Advances in Image Processing for Epileptogenic Zone Detection with MRI.

Focal epilepsy is a common and severe neurologic disorder. Neuroimaging aims to identify the epileptogenic zone (EZ), preferably as a macroscopic structural lesion. For approximately a third of patients with chronic drug-resistant focal epilepsy, the EZ cannot be precisely identified using standard 3.0-T MRI. This may be due to either the EZ being undetectable at imaging or the seizure activity being caused by a physiologic abnormality rather than a structural lesion. Computational image processing has recently been shown to aid radiologic assessments and increase the success rate of uncovering suspicious regions by enhancing their visual conspicuity. While structural image analysis is at the forefront of EZ detection, physiologic image analysis has also been shown to provide valuable information about EZ location. This narrative review summarizes and explains the current state-of-the-art computational approaches for image analysis and presents their potential for EZ detection. Current limitations of the methods and possible future directions to augment EZ detection are discussed.

Neurocognition in adults with intracranial tumors: does location really matter?

OBJECTIVE: As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. METHODS: This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p < .001 and p < .05 for voxel- and cluster-level, resp.). RESULTS: A cohort of 179 intracranial tumor patients was included [aged 19-85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20-30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. INTERPRETATION: Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

On the Threshold of Scientific Medicine: Gerard van Swieten and His Perception of the Pathophysiology in Traumatic Brain Injury.

Gerard van Swieten (1700-1772), famous pupil of Professor Herman Boerhaave (1668-1738) of Leiden University and personal physician of Austrian Habsburg Empress Maria Theresa (1717-1780). Herman Boerhaave was a renowned Dutch physician inside and outside Europe in the 18th century. He was not only appointed professor in medicine, chemistry, and botany but also a chancellor of the Leiden University in 1714 and published his well-known Aphorismi de cognoscendis et curandis morbis in 1709. Gerard van Swieten commented upon Boerhaave's aphorisms and demonstrated actual knowledge, less well-known among the medical community, about the pathophysiology of traumatic brain injury which half a century later (19th century) became known as the Monro-Kellie doctrine. Using the original commentaries upon Boerhaave's aphorisms by van Swieten himself, we explored his way of formulating the pathophysiological concept of traumatic brain injury, which still is valid today.

The expression of the distal dystrophin isoforms Dp140 and Dp71 in the human epileptic hippocampus in relation to cognitive functioning.

Dystrophin is an important protein within the central nervous system. The absence of dystrophin, characterizing Duchenne muscular dystrophy (DMD), is associated with brain related comorbidities such as neurodevelopmental (e.g., cognitive and behavioural) deficits and epilepsy. Especially mutations in the downstream part of the DMD gene affecting the dystrophin isoforms Dp140 and Dp71 are found to be associated with cognitive deficits. However, the function of Dp140 is currently not well understood and its expression pattern has previously been implicated to be developmentally regulated. Therefore, we evaluated Dp140 and Dp71 expression in human hippocampi in relation to cognitive functioning in patients with drug-resistant temporal lobe epilepsy (TLE) and post-mortem controls. Hippocampal samples obtained as part of epilepsy surgery were quantitatively analyzed by Western blot and correlations with neuropsychological test results (i.e., memory and intelligence) were examined. First, we demonstrated that the expression of Dp140 does not appear to differ across different ages throughout adulthood. Second, we identified an inverse correlation between memory loss (i.e., verbal and visual memory), but not intelligence (i.e., neither verbal nor performance), and hippocampal Dp140 expression. Finally, patients with TLE appeared to have similar Dp140 expression levels compared to post-mortem controls without neurological disease. Dp140 may thus have a function in normal cognitive (i.e., episodic memory) processes.

Brain tissue plasticity: protein synthesis rates of the human brain.

All tissues undergo continuous reconditioning via the complex orchestration of changes in tissue protein synthesis and breakdown rates. Skeletal muscle tissue has been well studied in this regard, and has been shown to turnover at a rate of 1-2% per day in vivo in humans. Few data are available on protein synthesis rates of other tissues. Because of obvious limitations with regard to brain tissue sampling no study has ever measured brain protein synthesis rates in vivo in humans. Here, we applied stable isotope methodology to directly assess protein synthesis rates in neocortex and hippocampus tissue of six patients undergoing temporal lobectomy for drug-resistant temporal lobe epilepsy (Clinical trial registration: NTR5147). Protein synthesis rates of neocortex and hippocampus tissue averaged 0.17 ± 0.01 and 0.13 ± 0.01%/h, respectively. Brain tissue protein synthesis rates were 3-4-fold higher than skeletal muscle tissue protein synthesis rates (0.05 ± 0.01%/h; P < 0.001). In conclusion, the protein turnover rate of the human brain is much higher than previously assumed.

Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy.

Despite the use of first-choice anti-epileptic drugs and satisfactory seizure outcome rates after resective epilepsy surgery, a considerable percentage of patients do not become seizure free. ANT-DBS may provide for an alternative treatment option in these patients. This literature review discusses the rationale, mechanism of action, clinical efficacy, safety, and tolerability of ANT-DBS in drug-resistant epilepsy patients. A review using systematic methods of the available literature was performed using relevant databases including Medline, Embase, and the Cochrane Library pertaining to the different aspects ANT-DBS. ANT-DBS for drug-resistant epilepsy is a safe, effective and well-tolerated therapy, where a special emphasis must be given to monitoring and neuropsychological assessment of both depression and memory function. Three patterns of seizure control by ANT-DBS are recognized, of which a delayed stimulation effect may account for an improved long-term response rate. ANT-DBS remotely modulates neuronal network excitability through overriding pathological electrical activity, decrease neuronal cell loss, through immune response inhibition or modulation of neuronal energy metabolism. ANT-DBS is an efficacious treatment modality, even when curative procedures or lesser invasive neuromodulative techniques failed. When compared to VNS, ANT-DBS shows slightly superior treatment response, which urges for direct comparative trials. Based on the available evidence ANT-DBS and VNS therapies are currently both superior compared to non-invasive neuromodulation techniques such as t-VNS and rTMS. Additional in-vivo research is necessary in order to gain more insight into the mechanism of action of ANT-DBS in localization-related epilepsy which will allow for treatment optimization. Randomized clinical studies in search of the optimal target in well-defined epilepsy patient populations, will ultimately allow for optimal patient stratification when applying DBS for drug-resistant patients with epilepsy.

Growing skull hemangioma: first and unique description in a patient with Klippel-Trénaunay-Weber syndrome.

We present the first and unique case of a rapid-growing skull hemangioma in a patient with Klippel-Trénaunay-Weber syndrome. This case report provides evidence that not all rapid-growing, osteolytic skull lesions need to have a malignant character but certainly need a histopathological verification. This material offers insight into the list of rare pathological diagnoses in an infrequent syndrome.

Methodology, outcome, safety and in vivo accuracy in traditional frame-based stereoelectroencephalography.

BACKGROUND: Stereoelectroencephalography (SEEG) is an established diagnostic technique for the localization of the epileptogenic zone in drug-resistant epilepsy. In vivo accuracy of SEEG electrode positioning is of paramount importance since higher accuracy may lead to more precise resective surgery, better seizure outcome and reduction of complications. OBJECTIVE: To describe experiences with the SEEG technique in our comprehensive epilepsy center, to illustrate surgical methodology, to evaluate in vivo application accuracy and to consider the diagnostic yield of SEEG implantations. METHODS: All patients who underwent SEEG implantations between September 2008 and April 2016 were analyzed. Planned electrode trajectories were compared with post-implantation trajectories after fusion of pre- and postoperative imaging. Quantitative analysis of deviation using Euclidean distance and directional errors was performed. Explanatory variables for electrode accuracy were analyzed using linear regression modeling. The surgical methodology, procedure-related complications and diagnostic yield were reported. RESULTS: Seventy-six implantations were performed in 71 patients, and a total of 902 electrodes were implanted. Median entry and target point deviations were 1.54 mm and 2.93 mm. Several factors that predicted entry and target point accuracy were identified. The rate of major complications was 2.6%. SEEG led to surgical therapy of various modalities in 53 patients (69.7%). CONCLUSIONS: This study demonstrated that entry and target point localization errors can be predicted by linear regression models, which can aid in identification of high-risk electrode trajectories and further enhancement of accuracy. SEEG is a reliable technique, as demonstrated by the high accuracy of conventional frame-based implantation methodology and the good diagnostic yield.

Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories.

Levetiracetam may induce serious behavioral disturbances, especially after surgical resection of frontal lobe low-grade glioma. Two patients, treated with levetiracetam, developed serious psychiatric complications postoperatively which completely resolved after switching to valproate. We aim to create awareness for this serious but reversible adverse effect of levetiracetam in this specific patient category.

Technical feasibility of integrating 7 T anatomical MRI in image-guided radiotherapy of glioblastoma: a preparatory study.

OBJECTIVES: The use of 7 Tesla (T) magnetic resonance imaging (MRI) has recently shown great potential for high-resolution soft-tissue neuroimaging and visualization of microvascularization in glioblastoma (GBM). We have designed a clinical trial to explore the value of 7 T MRI in radiation treatment of GBM. For this aim we performed a preparatory study to investigate the technical feasibility of incorporating 7 T MR images into the neurosurgical navigation and radiotherapy treatment planning (RTP) systems via qualitative and quantitative assessment of the image quality. MATERIALS AND METHODS: The MR images were acquired with a Siemens Magnetom 7 T whole-body scanner and a Nova Medical 32-channel head coil. The 7 T MRI pulse sequences included magnetization-prepared two rapid acquisition gradient echoes (MP2RAGE), T2-SPACE, SPACE-FLAIR and gradient echo sequences (GRE). A pilot study with three healthy volunteers and an anthropomorphic 3D phantom was used to assess image quality and geometrical image accuracy. RESULTS: The MRI scans were well tolerated by the volunteers. Susceptibility artefacts were observed in both the cortex and subcortical white matter at close proximity to air-tissue interfaces. Regional loss of signal and contrast could be minimized by the use of dielectric pads. Image transfer and processing did not degrade image quality. The system-related spatial uncertainty of geometrical distortion-corrected MP2RAGE pulse sequences was ≤2 mm. CONCLUSION: Integration of high-quality and geometrically-reliable 7 T MR images into neurosurgical navigation and RTP software is technically feasible and safe.

The start and development of epilepsy surgery in Europe: a historical review.

Epilepsy has not always been considered a brain disease, but was believed to be a demonic possession in the past. Therefore, trepanation was done not only for medical but also for religious or spiritual reasons, originating in the Neolithic period (3000 BC). The earliest documentation of trepanation for epilepsy is found in the writings of the Hippocratic Corpus and consisted mainly of just skull surgery. The transition from skull surgery to brain surgery took place in the middle of the nineteenth century when the insight of epilepsy as a cortical disorder of the brain emerged. This led to the start of modern epilepsy surgery. The pioneer countries in which epilepsy surgery was performed in Europe were the UK, Germany, and The Netherlands. Neurosurgical forerunners like Sir Victor Horsley, William Macewen, Fedor Krause, and Otfrid Foerster started with "modern" epilepsy surgery. Initially, epilepsy surgery was mainly done with the purpose to resect traumatic lesions or large surface tumours. In the course of the twentieth century, this changed to highly specialized microscopic navigation-guided surgery to resect lesional and non-lesional epileptogenic cortex. The development of epilepsy surgery in Southern Europe, which has not been described until now, will be elaborated in this manuscript. To summarize, in this paper, we provide (1) a detailed description of the evolution of European epilepsy surgery with special emphasis on the pioneer countries; (2) novel, never published information about the development of epilepsy surgery in Southern Europe; and (3) we review the historical dichotomy of invasive electrode implantation strategy (Anglo-Saxon surface electrodes versus French-Italian stereoencephalography (SEEG) model).

Current state of the art of traditional and minimal invasive epilepsy surgery approaches.

Introduction: Open resective surgery remains the main treatment modality for refractory epilepsy, but is often considered a last resort option due to its invasiveness. Research question: This manuscript aims to provide an overview on traditional as well as minimally invasive surgical approaches in modern state of the art epilepsy surgery. Materials and methods: This narrative review addresses both historical and contemporary as well as minimal invasive surgical approaches in epilepsy surgery. Peer-reviewed published articles were retrieved from PubMed and Scopus. Only articles written in English were considered for this work. A range of traditional and minimally invasive surgical approaches in epilepsy surgery were examined, and their respective advantages and disadvantages have been summarized. Results: The following approaches and techniques are discussed: minimally invasive diagnostics in epilepsy surgery, anterior temporal lobectomy, functional temporal lobectomy, selective amygdalohippocampectomy through a transsylvian, transcortical, or subtemporal approach, insulo-opercular corticectomies compared to laser interstitial thermal therapy, radiofrequency thermocoagulation, stereotactic radiosurgery, neuromodulation, high intensity focused ultrasound, and disconnection surgery including callosotomy, hemispherotomy, and subpial transections. Discussion and conclusion: Understanding the benefits and disadvantages of different surgical approaches and strategies in traditional and minimal invasive epilepsy surgery might improve the surgical decision tree, as not all procedures are appropriate for all patients.

Surgical complications of vagus nerve stimulation surgery: A 14-years single-center experience.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

DeepFLAIR: A neural network approach to mitigate signal and contrast loss in temporal lobes at 7 Tesla FLAIR images.

BACKGROUND AND PURPOSE: Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS: Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS: SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS: The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

The existence of cranial bone flap displacement during brain radiotherapy.

This retrospective study examined bone flap displacement during radiotherapy in 25 post-operative brain tumour patients. Though never exceeding 2.5 mm, the sheer frequency of displacement highlights the need for future research on larger populations to validate its presence and assess the potential clinical impact on planning tumour volume margins.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

Hemispherotomy Revised: A complication overview and a systematic review meta-analysis.

Introduction: Hemispherectomy/hemispherotomy has been employed in the management of catastrophic epilepsy. However, initial reports on the associated mortality and morbidity raised several concerns regarding the technique's safety. Their actual, current incidence needs to be systematically examined to redefine hemispherotomy's exact role. Research question: Our current study examined their incidence and evaluated the association of the various hemispherotomy surgical techniques with the reported complications. Material & methods: A PRISMA-compliant systematic review and meta-analysis was performed. We searched PubMed, Scopus, and Web of Science until December 2022. Fixed- and random-effects models were employed. Egger's regression test was used for estimating the publication bias, while subgroup analysis was utilized for defining the role of the different hemispherotomy techniques. Results: We retrieved a total of 37 studies. The overall procedure mortality was 5%, with a reported mortality of 7% for hemispherectomy and 3% for hemispherotomy. The reported mortality has decreased over the last 30 years from 32% to 2%. Among the observed post-operative complications aseptic meningitis and/or fever occurred in 33%. Hydrocephalus requiring a shunt insertion occurred in 16%. Hematoma evacuation was necessary in 8%, while subgaleal effusion in another 8%. Infections occurred in 11%. A novel post-operative cranial nerve deficit occurred in 11%, while blood transfusion was necessary in 28% of the cases. Discussion and conclusion: Our current analysis demonstrated that the evolution from hemispherectomy to hemispherotomy along with neuroanesthesia advances, had a tremendous impact on the associated mortality and morbidity. Hemispherotomy constitutes a safe surgical procedure in the management of catastrophic epilepsies.

Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery-protocol for a multicentre, prospective cohort study.

INTRODUCTION: Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. METHODS AND ANALYSIS: A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. ETHICS AND DISSEMINATION: The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019-1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. TRIAL REGISTRATION: NL8278; Pre-results.

Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Background: Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance. Methods: GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ. Results: WES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect. Conclusions: Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.