ABT-888 enhances cytotoxic effects of temozolomide independent of MGMT status in serum free cultured glioma cells

Background: The current standard of care for Glioblastoma Multiforme (GBM) consists of fractionated focal irradiation with concomitant temozolomide (TMZ) chemotherapy. A promising strategy to increase the efficacy of TMZ is through interference with the DNA damage repair machinery, by poly(ADP-ribose) polymerase protein inhibition(PARPi). The o

A Systematic Comparison Identifies an ATP-Based Viability Assay as Most Suitable Read-Out for Drug Screening in Glioma Stem-Like Cells

Serum-free culture methods for patient-derived primary glioma cultures, selecting for glioma stem-like cells (GSCs), are becoming the gold standard in neurooncology research. These GSCs can be implemented in drug screens to detect patient-specific responses, potentially bridging the translational gap to personalized medicine. Since numerous compounds are available, a rapid and reliable readout for drug efficacies is required. This can be done using approaches that measure viability, confluency, cytotoxicity, or apoptosis. To determine which assay is best suitable for drug screening, 10 different assays were systematically tested on established glioma cell lines and validated on a panel of GSCs. General applicability was assessed using distinct treatment modalities, being temozolomide, radiation, rapamycin, and the oncolytic adenovirus Delta24-RGD. The apoptosis and cytotoxicity assays did not unequivocally detect responses and were excluded from further testing. The NADH- and ATP-based viability assays revealed comparable readout for all treatments; however, the latter had smaller standard deviations and direct readout. Importantly, drugs that interfere with cell metabolism require alternative techniques such as confluency monitoring to accurately measure treatment effects. Taken together, our data suggest that the combination of ATP luminescence assays with confluency monitoring provides the most specific and reproducible readout for drug screening on primary GSCs

Between‐hospital variation in rates of complications and decline of patient performance after glioblastoma surgery in the dutch Quality Registry Neuro Surgery

Introduction: For decisions on glioblastoma surgery, the risk of complications and decline in performance is decisive. In this study, we determine the rate of complications and performance decline after resections and biopsies in a national quality registry, their risk factors and the risk-standardized variation between institutions. Methods: Data from all 3288 adults with first-time glioblastoma surgery at 13 hospitals were obtained from a prospective population-based Quality Registry Neuro Surgery in the Netherlands between 2013 and 2017. Patients were stratified by biopsies and resections. Complications were categorized as Clavien-Dindo grades II and higher. Performance decline was considered a deterioration of more than 10 Karnofsky points at 6 weeks. Risk factors were evaluated in multivariable logistic regression analysis. Patient-specific expected and observed complications and performance declines were summarized for institutions and analyzed in funnel plots. Results: For 2271 resections, the overall complication rate was 20 % and 16 % declined in performance. For 1017 biopsies, the overall complication rate was 11 % and 30 % declined in performance. Patient-related characteristics were significant risk factors for complications and performance decline, i.e. higher age, lower baseline Karnofsky, higher ASA classification, and the surgical procedure. Hospital characteristics, i.e. case volume, university affiliation and biopsy percentage, were not. In three institutes the observed complication rate was significantly less than expected. In one institute significantly more performance declines were observed than expected, and in one institute significantly less. Conclusions: Patient characteristics, but not case volume, were risk factors for complications and performance decline after glioblastoma surgery. After risk-standardization, hospitals varied in complications and performance declines

Modeling of Malignant Glioma and Investigations into Novel Treatments

Abstract With the advent of personalized medicine and large omics-based profiling studies into multiple diseases, new opportunities rise for the treatment of Malignant Glioma. This primary brain tumor remains unvariantly fatal and therefore urgently requires novel treatment options. In this thesis a novel model for glioma stem-like cells is characterized for molecular recapitulation of driving alterations found in patient tumors. In addition, the model is verified to reproduce in vitro the clinical outcome found in patients treated with the golden standard chemotherapeutic temozolomide. As a result of these characterization studies the model was implemented in several drug screens to explore the possibility of augmentation through combination therapy with temozolomide and oncolytic virotherapy with Delta24-RGD, reovirus and herpes virus. Mechanistic studies into response profiles were undertaken, which provided leads for biomarkers for therapeutic effect and patient selection. In addition, several contemporary reviews are provided to further substantiate these findings and place the data into context with recently published work of others. In conclusion, this thesis provides several leads into the implementation of patient tailored medicine for malignant glioma patients that should subsequently be further validated in animal and patient trials

Laser speckle imaging identification of increases in cortical microcirculatory blood flow induced by motor activity during awake craniotomy ; Clinical article

Object. The goal of awake neurosurgery is to maximize resection of brain lesions with minimal injury to functional brain areas. Laser speckle imaging (LSI) is a noninvasive macroscopic technique with high spatial and temporal resolution used to monitor changes in capillary perfusion. In this study, the authors hypothesized that LSI can be useful as a noncontact method of functional brain mapping during awake craniotomy for tumor removal. Such a modality would be an advance in this type of neurosurgery since current practice involves the application of invasive intraoperative single-point electrocortical (electrode) stimulation and measurements. Methods. After opening the dura mater, patients were woken up, and LSI was set up to image the exposed brain area. Patients were instructed to follow a rest-activation-rest protocol in which activation consisted of the handclenching motor task. Subsequently, exposed brain areas were mapped for functional motor areas by using standard electrocortical stimulation (ECS). Changes in the LSI signal were analyzed offline and compared with the results of ECS. Results. In functional motor areas of the hand mapped with ECS, cortical blood flow measured using LSI significantly increased from 2052 ±818 AU to 2471 ±675 AU during hand clenching, whereas capillary blood flow did not change in the control regions (areas mapped using ECS with no functional activity). Conclusions. The main finding of this study was that changes in laser speckle perfusion as a measure of cortical microvascular blood flow when performing a motor task with the hand relate well to the ECS map. The authors have shown the feasibility of using LSI for direct visualization of cortical microcirculatory blood flow changes during neurosurgery