Glioblastoma (GBM) exhibits developmental programs and marked cellular heterogeneity, yet how these features are organized into connected lineage hierarchies remains unclear. Here we identify a rare tumor-intrinsic population, termed the neurovascular progenitor (NVP), that occupies an intermediate position between the major GBM organizational axes. NVP cells co-express neural progenitor and perivascular transcriptional features, are consistently detected across independent patient cohorts, retain canonical GBM copy-number alterations, and localize in situ in both vessel-associated and parenchymal niches. Using direct-from-patient lineage tracing in a human organoid tumor transplantation system, we show that individual NVP cells clonally generate both neural-like and mesenchymal/vascular-like malignant progeny, providing a concrete lineage link between states that are commonly considered mutually exclusive. Despite comprising ∼1% of tumor cells, NVP-derived lineages account for a majority of observed tumor cell types and disproportionately contribute to cycling compartments. Orthogonally, ablation of NVP-associated programs in an in vivo GBM model remodels tumor composition, elicits compensatory progenitor states, and significantly prolongs survival. Together, these findings position NVP as a fate-restricted yet highly influential lineage intermediate that serves as a functional bridge and organizational nexus within GBM hierarchies, linking population-level lineage architecture to the behavior of a specific progenitor cell type.

Background: Glioblastoma remains the most aggressive and treatment-resistant primary brain tumor, with patient outcomes strongly associated with the extent of surgical resection. Tumor recurrence is largely driven by infiltrating glioma cells that extend beyond the contrast-enhancing margin, which has traditionally served as the boundary for surgical resection. Advances in pre- and intraoperative imaging, functional mapping, and fluorescence guidance have challenged the conventional definition of “maximal safe resection” and given rise to the concept of supramaximal resection (SMR). This technique, where surgical resection extends beyond the contrast-enhancing border, has garnered significant interest in recent years and shown promising preliminary survival outcomes. However, the lack of standardized definitions and methodological consistency has limited reproducibility and clinical adoption. Methods: A systematic literature search of PubMed/MEDLINE, Embase, and Web of Science was performed from database inception through March 2026 in accordance with PRISMA guidelines. Studies investigating resection beyond the contrast-enhancing tumor margin in adult glioblastoma patients were evaluated for inclusion. Results: A total of 1045 records were identified, with 37 studies meeting inclusion criteria. Across studies, SMR was frequently associated with improved progression-free and overall survival in selected patients, particularly following complete contrast-enhancing tumor resection. However, substantial heterogeneity exists in SMR definitions, and the current body of evidence is largely retrospective and derived from high-volume centers. Conclusions: SMR represents a promising extension of maximal safe resection targeting infiltrative tumor beyond conventional imaging boundaries. While emerging evidence suggests survival benefits, variability in methodology and patient-specific factors require cautious interpretation. Future standardization and prospective validation are needed to better define the role of SMR within multimodal glioblastoma treatment.

Extensive molecular profiling has revealed profound heterogeneity in glioblastoma (GBM), yet how cellular lineages organize over time to govern tumor propagation and therapeutic response remains poorly understood. Existing single-cell approaches define transcriptional states but provide limited insight into how clonal dynamics shape functional tumor behavior. Here, we integrate high-complexity combinatorial DNA barcoding with single-cell transcriptomics in direct-from-patient IDH1-wild-type GBM, enabling lineage-resolved mapping of progenitor organization in a human microenvironmental context. Across 235,155 malignant cells from nine tumors, clonal relationships form reproducible lineage tracks in which distinct progenitor populations give rise to specific differentiated cell types, revealing that tumor growth is sustained by multiple non-redundant progenitors rather than a single dominant population. These progenitors exhibit distinct propensities for self-renewal, fate restriction, and cross-compartment interactions, collectively accounting for the full spectrum of tumor states. Using this lineage-resolved framework, we identify complementary drug targets in distinct progenitor compartments and demonstrate that hierarchy-informed combination therapies disrupt progenitor-progenitor interactions and reshape lineage output. These findings move beyond descriptive heterogeneity to define functional logic underlying GBM propagation and establish a generalizable framework for rational, cell type-specific combinatorial therapies.

Benign-appearing intracranial cysts may become symptomatic due to mass effect and require surgical treatment. Mechanisms underlying cyst formation and growth remain poorly understood. This study identified 16 patients who underwent surgical treatment for benign intracranial cysts. Cyst wall pathologic samples (n = 8) were characterized as arachnoid or glioependymal cysts using H&E and immunofluorescence staining. Five samples (62.5%) were found to be glioependymal while three (37.5%) were arachnoid cysts. Cyst fluid examined in 4 cases resembled cerebrospinal fluid (CSF) and showed no significant differences in composition between pathological subtypes. Single-cell sequencing and RNA expression profile comparisons between glioependymal and arachnoid cysts revealed distinct cellular profiles. Analyses of the innermost cell layer (ependymal cells versus arachnoid cells) suggested differing mechanisms of pathogenesis. Glioependymal cysts harbored upregulated expression of sodium transporters and aquaporin channels, which suggests possible CSF-like fluid production whereas arachnoid cysts may be associated with mechanical fluid accumulation. Thus, intracranial cysts represent multiple unique pathologic entities with differing cell types and RNA expression profiles. Further study into mechanisms of glioependymal cyst formation may allow for targeted interventions to reduce fluid production and avoid surgery.

Glioblastoma (GBM) is a devastating primary brain tumor with remarkable inter- and intra-tumoral heterogeneity. GBM cells assume a spectrum of neurodevelopmental-like phenotypes and co-opt normal neurophysiological processes, which include synaptic integration with their neuronal microenvironment. This is mediated by neuron-tumor synapses (NTS) that predominantly involve glutamatergic receptors, which drive calcium elevations that promote tumor proliferation and invasion. The exact relationship between synaptic signaling and tumor cell fate specification, however, remains largely unexplored. Here, we develop and leverage a synapse-optimized human organoid tumor transplantation (so-HOTT) model of GBM to decipher how glutamatergic signaling impacts GBM lineage trajectories. so-HOTT preserves patient tumor heterogeneity, features excitatory NTS, and enables clonal lineage tracing of tumor cells after NTS perturbations. Genetic and pharmacological inhibition of AMPA and kainate receptors in so-HOTT shifts tumor cell composition from neuronal fates toward progenitor-proximal astrocytic/mesenchymal states. This occurs through the attenuation of calcium signaling and reduced plasticity of malignant radial glia (RG)-like progenitors, a previously unrecognized target of NTS. Through the integration of inputs from the neuronal microenvironment into glutamatergic signaling, progenitor populations modulate their transcriptional programs and cell fate, ultimately shaping GBM tumor heterogeneity. Targeting synaptic input may thus constrain the heterogeneity that fuels GBM adaptation and therapeutic escape.

Database studies have identified population-level differences in neurosurgical-oncological outcomes. This study aimed to clarify these distinctions by evaluating associations between patient sociodemographics and metrics of care access, utilization, and clinical outcomes. We retrospectively reviewed a prospectively identified database of neurosurgical-oncology patients (n = 1476) over 5 years. We conducted pathology-specific, multivariate analyses to identify sociodemographics associated with access, utilization, and outcomes, then interviewed (n = 40) with newly diagnosed patients. Significant associations were found between sociodemographics (White n = 911; Hispanic/Latino n = 285; Asian n = 206; Black n = 74), sex (ANOVA P = 0.0043), age (P < 0.001), income (P < 0.001), primary language (P < 0.001), and insurance (P < 0.001). Emergent presentation and time from imaging to neurosurgical consultation were associated with English as an additional language (EAL) (P = 0.03, P = 0.03) and public insurance (P = 0.003, P = 0.003). Black patients had increased time from consultation to surgery (P = 0.011). White patients were less likely to undergo biopsy versus resection (P = 0.05). EAL was negatively associated with gross total resection (P = 0.009). Chemotherapy was negatively associated with EAL (P = 0.02), Black race (P = 0.005), and public insurance (P = 0.001). Radiotherapy was negatively associated with EAL (P = 0.04), public insurance (P = 0.001), and age (P = 0.04). Clinical outcomes did not vary by sociodemographics. Interviews identified health literacy, prior healthcare experiences, and patient-surgeon connection as strongest drivers of utilization. Demographic factors independently associate with healthcare access but not outcomes. Progression through recommended neurosurgical-oncological care is influenced by patient-neurosurgeon relationship and trust in healthcare systems.