Citations

Gliomas are diffusely infiltrative, requiring accurate and sensitive diagnostic tools during surgical resection. Mutations in isocitrate dehydrogenase enzyme (IDH) alter its normal activity and result in accumulation of a unique oncometabolite, 2-hydroxyglutarate (2HG), in tumor cells. However, IDH-wild-type (IDH-wt) gliomas are more common and typically more aggressive. Here, 86 human brain samples were analyzed by syringe touch spray mass spectrometry to evaluate molecular alterations in gliomas. Tandem mass spectrometry (MS/MS) experiments were performed to minimize isobaric and isomeric interferences, and a ratiometric approach (using only signals for endogenous compounds) was employed to improve reliability of the measurements. Multiple ratios for pairs of metabolite signal intensities were found to differentiate tumor samples from nontumor tissue and they stratified glioma subtypes by IDH mutation status and by tumor grade, with several ratios showing 100% agreement with independent clinical assignments ( P < 0.0001, Mann–Whitney U test). Increased carnitine relative abundances were found across all glioma subtypes. Importantly, α-aminoadipate was significantly elevated in grade 4 glioma, which may correlate with increased tumor malignancy. Grade 3 gliomas showed markedly higher 2HG abundance than grade 4 samples. In addition, a selection of ratios showed a linear trend with varying tumor cell percentage. Overall, the multiple metabolic ratio alterations indicate a high degree of heterogeneity among glioma subtypes. Furthermore, there are metabolites that can differentiate glioma from nontumor tissue and this measurement can be made by a simple ratiometric method which has potential to be used intraoperatively for margin assessment without diverging from standard of care.

OBJECTIVE Cognard type V dural arteriovenous fistulas (dAVFs), defined by spinal perimedullary venous drainage, represent a rare and aggressive neurovascular pathology. Comprehensive multicenter data remain scarce. The authors present the largest multicenter analysis to date, characterizing presentation, radiology, treatment, complications, and functional outcomes of Cognard type V dAVFs. METHODS The authors retrospectively analyzed patients with angiographically confirmed Cognard type V dAVFs from the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR), spanning 16 academic centers. Patient demographics, imaging features, treatment strategies, procedural complications, and modified Rankin Scale (mRS) scores were recorded. RESULTS Among 1077 patients with dAVFs, 37 (3%) had Cognard type V lesions. The mean patient age was 57 years, and 59.5% of patients were male. Most presented with nonhemorrhagic neurological deficits (68%), while 14% had hemorrhage. The most common location was the foramen magnum (32%). Embolization was the primary treatment in 67% of cases, complete obliteration was achieved in 71% of cases. Upfront microsurgery was performed in 22% of patients (obliteration rate 88%), and radiosurgery in 14% (success rate 40%). Salvage treatment further improved obliteration outcomes. Temporary complications occurred in 8% of patients (3/37): 2 with transient neurological deficits postembolization and 1 with transient hydrocephalus after surgery. Permanent complications were observed in 3% (1/37) due to treatment-related hemorrhage. At the last follow-up (mean 2.4 years), 69% (24/35) of patients maintained or improved to an mRS score ≤ 2. No deaths occurred. Functional improvement was seen in 29% (10/35), while mRS decline was in 40% of patients (14/35), all unrelated to the dAVF itself. CONCLUSIONS Cognard type V dAVFs carry a high risk of neurological morbidity. However, favorable functional outcomes are achievable with timely, multimodal intervention. Complication rates remain low, with most being transient. These data support aggressive but tailored management to prevent permanent disability in this high-risk population.

Abstract High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract

Abstract Intravital microscopy enables dynamic and real‐time visualisation of microscopic structures in living tissues without the need for fixation, with real‐life applicability being illustrated by several first‐in‐human studies in different cancers. Its use in preclinical models has yielded important observations of the microvasculature of both healthy and diseased tissues. It has further enabled the observation of the interactions between important components of the tissue microenvironment such as immune cells and neighbouring microvessels. Important recent technological advances, however, have enabled the translation of this technology to human use. Here, we review the main advances in intravital microscopy and some of the most recent uses in different human disease settings.

Abstract Glioblastoma (GBM) is an aggressive form of cancer, comprising ≈80% of malignant brain tumors. However, there are no effective treatments for GBM due to its heterogeneity and the presence of the blood‐brain barrier (BBB), which restricts the delivery of therapeutics to the brain. Despite in vitro models contributing to the understanding of GBM, conventional 2D models oversimplify the complex tumor microenvironment. Organ‐on‐a‐chip (OoC) models have emerged as promising platforms that recapitulate human tissue physiology, enabling disease modeling, drug screening, and personalized medicine. There is a sudden increase in GBM‐on‐a‐chip models that can significantly advance the knowledge of GBM etiology and revolutionize drug development by reducing animal testing and enhancing translation to the clinic. In this review, an overview of GBM‐on‐a‐chip models and their applications is reported for drug screening and discussed current challenges and potential future directions for GBM‐on‐a‐chip models.

The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis of isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, and Huashan Hospital, Shanghai. The infiltrative nature of gliomas makes rapid diagnosis necessary to guide the extent of surgical resection of central nervous system (CNS) tumors. The combination of tissue biopsy and MS analysis used here satisfies this requirement. The key feature of both described methods is the use of tandem MS to measure the oncometabolite 2-hydroxyglutarate (2HG) relative to endogenous glutamate (Glu) to characterize the presence of mutant tumor. The experiments i) provide IDH mutation status for individual patients and ii) demonstrate a strong correlation of 2HG signals with tumor infiltration. The measured ratio of 2HG to Glu correlates with IDH-mutant (IDH-mut) glioma ( P < 0.0001) in the tumor core data of both teams. Despite using different ionization methods and different mass spectrometers, comparable performance in determining IDH mutations from core tumor biopsies was achieved with sensitivities, specificities, and accuracies all at 100%. None of the 31 patients at Mayo Clinic or the 74 patients at Huashan Hospital were misclassified when analyzing tumor core biopsies. Robustness of the methodology was evaluated by postoperative re-examination of samples. Both teams noted the presence of high concentrations of 2HG at surgical margins, supporting future use of intraoperative MS to monitor for clean surgical margins. The power of MS diagnostics is shown in resolving contradictory clinical features, e.g., in distinguishing gliosis from IDH-mut glioma.