Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6–9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Neuronal-glioma interactions are increasingly recognized as critical in the development and progression of central nervous system tumors. Recent research highlights that gliomas can integrate into neural circuits through various mechanisms, including the synaptogenic factor thrombospondin-1 (TSP-1). This new mechanistic understanding of cancer neuroscience allows for novel insights into target discovery. Critically, therapies that modulate neuron-tumor interactions remain agnostic to other oncogenic changes within tumor cells yet may still target fundamental drivers of tumor growth. In line with these findings and controlling for critical confounding variables, we demonstrate a survival benefit associated with gabapentin (an antagonist of TSP-1) following surgical resection of newly diagnosed glioblastoma. This retrospective, multi-institutional cohort study included 1,072 patients, with a discovery cohort of 693 patients and an additional 379 patients from a separate site for external validation. Furthermore, our findings indicate that gabapentin administration is associated with reduced serum TSP-1 levels, suggesting its potential as a future biomarker.

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience.

The emergence of modern adjuvant therapies has significantly improved outcomes for patients with brain metastases. However, treatment-related side effects present an ongoing challenge, particularly, treatment-induced necrosis characterized by perilesional edema and inflammation. Standard management with steroids compromises the efficacy of otherwise efficacious immunotherapeutic approaches. This position paper critiques traditional management strategies that rely heavily on systemic corticosteroid therapy—often ineffective in providing lasting relief and associated with serious side effects—and proposes a paradigm shift that prioritizes surgical resection. Resection facilitates prompt edema reduction with a low recurrence rate of symptoms and mitigates the adverse effects of prolonged corticosteroid use. We propose increased consideration for resecting symptomatic radiation necrosis to facilitate improved efficacy of immunotherapies in patients with brain metastases.

BACKGROUND: Timely identification of stroke subtype is critical for triage and treatment. Existing prehospital stroke scales have limited diagnostic accuracy, especially in differentiating large vessel occlusion (LVO) from intracerebral hemorrhage (ICH). The LVOne point-of-care test measures d -dimer and GFAP (glial fibrillary acidic protein), biomarkers associated with thrombotic and hemorrhagic stroke, enabling biologically informed triage. METHODS: We validated a new version of the LVOne assay using plasma samples from 210 suspected stroke patients presenting within 6 hours of symptom onset, enrolled in the TIME (Testing of Identification Markers for Stroke) prospective observational cohort. This article reports a retrospective (secondary) laboratory analysis of these prospectively collected samples and clinical data. Samples were collected before neuroimaging or thrombolysis. LVOne version 1 combined d -dimer positivity, GFAP negativity, and Field Assessment Stroke Triage for Emergency Destination scoring for LVO detection only; version 2 uses improved GFAP measurement and a clinical decision rule enabling simultaneous diagnosis of LVO and ICH. Diagnostic performance (sensitivity, specificity, positive predictive value, negative predictive value) was calculated for each version. Receiver operating characteristic analyses and biomarker correlations with Field Assessment Stroke Triage for Emergency Destination were also performed. RESULTS: Both LVOne versions achieved high accuracy for LVO detection (sensitivity, 0.75; specificity, 0.92; negative predictive value, 0.97). Version 2 improved ICH specificity (0.99 versus 0.90) and positive predictive value (0.83 versus 0.23) versus version 1. Biomarker levels correlated with Field Assessment Stroke Triage for Emergency Destination scores but with limited explanatory power (GFAP R ² =0.077; d -dimer R ² =0.047), suggesting added information beyond clinical severity scales. In a specimen-matrix comparison (n=25), qualitative GFAP/ d -dimer classification was concordant across plasma, venous whole blood, and capillary whole blood. CONCLUSIONS: The updated LVOne assay enables simultaneous biomarker-based identification of both LVO and ICH in suspected stroke patients. Its rapid, low-complexity format supports prehospital use and may improve triage, reduce time to treatment, and optimize outcomes. Prospective field validation is warranted. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04292600.