SUPRAMAX-study: supramaximal resection versus maximal resection for glioblastoma patients: study protocol for an international multicentre prospective cohort study (ENCRAM 2201).

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

Patient-Specific Vascular Flow Phantom for MRI- and Doppler Ultrasound Imaging.

OBJECTIVE: Intraoperative Doppler ultrasound imaging of human brain vasculature is an emerging neuro-imaging modality that offers vascular brain mapping with unprecedented spatiotemporal resolution. At present, however, access to the human brain using Doppler Ultrasound is only possible in this intraoperative context, posing a significant challenge for validation of imaging techniques. This challenge necessitates the development of realistic flow phantoms outside of the neurosurgical operating room as external platforms for testing hardware and software. An ideal ultrasound flow phantom should provide reference-like values in standardized topologies such as a slanted pipe, and allow for measurements in structures closely resembling vascular morphology of actual patients. Additionally, the phantom should be compatible with other clinical cerebrovascular imaging modalities. To meet these criteria, we developed and validated a versatile, multimodal MRI- and ultrasound Doppler phantom. METHODS: Our approach incorporates the latest advancements in phantom research using tissue-mimicking material and 3D-printing with water-soluble resin to create wall-less patient-specific lumens, compatible for ultrasound and MRI. RESULTS: We successfully produced three distinct phantoms: a slanted pipe, a y-shape phantom representing a bifurcating vessel and an arteriovenous malformation (AVM) derived from clinical Digital Subtraction Angiography (DSA)-data of the brain. We present 3D ultrafast power Doppler imaging results from these phantoms, demonstrating their ability to mimic complex flow patterns as observed in the human brain. Furthermore, we showcase the compatibility of our phantom with Magnetic Resonance Imaging (MRI). CONCLUSION: We developed an MRI- and Doppler Ultrasound-compatible flow-phantom using customizable, water-soluble resin prints ranging from geometrical forms to patient-specific vasculature.

Differential contribution of language and executive functioning to verbal fluency performance in glioma patients.

Glioma patients often suffer from deficits in language and executive functioning. Performance in verbal fluency (generating words within one minute according to a semantic category-category fluency, or given letter-letter fluency) is typically impaired in this patient group. While both language and executive functioning play a role in verbal fluency, the relative contribution of both domains remains unclear. We aim to retrospectively investigate glioma patients' performance on verbal and nonverbal fluency and to explore the influence of language and executive functioning on verbal fluency. Sixty-nine adults with gliomas in eloquent areas underwent a neuropsychological test battery (verbal fluency, nonverbal fluency, language, and executive functioning tests) before surgery (T1) and a subgroup of 31 patients also at three (T2) and twelve months (T3) after surgery. Preoperatively, patients were impaired in all verbal fluency tasks and dissociations were found based on tumour location. In contrast, nonverbal fluency was intact. Different language and executive functioning tests predicted performance on category fluency animals and letter fluency, while no significant predictors for category fluency professions were found. The longitudinal results indicated that category fluency professions deteriorated after surgery (T1-T2, T1-T3) and that nonverbal fluency improved after surgery (T1-T3, T2-T3). Verbal fluency performance can provide information on different possible underlying deficits in language and executive functioning in glioma patients, depending on verbal fluency task selection. Efficient task (order) selection can be based on complexity. Category fluency professions can be selected to detect more permanent long-term deficits.

Evaluating the Predictive Value of Glioma Growth Models for Low-Grade Glioma After Tumor Resection.

Tumor growth models have the potential to model and predict the spatiotemporal evolution of glioma in individual patients. Infiltration of glioma cells is known to be faster along the white matter tracts, and therefore structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can be used to inform the model. However, applying and evaluating growth models in real patient data is challenging. In this work, we propose to formulate the problem of tumor growth as a ranking problem, as opposed to a segmentation problem, and use the average precision (AP) as a performance metric. This enables an evaluation of the spatial pattern that does not require a volume cut-off value. Using the AP metric, we evaluate diffusion-proliferation models informed by structural MRI and DTI, after tumor resection. We applied the models to a unique longitudinal dataset of 14 patients with low-grade glioma (LGG), who received no treatment after surgical resection, to predict the recurrent tumor shape after tumor resection. The diffusion models informed by structural MRI and DTI showed a small but significant increase in predictive performance with respect to homogeneous isotropic diffusion, and the DTI-informed model reached the best predictive performance. We conclude there is a significant improvement in the prediction of the recurrent tumor shape when using a DTI-informed anisotropic diffusion model with respect to istropic diffusion, and that the AP is a suitable metric to evaluate these models. All code and data used in this publication are made publicly available.

Preoperative assessment of eloquence in neurosurgery: a systematic review.

BACKGROUND AND OBJECTIVES: Tumor location and eloquence are two crucial preoperative factors when deciding on the optimal treatment choice in glioma management. Consensus is currently lacking regarding the preoperative assessment and definition of eloquent areas. This systematic review aims to evaluate the existing definitions and assessment methods of eloquent areas that are used in current clinical practice. METHODS: A computer-aided search of Embase, Medline (OvidSP), and Google Scholar was performed to identify relevant studies. This review includes articles describing preoperative definitions of eloquence in the study's Methods section. These definitions were compared and categorized by anatomical structure. Additionally, various techniques to preoperatively assess tumor eloquence were extracted, along with their benefits, drawbacks and ease of use. RESULTS: This review covers 98 articles including 12,714 participants. Evaluation of these studies indicated considerable variability in defining eloquence. Categorization of these definitions yielded a list of 32 brain regions that were considered eloquent. The most commonly used methods to preoperatively determine tumor eloquence were anatomical classification systems and structural MRI, followed by DTI-FT, functional MRI and nTMS. CONCLUSIONS: There were major differences in the definitions and assessment methods of eloquence, and none of them proved to be satisfactory to express eloquence as an objective, quantifiable, preoperative factor to use in glioma decision making. Therefore, we propose the development of a novel, objective, reliable, preoperative classification system to assess eloquence. This should in the future aid neurosurgeons in their preoperative decision making to facilitate personalized treatment paradigms and to improve surgical outcomes.

The effect of recorded music on pain endurance (CRESCENDo) - A randomized controlled trial.

INTRODUCTION: Clarifying the effect of music on pain endurance in an experimental design could aid in how music should be applied during both surgical and non-surgical interventions. This study aims to investigate the effect of music on pain endurance and the involvement of the sympathetic adrenomedullary axis (SAM) and the hypothalamic-pituitary-adrenocortical axis (HPA). MATERIALS AND METHODS: In this randomized controlled trial all participants received increasing electric stimuli through their non-dominant index finger. Participants were randomly assigned to the music group (M) receiving a 20-minute music intervention or control group (C) receiving a 20-minute resting period. The primary outcome was pain endurance, defined as amount milliampere tolerated. Secondary outcomes included anxiety level, SAM-axis based on heart rate variability (HRV) and salivary alpha-amylase, and HPA-axis activity based on salivary cortisol. RESULTS: In the intention-to-treat analysis, the effect of music on pain tolerance did not statistically differ between the M and C group. A significant positive effect of music on pain endurance was noted after excluding participants with a high skin impedance (p = 0.013, CI 0.35; 2.85). Increased HRV was observed in the M-group compared to the C-group for SDNN (B/95%CI:13.80/2.22;25.39, p = 0.022), RMSSD (B/95%CI:15.97/1.64;30.31, p = 0.032), VLF (B/95%CI:212.08/60.49;363.67, p = 0.008) and HF (B/95%CI:821.15/150.78;1491.52, p = 0.0190). No statistical significance was observed in other secondary outcomes. CONCLUSIONS: The effect of the music intervention on pain endurance was not statistically significant in the intention-to-treat analysis. The subgroup analyses revealed an increase in pain endurance in the music group after correcting for skin impedance, which could be attributed to increased parasympathetic activation.

Sympathetic components in left and right human cervical vagus nerve: implications for vagus nerve stimulation.

Cervical vagus nerve stimulation is in a great variety of clinical situations indicated as a form of treatment. It is textbook knowledge that at the cervical level the vagus nerve contains many different fiber classes. Yet, recently, several reports have shown that this nerve also may contain an additional class of potentially noradrenergic fibers, suggested to denote efferent sympathetic fibers. As such, the nature and presence of these fibers should be considered when choosing a stimulation protocol. We have studied human vagus material extracted from dissection room cadavers in order to further confirm the presence of this class of fibers, to study their origin and direction within the nerve and to determine their distribution and variability between subjects and pairs of left and right nerves of the same individual. Sections were studied with immunohistochemical techniques using antibodies against tyrosine hydroxylase (TH: presumed to indicate noradrenergic fibers), myelin basic protein and neurofilament. Our results show that at least part of the TH-positive fibers derive from the superior cervical ganglion or sympathetic trunk, do not follow a cranial but take a peripheral course through the nerve. The portion of TH-positive fibers is highly variable between individuals but also between the left and right pairs of the same individual. TH-positive fibers can distribute and wander throughout the fascicles but maintain a generally clustered appearance. The fraction of TH-positive fibers generally diminishes in the left cervical vagus nerve when moving in a caudal direction but remains more constant in the right nerve. These results may help to determine optimal stimulation parameters for cervical vagus stimulation in clinical settings.

Music to prevent deliriUm during neuroSurgerY (MUSYC): a single-centre, prospective randomised controlled trial.

OBJECTIVES: Delirium is a serious complication following neurosurgical procedures. We hypothesise that the beneficial effect of music on a combination of delirium-eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. DESIGN: Prospective randomised controlled trial. SETTING: Single centre, conducted at the neurosurgical department of the Erasmus Medical Center, Rotterdam, the Netherlands. PARTICIPANTS: Adult patients undergoing craniotomy were eligible. INTERVENTIONS: Patients in the intervention group received preferred recorded music before, during and after the operation until day 3 after surgery. Patients in the control group were treated according to standard of clinical care. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was presence or absence of postoperative delirium within the first 5 postoperative days measured with the Delirium Observation Screening Scale (DOSS) and, in case of a daily mean score of 3 or higher, a psychiatric evaluation with the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Secondary outcomes included anxiety, heart rate variability (HRV), depth of anaesthesia, delirium severity and duration, postoperative complications, length of stay and location of discharge. RESULTS: We enrolled 189 patients (music=95, control=94) from July 2020 through September 2021. Delirium, as assessed by the DOSS, was less common in the music (n=11, 11.6%) than in the control group (n=21, 22.3%, OR:0.49, p=0.048). However, after DSM-5 confirmation, differences in delirium were not significant (4.2% vs 7.4%, OR:0.47, p=0.342). Moreover, music increased the HRV (root mean square of successive differences between normal heartbeats, p=0.012). All other secondary outcomes were not different between groups. CONCLUSION: Our results support the efficacy of music in reducing the incidence of delirium after craniotomy, as found with DOSS but not after DSM-5 confirmation, substantiated by the effect of music on preoperative autonomic tone. Delirium screening tools should be validated and the long-term implications should be evaluated after craniotomy. TRIAL REGISTRATION NUMBER: Trialregister.nl: NL8503 and ClinicalTrials.gov: NCT04649450.

Case report: High-resolution, intra-operative µDoppler-imaging of spinal cord hemangioblastoma.

Surgical resection of spinal cord hemangioblastomas remains a challenging endeavor: the neurosurgeon's aim to reach total tumor resections directly endangers their aim to minimize post-operative neurological deficits. The currently available tools to guide the neurosurgeon's intra-operative decision-making consist mostly of pre-operative imaging techniques such as MRI or MRA, which cannot cater to intra-operative changes in field of view. For a while now, spinal cord surgeons have adopted ultrasound and its submodalities such as Doppler and CEUS as intra-operative techniques, given their many benefits such as real-time feedback, mobility and ease of use. However, for highly vascularized lesions such as hemangioblastomas, which contain up to capillary-level microvasculature, having access to higher-resolution intra-operative vascular imaging could potentially be highly beneficial. µDoppler-imaging is a new imaging modality especially fit for high-resolution hemodynamic imaging. Over the last decade, µDoppler-imaging has emerged as a high-resolution, contrast-free sonography-based technique which relies on High-Frame-Rate (HFR)-ultrasound and subsequent Doppler processing. In contrast to conventional millimeter-scale (Doppler) ultrasound, the µDoppler technique has a higher sensitivity to detect slow flow in the entire field-of-view which allows for unprecedented visualization of blood flow down to sub-millimeter resolution. In contrast to CEUS, µDoppler is able to image high-resolution details continuously, without being contrast bolus-dependent. Previously, our team has demonstrated the use of this technique in the context of functional brain mapping during awake brain tumor resections and surgical resections of cerebral arteriovenous malformations (AVM). However, the application of µDoppler-imaging in the context of the spinal cord has remained restricted to a handful of mostly pre-clinical animal studies. Here we describe the first application of µDoppler-imaging in the case of a patient with two thoracic spinal hemangioblastomas. We demonstrate how µDoppler is able to identify intra-operatively and with high-resolution, hemodynamic features of the lesion. In contrast to pre-operative MRA, µDoppler could identify intralesional vascular details, in real-time during the surgical procedure. Additionally, we show highly detailed post-resection images of physiological human spinal cord anatomy. Finally, we discuss the necessary future steps to push µDoppler to reach actual clinical maturity.

Microvasculature Features Derived from Hybrid EPI MRI in Non-Enhancing Adult-Type Diffuse Glioma Subtypes.

In this study, we used the vessel size imaging (VSI) MRI technique to characterize the microvasculature features of three subtypes of adult-type diffuse glioma lacking enhancement. Thirty-eight patients with confirmed non-enhancing glioma were categorized into three subtypes: Oligo (IDH-mut&1p/19q-codeleted), Astro (IDH-mut), and GBM (IDH-wt). The VSI technique provided quantitative maps of cerebral blood volume (CBV), microvasculature (µCBV), and vessel size for each patient. Additionally, tissue samples of 21 patients were histopathologically analyzed, and microvasculature features were quantified. Both MRI- and histology-derived features were compared across the three glioma subtypes with ANOVA or Kruskal-Wallis tests. Group averages of CBV, µCBV, and vessel size were significantly different between the three glioma subtypes (p < 0.01). Astro (IDH-mut) had a significantly lower CBV and µCBV compared to Oligo (IDH-mut&1p/19q-codeleted) (p = 0.004 and p = 0.001, respectively), and a higher average vessel size compared to GBM (IDH-wt) (p = 0.01). The histopathological analysis showed that GBM (IDH-wt) possessed vessels with more irregular shapes than the two other subtypes (p < 0.05). VSI provides a good insight into the microvasculature characteristics of the three adult-type glioma subtypes even when lacking enhancement. Further investigations into the specificity of VSI to differentiate glioma subtypes are thus warranted.

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma.

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

Functional imaging of the exposed brain.

When the brain is exposed, such as after a craniotomy in neurosurgical procedures, we are provided with the unique opportunity for real-time imaging of brain functionality. Real-time functional maps of the exposed brain are vital to ensuring safe and effective navigation during these neurosurgical procedures. However, current neurosurgical practice has yet to fully harness this potential as it pre-dominantly relies on inherently limited techniques such as electrical stimulation to provide functional feedback to guide surgical decision-making. A wealth of especially experimental imaging techniques show unique potential to improve intra-operative decision-making and neurosurgical safety, and as an added bonus, improve our fundamental neuroscientific understanding of human brain function. In this review we compare and contrast close to twenty candidate imaging techniques based on their underlying biological substrate, technical characteristics and ability to meet clinical constraints such as compatibility with surgical workflow. Our review gives insight into the interplay between technical parameters such sampling method, data rate and a technique's real-time imaging potential in the operating room. By the end of the review, the reader will understand why new, real-time volumetric imaging techniques such as functional Ultrasound (fUS) and functional Photoacoustic Computed Tomography (fPACT) hold great clinical potential for procedures in especially highly eloquent areas, despite the higher data rates involved. Finally, we will highlight the neuroscientific perspective on the exposed brain. While different neurosurgical procedures ask for different functional maps to navigate surgical territories, neuroscience potentially benefits from all these maps. In the surgical context we can uniquely combine healthy volunteer studies, lesion studies and even reversible lesion studies in in the same individual. Ultimately, individual cases will build a greater understanding of human brain function in general, which in turn will improve neurosurgeons' future navigational efforts.

Localization patterns of speech and language errors during awake brain surgery: a systematic review.

Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with eloquent area gliomas. DES detects speech and language errors, which indicate functional boundaries that must be maintained to preserve quality of life. During DES, traditional object naming or other linguistic tasks such as tasks from the Dutch Linguistic Intraoperative Protocol (DuLIP) can be used. It is not fully clear which speech and language errors occur in which brain locations. To provide an overview and to update DuLIP, a systematic review was conducted in which 102 studies were included, reporting on speech and language errors and the corresponding brain locations during awake craniotomy with DES in adult glioma patients up until 6 July 2020. The current findings provide a crude overview on language localization. Even though subcortical areas are in general less often investigated intraoperatively, still 40% out of all errors was reported at the subcortical level and almost 60% at the cortical level. Rudimentary localization patterns for different error types were observed and compared to the dual-stream model of language processing and the DuLIP model. While most patterns were similar compared to the models, additional locations were identified for articulation/motor speech, phonology, reading, and writing. Based on these patterns, we propose an updated DuLIP model. This model can be applied for a more adequate "location-to-function" language task selection to assess different linguistic functions during awake craniotomy, to possibly improve intraoperative language monitoring. This could result in a better postoperative language outcome in the future.

Postoperative Delirium After Intracranial Surgery: A Retrospective Cohort Study.

BACKGROUND: The clinical relevance of postoperative delirium (POD) in neurosurgery remains unclear and should be investigated because these patients are vulnerable. Hence, we investigated the impact of POD, by means of incidence and health outcomes, and identified independent risk factors. METHODS: Adult patients undergoing an intracranial surgical procedure in the Erasmus Medical Center Rotterdam between June 2017 and September 2020 were retrospectively included. POD incidence, defined by a Delirium Observation Screening Scale (DOSS) ≥3 or antipsychotic treatment for delirium within 5 days after surgery, was calculated. Logistic regression analysis on the full data set was conducted for the multivariable risk factor and health outcome analyses. RESULTS: After including 2901 intracranial surgical procedures, POD was present in 19.4% with a mean onset in days of 2.62 (standard deviation, 1.22) and associated with more intensive care unit admissions and more discharge toward residential care. Onset of POD was not associated with increased length of hospitalization or mortality. We identified several independent nonmodifiable risk factors such as age, preexisting memory problems, emergency operations, craniotomy compared with burr-hole surgery, and severe blood loss. Moreover, we identified modifiable risk factors such as low preoperative potassium and opioid and dexamethasone administration. CONCLUSIONS: Our POD incidence rates and correlation with more intensive care unit admission and discharge toward residential care suggest a significant impact of POD on neurosurgical patients. We identified several modifiable and nonmodifiable risk factors, which shed light on the pathophysiologic mechanisms of POD in this cohort and could be targeted for future intervention studies.

Impact of maximal extent of resection on postoperative deficits, patient functioning, and survival within clinically important glioblastoma subgroups.

BACKGROUND: The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes. METHODS: Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients. RESULTS: One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P < .0001), and in the subgroups with IDH wildtype tumors (18.5 months, P = .00055), MGMT methylated tumors (35.0 months, P < .0001), aged <70 (20.0 months, P < .0001), NIHSS 0-1 (19.0 months, P = .0038), KPS 90-100 (19.5 months, P = .0012), and KPS ≤80 (17.0 months, P = .036). GTR was significantly associated with improved OS in the overall cohort (HR 0.58, P = .0070) and improved PFS in the NIHSS 0-1 subgroup (HR 0.47, P = .012). GTR combined with preservation of neurological function (OFO 1 grade) yielded the longest survival times (median OS 22.0 months, P < .0001), which was significantly more frequently achieved in the awake mapping group (50.0%) than in the asleep group (21.8%) (P < .0001). CONCLUSIONS: Maximum resection was especially beneficial in the subgroups aged <70, NIHSS 0-1, and KPS 90-100 without increasing the risk of postoperative NIHSS or KPS worsening. These findings may assist surgical decision making in individual glioblastoma patients.

Combined molecular subtyping, grading, and segmentation of glioma using multi-task deep learning.

BACKGROUND: Accurate characterization of glioma is crucial for clinical decision making. A delineation of the tumor is also desirable in the initial decision stages but is time-consuming. Previously, deep learning methods have been developed that can either non-invasively predict the genetic or histological features of glioma, or that can automatically delineate the tumor, but not both tasks at the same time. Here, we present our method that can predict the molecular subtype and grade, while simultaneously providing a delineation of the tumor. METHODS: We developed a single multi-task convolutional neural network that uses the full 3D, structural, preoperative MRI scans to predict the IDH mutation status, the 1p/19q co-deletion status, and the grade of a tumor, while simultaneously segmenting the tumor. We trained our method using a patient cohort containing 1508 glioma patients from 16 institutes. We tested our method on an independent dataset of 240 patients from 13 different institutes. RESULTS: In the independent test set, we achieved an IDH-AUC of 0.90, an 1p/19q co-deletion AUC of 0.85, and a grade AUC of 0.81 (grade II/III/IV). For the tumor delineation, we achieved a mean whole tumor Dice score of 0.84. CONCLUSIONS: We developed a method that non-invasively predicts multiple, clinically relevant features of glioma. Evaluation in an independent dataset shows that the method achieves a high performance and that it generalizes well to the broader clinical population. This first-of-its-kind method opens the door to more generalizable, instead of hyper-specialized, AI methods.

IDH1/2 wildtype gliomas grade 2 and 3 with molecular glioblastoma-like profile have a distinct course of epilepsy compared to IDH1/2 wildtype glioblastomas.

BACKGROUND: IDH1/2 wildtype (IDHwt) glioma WHO grade 2 and 3 patients with pTERT mutation and/or EGFR amplification and/or + 7/-10 chromosome gain/loss have a similar overall survival time as IDHwt glioblastoma patients, and are both considered glioblastoma IDHwt according to the WHO 2021 classification. However, differences in seizure onset have been observed. This study aimed to compare the course of epilepsy in the 2 glioblastoma subtypes. METHODS: We analyzed epilepsy data of an existing cohort including IDHwt histologically lower-grade glioma WHO grade 2 and 3 with molecular glioblastoma-like profile (IDHwt hLGG) and IDHwt glioblastoma patients. Primary outcome was the incidence proportion of epilepsy during the disease course. Secondary outcomes included, among others, onset of epilepsy, number of seizure days, and antiepileptic drug (AED) polytherapy. RESULTS: Out of 254 patients, 78% (50/64) IDHwt hLGG and 68% (129/190) IDHwt glioblastoma patients developed epilepsy during the disease (P = .121). Epilepsy onset before histopathological diagnosis occurred more frequently in IDHwt hLGG compared to IDHwt glioblastoma patients (90% vs 60%, P < .001), with a significantly longer median time to diagnosis (3.5 vs 1.3 months, P < .001). Median total seizure days was also longer for IDHwt hLGG patients (7.0 vs 3.0, P = .005), and they received more often AED polytherapy (32% vs 17%, P = .028). CONCLUSIONS: Although the incidence proportion of epilepsy during the entire disease course is similar, IDHwt hLGG patients show a significantly higher incidence of epilepsy before diagnosis and a significantly longer median time between first seizure and diagnosis compared to IDHwt glioblastoma patients, indicating a distinct clinical course.

Physical fitness and its association with fatigue in patients with low-grade glioma.

PURPOSE: To evaluate physical fitness and its association with fatigue in patients with low grade glioma (LGG). METHODS: Cross-sectional study. Muscle strength was measured with a digital dynamometer, cardiorespiratory fitness (peak oxygen uptake (VO2peak), maximal workload (MWL)) by cardiopulmonary-exercise-testing, and fatigue by using the Multidimensional Fatigue Inventory. RESULTS: Thirty patients were included, mean age of 44.1 (SD11.2) years, and 67% were men, 31.2 (SD18) months post-diagnosis. Muscle strength (p < 0.01), and cardiorespiratory fitness (VO2peak, MWL) (p < 0.01) were significantly decreased compared to predicted values based on age and gender. Thirty percent of the patients experienced severe physical fatigue, and severe mental fatigue was reported in 57% of the patients. Cardiorespiratory fitness showed weak to moderate (r - 0.46 to r - 0.52) but significant (p < 0.01) correlations with physical fatigue, not with mental and general fatigue. Muscle strength was not associated with fatigue. A lower VO2peak was independently associated with a higher level of physical fatigue, adjusted for Karnofsky Performance Status (R2 0.40). CONCLUSIONS: Physical fitness (muscle strength, cardiorespiratory fitness) is reduced in patients with LLG, and a lower level of cardiorespiratory fitness (VO2peak) is independently associated with a higher level of experienced physical fatigue. Trials to explore the benefit of exercise programs to improve cardiorespiratory fitness and, consequently, fatigue are warranted.Implications for rehabilitationPhysical fitness (muscle strength and cardiorespiratory fitness) is reduced in patients with low-grade glioma.Patients with low-grade glioma should be screened for fatigue with the multidimensional fatigue inventory, to differentiate between mental and physical fatigue.Patients with low-grade glioma with severe physical fatigue should be screened for reduced physical fitness, especially cardiorespiratory fitness by objective cardiopulmonary-exercise-testing.Rehabilitation exercise programs to improve cardiorespiratory fitness and, consequently, (physical) fatigue could be warranted in patients with low-grade glioma.

MRI-Based Assessment of Brain Tumor Hypoxia: Correlation with Histology.

Cerebral hypoxia significantly impacts the progression of brain tumors and their resistance to radiotherapy. This study employed streamlined quantitative blood-oxygen-level-dependent (sqBOLD) MRI to assess the oxygen extraction fraction (OEF)-a measure of how much oxygen is being extracted from vessels, with higher OEF values indicating hypoxia. Simultaneously, we utilized vessel size imaging (VSI) to evaluate microvascular dimensions and blood volume. A cohort of ten patients, divided between those with glioma and those with brain metastases, underwent a 3 Tesla MRI scan. We generated OEF, cerebral blood volume (CBV), and vessel size maps, which guided 3-4 targeted biopsies per patient. Subsequent histological analyses of these biopsies used hypoxia-inducible factor 1-alpha (HIF-1α) for hypoxia and CD31 for microvasculature assessment, followed by a correlation analysis between MRI and histological data. The results showed that while the sqBOLD model was generally applicable to brain tumors, it demonstrated discrepancies in some metastatic tumors, highlighting the need for model adjustments in these cases. The OEF, CBV, and vessel size maps provided insights into the tumor's hypoxic condition, showing intertumoral and intratumoral heterogeneity. A significant relationship between MRI-derived measurements and histological data was only evident in the vessel size measurements (r = 0.68, p < 0.001).