TY  - JOUR
AB  - BACKGROUNDFollowing
       maximal safe resection and standard adjuvant radio- and chemotherapy, 
      approved maintenance therapies for glioblastoma are lacking. 
      Intracavitary radioimmunotherapy (iRIT) injected into the resection 
      cavity offers a promising strategy for improving local tumor. MATERIAL AND METHODSThe
       NOA-22 study (NCT05533242) investigates the 6A10-Fab fragment targeting
       carboxyanhydrase XII, labelled with lutetium-177, in a prospective, 
      single-armed, multicenter phase I study setting, following a modified 3 +
       3-design. Malignant glioma (WHO grades 3 + 4) IV and III) after 
      concomitant radio-chemotherapy and adjuvant standard chemotherapy with 
      no or small residual disease are included. The injected activity is 
      adapted to the volume of the resection cavity, resulting in a dose of 
      44Gy (cohort 1), 48Gy (cohort 2) and 52Gy (cohort 3). Primary study 
      objective is to determine the maximum tolerated dose and safety of 
      adjuvant radio-immunotherapy with lutetium-177 labeled 6A10-Fab 
      fragments. RESULTSThree
       patients with glioblastoma concluded the first study cohort. No 
      toxicities beyond grade 2 (CTCAE Version 5) were noted. One patient 
      presented with a symptomatic increase in focal contrast enhancement and 
      perifocal edema that decreased after a course of steroid treatment, 
      consistent with therapy-associated changes. Dosimetry did not reveal 
      absorbed doses above upper dose limits for organs at risk. All patients 
      remain clinically stable and without tumor progression. CONCLUSIONIntracavitary
       injection of Lutetium-177 labeled 6A10 Fab fragments appears to be 
      feasible and safe. The study currently enrolls patients in a planned 
      escalated dose scheme of 48 Gy cumulative dose in cohort 2.
AU  - Müther, M.*
AU  - Böning, G.*
AU  - Gildehaus, F.J.*
AU  - Delbridge, C.*
AU  - Albert, N.L.*
AU  - Schäfers, M.*
AU  - Delker, A.*
AU  - Stegger, L.*
AU  - Zeidler, R.
AU  - Reulen, H.J.*
AU  - Röll, W.*
AU  - Stummer, W.*
C1  - 75714
C2  - 57991
SP  - iii81 - iii82
TI  - P07.21.A A PHASE I TRIAL TO DETERMINE THE MAXIMUM TOLERATED DOSE AND PATIENT-SPECIFIC DOSIMETRY OF FRACTIONATED INTRACAVITARY RADIOIMMUNOTHERAPY WITH LUTETIUM-177 LABELED 6A10 FAB FRAGMENTS IN PATIENTS WITH GLIOBLASTOMA - PRELIMINARY RESULTS FROM THE FIRST PATIENT COHORT.
JO  - Neuro. Oncol.
VL  - 27
IS  - Supplement_3
PY  - 2025
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - BACKGROUND: Glioblastoma (GB), particularly IDH-wildtype, is the most aggressive brain malignancy with a dismal prognosis. Despite advances in molecular profiling, the complexity of its tumor microenvironment and spatial organization remains poorly understood. This study aimed to create a comprehensive single-cell and spatial atlas of GB to unravel its cellular heterogeneity, spatial architecture, and clinical relevance. METHODS: We integrated single-cell RNA sequencing data from 26 datasets, encompassing over 1.1 million cells from 240 patients, to construct GBmap, a harmonized single-cell atlas. High-resolution spatial transcriptomics was employed to map the spatial organization of GB tissues. We developed the Tumor Structure Score (TSS) to quantify tumor organization and correlated it with patient outcomes. RESULTS: We showcase the applications of GBmap for reference mapping, transfer learning, and biological discoveries. GBmap revealed extensive cellular heterogeneity, identifying rare populations such as tumor-associated neutrophils and homeostatic microglia. Spatial analysis uncovered seven distinct tumor niches, with hypoxia-dependent niches strongly associated with poor prognosis. The TSS demonstrated that highly organized tumors, characterized by well-defined vasculature and hypoxic niches, correlated with worse survival outcomes. CONCLUSIONS: This study provides a comprehensive resource for understanding glioblastoma heterogeneity and spatial organization. GBmap and the TSS provide an integrative view of tumor architecture in GB, highlighting hypoxia-driven niches that may represent avenues for further investigation. Our resource can facilitate exploratory analyses and hypothesis generation to better understand disease progression.
AU  - Ruiz-Moreno, C.*
AU  - Salas, S.M.*
AU  - Samuelsson, E.*
AU  - Minaeva, M.
AU  - Ibarra Del Rio, I.A.
AU  - Grillo, M.*
AU  - Brandner, S.*
AU  - Roy, A.*
AU  - Forsberg-Nilsson, K.*
AU  - Kranendonk, M.E.G.*
AU  - Theis, F.J.
AU  - Nilsson, M.*
AU  - Stunnenberg, H.G.*
C1  - 74298
C2  - 57422
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 15
TI  - Charting the single-cell and spatial landscape of IDH-wildtype glioblastoma with GBmap.
JO  - Neuro. Oncol.
PB  - Oxford Univ Press Inc
PY  - 2025
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - BACKGROUND: Surgical resection is the standard of care for patients with large or symptomatic brain metastases (BMs). Despite improved local control after adjuvant stereotactic radiotherapy, the risk of local failure (LF) persists. Therefore, we aimed to develop and externally validate a pre-therapeutic radiomics-based prediction tool to identify patients at high LF risk. METHODS: Data were collected from A Multicenter Analysis of Stereotactic Radiotherapy to the Resection Cavity of Brain Metastases (AURORA) retrospective study (training cohort: 253 patients from two centers; external test cohort: 99 patients from five centers). Radiomic features were extracted from the contrast-enhancing BM (T1-CE MRI sequence) and the surrounding edema (FLAIR sequence). Different combinations of radiomic and clinical features were compared. The final models were trained on the entire training cohort with the best parameter set previously determined by internal 5-fold cross-validation and tested on the external test set. RESULTS: The best performance in the external test was achieved by an elastic net regression model trained with a combination of radiomic and clinical features with a concordance index (CI) of 0.77, outperforming any clinical model (best CI: 0.70). The model effectively stratified patients by LF risk in a Kaplan-Meier analysis (p < 0.001) and demonstrated an incremental net clinical benefit. At 24 months, we found LF in 9% and 74% of the low and high-risk groups, respectively. CONCLUSIONS: A combination of clinical and radiomic features predicted freedom from LF better than any clinical feature set alone. Patients at high risk for LF may benefit from stricter follow-up routines or intensified therapy.
AU  - Buchner, J.A.*
AU  - Kofler, F.
AU  - Mayinger, M.*
AU  - Christ, S.M.*
AU  - Brunner, T.B.*
AU  - Wittig, A.*
AU  - Menze, B.*
AU  - Zimmer, C.*
AU  - Meyer, B.*
AU  - Guckenberger, M.*
AU  - Andratschke, N.*
AU  - El Shafie, R.A.*
AU  - Debus, J.*
AU  - Rogers, S.*
AU  - Riesterer, O.*
AU  - Schulze, K.*
AU  - Feldmann, H.J.*
AU  - Blanck, O.*
AU  - Zamboglou, C.*
AU  - Ferentinos, K.*
AU  - Bilger-Zähringer, A.*
AU  - Grosu, A.L.*
AU  - Wolff, R.*
AU  - Piraud, M.
AU  - Eitz, K.A.
AU  - Combs, S.E.
AU  - Bernhardt, D.*
AU  - Rueckert, D.*
AU  - Wiestler, B.*
AU  - Peeken, J.C.
C1  - 70779
C2  - 55744
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1638-1650
TI  - Radiomics-based prediction of local control in patients with brain metastases following postoperative stereotactic radiotherapy.
JO  - Neuro. Oncol.
VL  - 26
IS  - 9
PB  - Oxford Univ Press Inc
PY  - 2024
SN  - 1522-8517
ER  - 

TY  - JOUR
AU  - Kurz, S.C.*
AU  - Stammberger, A.*
AU  - Rosahl, S.K.*
AU  - Abrey, L.E.*
AU  - Albert, N.L.*
AU  - Baumgarten, L.V.*
AU  - Gempt, J.*
AU  - Grosu, A.L.*
AU  - Leidgens, V.*
AU  - McLean, A.*
AU  - Renovanz, M.*
AU  - Schwarzenberger, J.*
AU  - Sevenich, L.*
AU  - Urbanic Purkart, T.*
AU  - Combs, S.E.
AU  - Tabatabai, G.*
AU  - Hegi, M.*
AU  - Nowosielski, M.*
C1  - 68620
C2  - 54769
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 2302-2304
TI  - Towards more Diversity in Neuro-oncology Leadership-the DivINe Initiative.
JO  - Neuro. Oncol.
VL  - 25
IS  - 12
PB  - Oxford Univ Press Inc
PY  - 2023
SN  - 1522-8517
ER  - 

TY  - JOUR
AU  - Kebir, S.*
AU  - Lazaridis, L.*
AU  - Wick, W.*
AU  - Platten, M.*
AU  - Tabatabai, G.*
AU  - Combs, S.E.
AU  - Schmidt, T.*
AU  - Agkatsev, S.*
AU  - Blau, T.*
AU  - Maeurer, I.*
AU  - Kahlert, U.*
AU  - Sagerer, A.*
AU  - Berberich, A.*
AU  - Heider, S.*
AU  - Muether, M.*
AU  - Bodensohn, R.*
AU  - Behling, F.*
C1  - 65402
C2  - 52283
SP  - 1609-1611
TI  - Gender disparity regarding work-life balance satisfaction among German neuro-oncologists: A YoungNOA survey.
JO  - Neuro. Oncol.
VL  - 24
IS  - 9
PY  - 2022
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - BACKGROUND: The transcription factor NFκB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFκB activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. METHODS: In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFκB can be converted into a tumor suppressor by the non-psychotropic cannabinoid Cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study we performed pharmacological assays, gene expression profiling, biochemical and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM-datasets. RESULTS: We found that CBD promotes DNA binding of the NFκB subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which permits genetic transactivation. Strikingly, sustained DNA binding by RELA lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen-species (ROS), while high ROS-content in other tumors blocked CBD induced hGSC death. Consequently, ROS levels served as predictive biomarker for CBD-sensitive tumors. CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NFκB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.
AU  - Volmar, M.N.M.*
AU  - Cheng, J.*
AU  - Alenezi, H.*
AU  - Richter, S.*
AU  - Haug, A.*
AU  - Hassan, Z.*
AU  - Goldberg, M.*
AU  - Li, Y.*
AU  - Hou, M.*
AU  - Herold-Mende, C.*
AU  - Maire, C.L.*
AU  - Lamszus, K.*
AU  - Flüh, C.*
AU  - Held-Feindt, J.*
AU  - Gargiulo, G.*
AU  - Topping, G.J.*
AU  - Schilling, F.*
AU  - Saur, D.*
AU  - Schneider, G.*
AU  - Synowitz, M.*
AU  - Schick, J.
AU  - Kälin, R.E.*
AU  - Glass, R.*
C1  - 61841
C2  - 50308
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1898-1910
TI  - Cannabidiol converts NFκB into a tumor suppressor in glioblastoma with defined antioxidative properties.
JO  - Neuro. Oncol.
VL  - 23
IS  - 11
PB  - Oxford Univ Press Inc
PY  - 2021
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - BACKGROUND: Because of the increased risk in cancer patients of developing complications caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), physicians have to balance the competing risks of the negative impact of the pandemic and the primary tumor. In this consensus statement, an international group of experts present mitigation strategies and treatment guidance for patients suffering from high grade gliomas (HGG) during the coronavirus disease 2019 (COVID-19) pandemic. METHOD / RESULTS: 16 international experts in the treatment of HGG contributed to this consensus-based practice recommendation including neuro-oncologists, neurosurgeons, radiation -oncologists and a medical physicist. Generally, treatment of neuro-oncological patients cannot be significantly delayed and initiating therapy should not be outweighed by COVID-19. We present detailed interdisciplinary treatment strategies for molecular subgroups in two pandemic scenarios, a scale-up phase and a crisis phase. CONCLUSION: This practice recommendation presents a pragmatic framework and consensus-based mitigation strategies for the treatment of HGG patients during the SARS-CoV-2 pandemic.
AU  - Bernhardt, D.
AU  - Wick, W.*
AU  - Weiss, S.E.*
AU  - Sahgal, A.*
AU  - Lo, S.S.*
AU  - Suh, J.H.*
AU  - Chang, E.L.*
AU  - Foote, M.*
AU  - Perry, J.*
AU  - Meyer, B.*
AU  - Vajkoczy, P.*
AU  - Wen, P.Y.*
AU  - Straube, C.
AU  - Pigorsch, S.U.
AU  - Wilkens, J.J.*
AU  - Combs, S.E.
C1  - 59022
C2  - 48542
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 928-935
TI  - Neuro-oncology managment during the COVID-19 pandemic with a focus on WHO grade III and IV gliomas.
JO  - Neuro. Oncol.
VL  - 22
IS  - 7
PB  - Oxford Univ Press Inc
PY  - 2020
SN  - 1522-8517
ER  - 

TY  - JOUR
AU  - Bernhardt, D.
AU  - Combs, S.E.
C1  - 59951
C2  - 49798
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
TI  - Reply to: Call of duty: Neuro-oncology outpatient management during the COVID-19 pandemic in Milan, ITALY.
JO  - Neuro. Oncol.
VL  - 22
IS  - 12
PB  - Oxford Univ Press Inc
PY  - 2020
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - Background. Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.Methods. Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.Results. Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on proopiomelanocortin production and adrenocorticotropic hormone secretion.Conclusions. USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
AU  - Sbiera, S.*
AU  - Perez-Rivas, L.G.*
AU  - Taranets, L.*
AU  - Weigand, I.*
AU  - Flitsch, J.*
AU  - Graf, E.
AU  - Monoranu, C.M.*
AU  - Saeger, W.*
AU  - Hagel, C.*
AU  - Honegger, J.*
AU  - Assié, G.*
AU  - Hermus, A.R.*
AU  - Stalla, G.K.*
AU  - Herterich, S.*
AU  - Ronchi, C.L.*
AU  - Deutschbein, T.*
AU  - Reincke, M.*
AU  - Strom, T.M.
AU  - Popov, N.*
AU  - Theodoropoulou, M.*
AU  - Fassnacht, M.*
C1  - 56378
C2  - 47045
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1273-1283
TI  - Driver mutations in USP8 wild-type Cushing's disease.
JO  - Neuro. Oncol.
VL  - 21
IS  - 10
PB  - Oxford Univ Press Inc
PY  - 2019
SN  - 1522-8517
ER  - 

TY  - JOUR
AU  - Volmar, M.*
AU  - Nagl, B.*
AU  - Haug, A.*
AU  - Richter, S.*
AU  - Alenezi, H.*
AU  - Herold-Mende, C.*
AU  - Lamszus, K.*
AU  - Synowitz, M.*
AU  - Schick, J.
AU  - Kalin, R.*
AU  - Glass, R.*
C1  - 58481
C2  - 48095
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 70-71
TI  - RelA-activity is essential for cannabidiol-mediated cytotoxicity in an identified subset of glioblastoma.
JO  - Neuro. Oncol.
VL  - 21
PB  - Oxford Univ Press Inc
PY  - 2019
SN  - 1522-8517
ER  - 

TY  - JOUR
AU  - Andor, N.*
AU  - Harness, J.V.*
AU  - Lopez, S.G.*
AU  - Fung, T.L.*
AU  - Mewes, H.-W.
AU  - Petritsch, C.*
C1  - 29263
C2  - 33700
SP  - 136-137
TI  - Clonal expansions and evolving subpopulations in glioblastoma multiforme.
JO  - Neuro. Oncol.
VL  - 15
PB  - Oxford Univ Press
PY  - 2013
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - Implementation of chemotherapy with the drug temozolomide increased the overall survival of patients with glioblastoma multiforme (GBM; WHO grade IV), in particular when the O-6-methylguanine DNA methyltransferase (MGMT) promoter is epigenetically silenced. Nevertheless, the prognosis remains poor, and relapse in GBM occurs regularly. This clinical behavior seems to be due to the existence of a therapy-resistant subpopulation of cells that induce tumor regrowth. The objective of this work was to analyze the role of aldehyde dehydrogenase (ALDH) 1A1 in mediating temozolomide resistance and its value as a predictor of clinical outcome in GBM patients. Nine GBM cell lines were treated with temozolomide alone or in combination with 4-diethylaminobenzaldehyde (DEAB), an inhibitor of ALDH1A1, or with ALDH1A1 short hairpin (sh)RNA. ALDH1A1 expression and MGMT status of 70 primary GBM patients were correlated with median survival. ALDH1A1 overexpression predicted temozolomide resistance in vitro. Sensitivity of ALDH1A1 positive/MGMT-positive cells to temozolomide could be restored by inhibition of ALDH1A1 by DEAB or by knockdown with shRNA, as indicated by increased cytotoxicity, reduced clonogenicity, and accumulation in the G2/M cell-cycle phase. The prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels (P .0001). ALDH1A1 is a new mediator for resistance of GBM to temozolomide and a reliable predictor of clinical outcome and may serve as a potential target to improve treatment of human GBM.
AU  - Schäfer, A.*
AU  - Teufel, J.*
AU  - Ringel, F.*
AU  - Bettstetter, M.*
AU  - Hoepner, I.*
AU  - Rasper, M.*
AU  - Gempt, J.*
AU  - Koeritzer, J.*
AU  - Schmidt-Graf, F.*
AU  - Meyer, B.*
AU  - Beier, C.P.*
AU  - Schlegel, J.
C1  - 11481
C2  - 30752
SP  - 1452-1464
TI  - Aldehyde dehydrogenase 1A1 - a new mediator of resistance to temozolomide in glioblastoma.
JO  - Neuro. Oncol.
VL  - 14
IS  - 12
PB  - Oxford Univ. Press
PY  - 2012
SN  - 1522-8517
ER  - 

TY  - JOUR
AB  - Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.
AU  - Rasper, M.*
AU  - Schäfer, A.*
AU  - Piontek, G.*
AU  - Teufel, J.*
AU  - Brockhoff, G.*
AU  - Ringel, F.*
AU  - Heindl, S.*
AU  - Zimmer, C.*
AU  - Schlegel, J.
C1  - 5934
C2  - 27587
SP  - 1024-1033
TI  - Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity.
JO  - Neuro. Oncol.
VL  - 12
IS  - 10
PB  - Oxfors Univ. Press Inc.
PY  - 2010
SN  - 1522-8517
ER  -