Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs. We therefore grew well-characterized IDH1mut (n = 4) and IDH1wt (n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1wt than in IDH1mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1mut and IDH1wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1mut GSCs a hypoxia-related survival score (HRS-score) of five genes (LYVE1, FAM162A, WNT6, OTP, PLOD1) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders.

The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology. Difficulties in cultivating IDH mutant glioma stem cells (IDHmut GSCs) resulted in a paucity of preclinical models in IDHmut glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDHmut GSC lines and performed a large-scale drug screening with 147 Food and Drug Administration (FDA)-approved anticancer drugs. GSCs were subjected to the test compounds for 72 h in concentrations ranging from 0.0001 to 1 µM. Cell viability was assessed by CellTiterGlo and the induction of apoptosis by flow cytometry with Annexin V/propidium iodide staining. The initial screen was performed with two IDHmut GSC lines and identified seven drugs (bortezomib, carfilzomib, daunorubicin, doxorubicin, epirubicin, omacetaxine, plicamycin) with a substantial antiproliferative activity, as reflected by half maximal inhibitory concentrations (IC50) below 1 µM and maximum inhibitory effects (Emax) below 25%. These findings were validated in an additional four IDHmut GSC lines. The candidate drugs, of which plicamycin and omacetaxine are known to cross the blood brain barrier, were used for subsequent cell death analyses. A significant induction of apoptosis was observed at IC50 values of the respective drugs. In summary, we were able to identify seven FDA-approved drugs that should be further taken into clinical investigations for the treatment of IDHmut gliomas.

Purpose To prospectively identify and quantify neurosurgical adverse events (AEs) in a tertiary care hospital. Methods From January 2021 to December 2021, all patients treated in our department received a peer-reviewed AE-evaluation form at discharge. An AE was defined as any event after surgery that resulted in an undesirable clinical outcome, which is not caused by the underlying disease, that prolonged patient stay, resulted in readmission, caused a new neurological deficit, required revision surgery or life-saving intervention, or contributed to death. We considered AEs occurring within 30 days after discharge. AEs were categorized in wound event, cerebrospinal fluid (CSF) event, CSF shunt malfunction, post-operative infection, malpositioning of implanted material, new neurological deficit, rebleeding, and surgical goal not achieved and non-neurosurgical AEs. Results 2874 patients were included. Most procedures were cranial (45.1%), followed by spinal (33.9%), subdural (7.7%), CSF (7.0%), neuromodulation (4.0%), and other (2.3%). In total, there were 621 AEs shared by 532 patients (18.5%). 80 (2.8%) patients had multiple AEs. Most AEs were non-neurosurgical (222; 8.1%). There were 172 (6%) revision surgeries. Patients receiving cranial interventions had the most AEs (19.1%) although revision surgery was only necessary in 3.1% of patients. Subdural interventions had the highest revision rate (12.6%). The majority of fatalities was admitted as an emergency (81/91 patients, 89%). Ten elective patients had lethal complications, six of them related to surgery (0.2%). Conclusion This study presents the one-year results of a prospectively compiled AE database. Neurosurgical AEs arose in one in five patients. Although the need for revision surgery was low, the rate of AEs highlights the importance of a systematic AE database to deliver continued high-quality in a high-volume center.