protein expression in Sunitinib treated BTICs. Furthermore we observed an intracellular accumulation of autophagosomes. Co-administration of the autophagy inhibitor Chloroquine could enhance the sensitivity to Sunitinib treatment. In summary our data suggest that ATF4 expression may be predictive for response to Sunitinib and might also be involved in general resistance mechanisms in HGGs. Further studies are ongoing to elucidate the induction of apoptosis and autophagy in dependence of ATF4 expression and its contribution to therapy response. *Resection of prerolandic motor areas defined by ntms motor evoked potentials correlates with postoperative motor function Tobias Moser, Lucia Bulubasova, Jamil Sabih, Florian Ringel, Bernhard Meyer, Sandro M. Krieg Department of Neurosurgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Navigated transcranial magnetic stimulation (ntms) is used to determine the distribution of motor eloquent areas. As shown in previous studies there are primary motor areas frontal to the precentral gyrus. However there is no clear evidence about the importance and eloquence of these areas for surgical considerations. We therefore investigated the correlation surgically resected ntms-positive prerolandic motor areas and postsurgical loss of motor function. Forty patients with gliomas in the precentral or prerolandic cortex where examined with ntms prior to surgery to determine the localization of the primary motor areas. Based on the fusion of the mapping points with the postsurgical MRI, we identified 16

17 ntms-positive points which were resected in the infiltration zone oft he tumor. The resected points where then classified in localization and latency of the motor evoked potentials. The 40 patients with an average age of 57.1 years presented tumor entities consisting of 25 glioblastomas, 8 diffuse and 5 anaplastic astrocytomas, one anaplastic oligodendroglioma and one oligoastrocytoma. Within the 40 patients 27 showed ntms-positive motor eloquent points in the prerolandic gyri during ntms mapping. The resection of ntms-positive cortical areas lead to a considerable number of transient pareses, which we observed in 8 patients with direct postsurgical motor function deficits. In 5 of these patients ntms points were resected in the prerolandic gyri, in two patients points within the precentral gyrus and one patient was showing a pareses without resection of motor eloquent spots. Despite ntms identifies a considerably high number of prerolandic motor areas, these should also be considered as highly eloquent and spared during resection. *Synergie von Strahlentherapie und Antigen-spezifischer Vakzinierung in der Behandlung maligner Gliome Katharina Ochs 1,2, Martina Ott 1,2, Sara Chiblak 3,4,5, Michael O. Breckwoldt 6, Amir Abdollahi 3,4,5, Wolfgang Wick 1,7, Michael Platten 1,2 1 Neurologische Klinik, Universitätsklinikum Heidelberg und Nationales Zentrum für Tumorerkrankungen (NCT), Heidelberg, Deutschland; 2 Klinische Kooperationseinheit Neuroimmunologie und Hirntumorimmunologie, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Deutschland; 3 Abteilung für Radioonkologie und Strahlentherapie, Universitätsklinikum Heidelberg, Heidelberg, Deutschland 4 Deutsches Konsortium für Translationale Krebsforschung (DKTK), Zentrum für Medizinische Strahlenforschung in der Onkologie, Heidelberger Institut für Radioonkologie (HIRO), Heidelberg, Deutschland 5 Molekulare und Translationale Radioonkologie, Heidelberger Ionen-Therapie Zentrum (HIT), Medizinische Fakultät der Universität Heidelberg und Nationales Zentrum für Tumorerkrankungen (NCT), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Deutschland 6 Abteilung für Neuroradiologie, Universitätsklinikum Heidelberg, Heidelberg, Deutschland 7 Klinische Kooperationseinheit Neuroonkologie, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Deutschland In der Behandlung maligner Gliome gewinnen Immuntherapien wie beispielsweise die Vakzinierung gegen Tumor-spezifische Antigene zunehmend an Bedeutung, wobei immunsuppressive Faktoren des Tumormikromilieus das Entstehen einer effektiven Anti-Gliom-Immunantwort erschweren. Zudem ist bisher weitgehend unklar, wie eine Immunisierung in die Standardtherapie, die eine kombinierte Radiochemotherapie umfasst, integriert werden soll. Ziel dieser Studie ist, mit Hilfe eines syngenen orthotopen Mausmodells Effektivität und molekulare Mechanismen 17

18 einer kombinierten Radioimmuntherapie bestehend aus einer Peptidvakzinierung und einer niedrig dosierten Bestrahlung zu untersuchen. Während eine alleinige Vakzinierung von Mäusen mit das hoch immunogene Modell- Tumorantigen gp100 überexprimierenden GL261-Gliomen keinen therapeutischen Nutzen zeigte, führte eine fraktionierte Bestrahlung mit 5 x 2 Gy zu einer relevanten Verzögerung des Tumorwachstums. Eine Kombination aus anti-gp100-vakzinierung und Bestrahlung dagegen hatte bei ca. 70 % der Mäuse eine komplette Regression zuvor etablierter Gliome zur Folge. Durchfusszytometrische Analysen der Tumorinfiltrierenden Lymphozyten zeigten einen signifikanten Anstieg der gp100- spezifischen zytotoxischen T-Zellen in der kombiniert behandelten Gruppe im Vergleich zu den jeweiligen monotherapierten Kontrollgruppen. Auch die Kombination einer Photonenbestrahlung mit einem adoptiven Transfer gp100- spezifischer CD8-positiver T-Zellen aus T-Zell-Rezeptor-transgenen Mäusen führte zu einer signifikanten Akkumulation der transferierten T-Zellen im Tumor interessanterweise allerdings ohne Effekt auf das Tumorwachstum. Eine niedrig dosierte, fraktionierte Bestrahlung scheint also das Gliom-Mikromilieu so zu verändern, dass die Infiltration Antigen-spezifischer zytotoxischer T-Zellen gefördert und so das Entstehen einer Vakzinierungs-induzierten effektiven Immunantwort erleichtert wird. Hippocampal-avoiding WBRT selectively prevents hippocampal atrophy as determined by automated volumetry Oliver Oehlke 1, Deborah Sturm 1, Karl Egger 2, Anca-Ligia Grosu 1,3,4, Lars Frings 1,5,6 1 Department of Radiation Oncology, University Medical Center Freiburg, Germany 2 Department of Neuroradiology, University Medical Center Freiburg, Germany 3 German Consortium for Translational Cancer Research (DKTK), Freiburg, Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Department of Nuclear Medicine, University Medical Center Freiburg, Germany 6 Center for Geriatrics and Gerontology, University Medical Center Freiburg, Germany Hippocampal-avoiding whole brain radiotherapy (HA-WBRT) for multiple brain metastases may prevent treatment-related cognitive decline, compared to standard WBRT. Reduction in hippocampal volume over time has been shown to be significantly related to decline in memory and learning. This study aims at exploring brain volume changes after whole brain radiotherapy with hippocampal avoidance (HA-WBRT). Twenty-two patients who had been assigned to HA-WBRT following clinical indication received MRI before and up to 19 months after treatment (Mean = 5 months). Observer-independent, automated volumetry of the hippocampi, the lateral ventricles, and the whole brain was performed on 77 MRI data sets using Matlab and statistical parametric mapping (SPM8). Longitudinal volumes have been tested for significant brain changes after HA-WBRT. Linear mixed models were computed with regional volumes as dependent variables and predictor variable time with random intercepts and slopes for time across subjects and variance components as covariance structure (controlling for age). Volume change rates after RT have been calculated for each region. 18

19 At the group level, hippocampal [-0.02 ml (-0.19%) per month] and whole brain volumes [-2.03 ml (-0.19%) per month] showed decreases which did not reach significance. By contrast, the lateral ventricles significantly expanded [p < ; +1.2 ml (3.6%) per month (43% per year)]. In this pilot study we observed no significant hippocampal atrophy after HA-WBRT. The lateral ventricles, however, expanded after treatment, indicating cerebral atrophy at a higher rate than reported in the literature on healthy subjects. While brain tissue degeneration seems to occur in this group of patients, hippocampal tissue is spared from this process. *Supportive care in patients with high-grade gliomas how to integrate clinical assessment in daily routine? Results of a prospective multicentric trial ERASMUS in 175 patients. Den Bedarf an supportiven Maßnahmen bei Patienten mit malignen Gliomen im ambulanten Bereich frühzeitig erkennen - Ergebnisse aus einer prospektiven teilrandomisierten multizentrischen Studie ERhaltung von Lebensqualität, Aktivität und psychischer Stabilität in Mainz, Ulm/Günzburg und Stuttgart. Mirjam Renovanz 1, Marlene Hechtner 2, Anne-Katrin Hickmann 3, Minou Nadji-Ohl 3, Mareile Janko 1, Karoline Kohlmann 1, Jochem König 2, Jan Coburger 4, Alf Giese 1 1 Klinik für Neurochirurgie, Universitätsmedizin Mainz, Mainz 2 Institut für medizinische Biometrie, Epidemiologie und Informatik, Universitätsmedizin Mainz 3 Neurochirurgische Klinik, Klinikum Stuttgart, Stuttgart 4 Klinik für Neurochirurgie, Universität Ulm, Standort Günzburg, Günzburg Improving quality, effectiveness, and efficiency of therapy and care in patients with malignant gliomas involves assessment of psychosocial and supportive care needs. The aim of this study was 1) to test and optimize an assessment of psychosocial and supportive care needs in patients with high-grade gliomas in an outpatient setting and 2) to assess possible predictors for the patients need of psychosocial help during the further course of a glioma disease aiming at a more patient-centered health care. In neuro-oncological outpatient departments of three study centers 175 glioma patients were assessed using EORTC QLQ-C30 + BN20, Distress Thermometer (DT) and SCNS-SF34-G. The questionnaires were completed either with personal aid (group A) or by patients alone (group B). Socio-demographic data, tumor stage, KPS, and adjuvant therapies were documented. Feasibility to implement the questionnaires in clinical routine was tested by evaluating time needed to complete the questionnaire, rate of missing values, errors in completion by comparing Groups A and B. Socio-demographic data, perioperative data (e.g. (eloquent) localization of the tumor, and clinical data (ECOG/KPS, adjuvant therapies) of the patients were assessed and their probable influence on the mental status analyzed by multivariable linear and logistic regression models. The study included 175 patients, m:f ratio was 1.1:1. The 72 (41%) patients in group A needed an average of 25 min (range 10 to >50) for completion of all 3 surveys. 19

20 Most of the patients (>90%) had no problems in answering QLQ-C30+BN20 and DT, but 33% misunderstood questions within SCNS. There was no evidence that assistance of personal aid influenced the results of DT (mean 4.6±2.7 vs. 4.6±2.8, p=0.88) and the EORTC-scores (e.g. C30, global health scale 62.3±22.1 vs. 58.9±23.3, p t =0.33). However, the proportion of incorrectly filled items in the SCNS questionnaires was slightly lower in group A than in group B (7 (10%) vs. 19 (20%), p=0.07). In several regression analysis models the following issues: study center, gender, profession, age, entity and WHO, and ongoing chemotherapy were not found to influence the probability of patients need or desire for psychosocial support according to DT>6, whereas we found KPS highly significant influencing the patients wish for psychosocial support (p>0,0001, CI: 0,881-0,963). Linear regression for global health status (EORTC, C30) showed that cognitive functioning was influenced by localization of the tumor. Early identification of psychosocial and supportive care needs in brain tumor patients is of high importance for treatment success. However, the SCNS-SF34 turned out to be not a suitable tool in glioma patients, whereas the DT and EORTC were well implemented and useful in clinical routine. Supportive care surveys specifically designed for needs and abilities of glioma patients are needed and tailored assessment should be integrated in outpatient routine. *Next-Generation-Sequencing in routine neuropathology diagnostics Felix Sahm 1,2, Daniel Schrimpf 1,2, Jochen Meyer 2, David Jones 3, David Reuss 1,2, David Capper 1,2, Christian Koelsche 1,2, Annekathrin Kratz 1,2, Andrey Korshunov 1,2, Mark Zapatka 4, Stephan Wolf 5, Stefan Pfister 3,6, Andreas Unterberg 7, Wolfgang Wick 8,9, Andreas von Deimling 1,2 1 Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, INF 224, Heidelberg, Germany 2 Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), INF 224 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), INF 224 Heidelberg, Germany 4 Division of Molecular Genetics, German Cancer Research Center (DKFZ), INF 280, Heidelberg, Germany 5 Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. 6 Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany 7 Department of Neurosurgery, University Hospital Heidelberg, INF 400, Heidelberg, Germany 8 Neurology Clinic, University Hospital Heidelberg and National Center for Tumor Diseases, INF 400, Heidelberg, Germany 9 Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), INF 224 Heidelberg, Germany 20

21 With the numbers of prognostic and predictive genetic markers in neuro-oncology steadily growing, the need for comprehensive molecular work-up of neuropathology samples has tremendously increased. Although several aberrations can be detected by immunohistochemistry (mutant IDH1R132H and BRAFV600E protein, loss of ATRX expression), the traditional detection of mutations, intragenic deletions and gene fusions requires time consuming methods such as Sanger sequencing and fluorescence in-situ hybridization. Covering all potentially clinically relevant genes in diagnostic routine is virtually impossible by these means. Thus, reliable highthroughput methods allowing parallel analysis of multiple targets will be required in diagnostic neuropathology. We developed an enrichment-based gene panel comprising the entire coding and selected promoter regions of 130 genes recurrently mutated in brain tumors. Optimization of probe design, extraction, library generation and sequencing conditions on 150 samples yielded a 5-workday routine workflow from FFPE sample to neuropathological report: Library generation is based on the Agilent SureSelect enrichment technology and sequencing is performed on an Illumina NextSeq 500. Raw data are processed with BWA-MEM for alignment, SAMtools mpileup for single nucleotide variant calling, Platypus for indel calling and De-Fuse for fusion detection. Variants in the germline, where available, are subtracted from the variants in the tumor. Variants in the tumor are subsequently annotated with dbsnp, 1000-genome and COSMIC entries as well as with SIFT and PolyPhen2 scores to inform on their biological relevance. An average coverage of 500x enables detection of mutations also in samples with low tumor cell content. Presence of entity-specific signatures (e.g. rare IDH1 variant, ATRX, TP53; IDH2, TERT, CIC) added valuable information in cases where only small samples, representing the infiltration zone of the tumor, is provided. Further, inclusion of intronic regions of genes involved in fusion events enables the detection of 7 pivotal fusion events in parenchymal and meningeal brain tumors. Finally, high density of the designed probes, combined with the high coverage, permits the detection of copy number variations within the target regions with high resolution. In conclusion, we present the settings for high-throughput next-generationsequencing in routine neuropathology diagnostics. Such approach will likely become indispensable as more therapeutic targets emerge and genetic information enters the classification of brain tumors. Evaluation of Postoperative Imaging Protocols in Low-Grade WHO II Astrocytomas: Preference for Late Postoperative MRI for Precise Assessment of Resection Extent Moritz Scherer 1, Christine Jungk 1, Andreas Mock 1, Alexander Radbruch 2, Christel Herold-Mende 1, Andreas Unterberg 1 1 Neurochirurgische Klinik, Universitätsklinikum Heidelberg 2 Abteilung für Neuroradiologie, Neurologische Klinik, Universitätsklinikum Heidelberg The extent of resection (EOR) after surgery has frequently been identified as an independent positive prognosticator for survival in low-grade gliomas. However, times when to determine the EOR after surgery have been chosen very heterogeneously in past studies limiting the comparability of results. Particularly in non contrast- 21

22 enhancing tumors, surgical trauma and formation of edema are sources of bias for the interpretation of early postoperative imaging. This study sought to evaluate differences of early vs. late postoperative imaging to determine the most appropriate time for the assessment of EOR. In total, 29 cases with primary resections for WHO II astrocytomas and simultaneous early (24-48h) and late (median 3,6m, range 1,9-7,5m) postoperative imaging were retrospectively identified since Cases were adjusted for histology and previous radiation therapy to exclude confounders of image interpretation. Volumetric analysis and calculation of EOR was performed on FLAIR sequences (Fluid-Attenuated Inversion Recovery) early and late postoperatively. Influence of volumetric values on progression-free survival (PFS) was calculated in univariate models. Median postoperative EOR significantly increased by 23% from 67% early, to 90% late postoperatively (p<0,01, Wilcoxon matched pairs test). Moreover, correlation analysis confirmed this difference to be systematic (Spearman r=0,71, p<0,0001). Evidence of surgical trauma (ischemia, edema) was found on 66% (19/29) of early postoperative MRI diffusion-weighted-imaging (DWI). In survival analysis, only late EOR was significantly associated with PFS (HR=0,23, p=0,04), early EOR was not a significant confounder of survival. After resection of WHO II astrocytomas, EOR depends strongly upon the time when it is defined after surgery. EOR was systematically underestimated early after surgery and only late EOR was a significant prognosticator for PFS in this series. Postsurgical trauma can mimic FLAIR hyperintensity that bias early postoperative image interpretation and might account for differences in EOR calculation. Results from this analysis advocate the use of late instead of early postoperative imaging for the evaluation of residual tumor and definition of EOR in non contrast-enhancing astrocytomas. *Über die parakrinen immunmodulatorischen Effekte des Onkometaboliten 2- HG im Gliommikromilieu Theresa Schumacher 1,2, Lukas Bunse 1,2, Stefan Pusch 3,4, Andreas von Deimling 3,4, Wolfgang Wick 2,5, und Michael Platten 1,2 1, KKE Neuroimmunologie und Hirntumorimmunologie, Deutsches Krebsforschungszentrum, Heidelberg; 2, Neurologische Klinik, Universitätsklinik Heidelberg; 3, KKE Neuropathologie, Deutsches Krebsforschungszentrum, Heidelberg; 4, Abteilung Neuropathologie, Universitätsklinik Heidelberg; 5, KKE Neuroonkologie, Deutsches Krebsforschungszentrum Mutationen in den Genen der Isozitratdehydrogenasen (IDH) betreffen ca. 80 % aller niedriggradigen und anaplastischen Gliome sowie sekundärer Glioblastome und resultieren fast ausschließlich im Aminosäureaustausch von Arginin zu Histidin an Position 132 (R132H). Allen IDH Mutationen ist die neomorphe Produktion des Onkometaboliten 2-Hydroxyglutarat (2-HG) gemein, der durch Inhibition von DNAund Histonmethylierung zu genomweiter Hypermethylierung (G-CIMP), genetischer Instabilität und letztendlich zur malignen Transformation führt. In zahlreichen präklinischen Studien wurden tumormetabolische Konsequenzen durch die intrazelluläre Akkumulation von 2-HG gezeigt, wie z.b. die Entdifferenzierung durch DNA-Hypermethylierung, aber auch Veränderungen zellulärer Signalwege wie die 22