use-cerebral-open-flow-microperfusion-for-longitudinal-collection

Use of Cerebral Open-Flow Microperfusion for the Longitudinal Collection of Interstitial Fluid in an Animal Model of Glioblastoma

Diseases of the central nervous system (CNS) manifest through a complex, dynamic network of intercellular communication. Glioblastoma (GBM), the most ...

Northwestern University

Glioma is the most common primary brain tumor and is often associated with treatment resistance and poor prognosis. Standard treatment typically involves radiotherapy and temozolomide-based chemotherapy, both of which induce cellular senescence-a tumor suppression mechanism.

Cellular senescence in glioma.

Gliomas represent a heterogeneous group of primary brain tumors with variable biological behavior. High-grade variants, notably glioblastomas, exhibit aggressive growth and a poor prognosis. Although surgical resection is central to management, it may lead to systemic and regional postoperative complications that adversely affect outcomes. While neurological complications have been extensively studied, comprehensive analyses of non-neurological sequelae remain limited. This study aimed to estimate the pooled proportion of postoperative systemic and regional complications following glioma resection and to identify factors influencing these proportions. A systematic review and meta-analysis was conducted per PRISMA guidelines. PubMed, Web of Science, and Embase were searched for English-language articles published between January 2000 and November 2024 reporting postoperative complications in glioma resection patients. Pooled proportion were calculated using a random-effects model, and meta-regression assessed the impact of covariates including patient age, gender, publication date, geographical location, and sample size. Seventy-seven studies were included. The pooled proportions for postoperative complications were as follows: venous thromboembolism, 4.92% (95% CI: 1.51-10.05%); deep vein thrombosis, 4.75% (95% CI: 2.86-7.05%); urinary tract infection, 3.77% (95% CI: 0.81-8.47%); hydrocephalus, 2.53% (95% CI: 1.37-3.97%); pulmonary infection, 2.39% (95% CI: 1.15-3.99%); cerebrospinal fluid leak, 2.22% (95% CI: 0.99-3.87%); surgical site infection, 2.21% (95% CI: 1.48-3.07%); meningitis, 1.49% (95% CI: 0.47-2.96%); pulmonary embolism, 1.33% (95% CI: 0.74-2.06%); and sepsis, 1.12% (95% CI: 0.08-3.02%). Significant heterogeneity was observed across studies, with meta-regression revealing that geographical location, publication date, and patient age were significant moderators influencing certain complication rates. This meta-analysis demonstrates that, while systemic and regional complication rates following glioma resection are relatively low, they remain clinically significant. In particular, venous thromboembolism and deep vein thrombosis are notably prevalent. Moreover, significant heterogeneity-shaped by geography, publication date, and patient age-underscores the need for tailored perioperative strategies and further research.

Regional and systemic complications following glioma resection: a systematic review and meta-analysis.

Glioblastoma (GBM) remains one of the deadliest primary brain tumors, with rapid recurrence and near-universal resistance to temozolomide (TMZ) limiting long-term survival. In this study, we identify a clinically actionable mechanism of resistance driven by the LMNA-PRKDC axis, which enhances DNA repair and tumor cell survival following TMZ treatment. Using patient-derived xenograft models of recurrent GBM, we demonstrate that resistant tumors exhibit elevated LMNA expression and increased physical interaction with PRKDC, a central regulator of non-homologous end joining (NHEJ). This interaction accelerates the repair of TMZ-induced DNA lesions, contributing to therapeutic failure. Proteomic profiling and targeted immunoprecipitation revealed a distinct LMNA-PRKDC-associated DNA repair complex. Inhibition of PRKDC with the ATP-competitive inhibitor KU57788 reversed resistance, restoring TMZ sensitivity and impairing tumor growth in vivo. Single-cell RNA sequencing of primary and recurrent GBM specimens further identified LMNA-PRKDC co-expression as a hallmark of treatment-resistant, glioma stem-like cell populations. Importantly, high LMNA-PRKDC expression was associated with inferior survival outcomes in GBM patient cohorts. These results establish the LMNA-PRKDC axis as a functional driver of TMZ resistance through enhanced DNA repair capacity in stem-like tumor subpopulations. Our findings support pharmacologic inhibition of PRKDC as a rational strategy to resensitize resistant GBM to standard chemotherapy and offer a foundation for future biomarker-driven clinical trials targeting DNA repair vulnerabilities in recurrent disease.

Article	Year
Cellular senescence in glioma. Journal of neuro-oncology\| PubMed ID: 37458855	2023
Regional and systemic complications following glioma resection: a systematic review and meta-analysis. Neurosurgical review\| PubMed ID: 40138052	2025
LMNA-PRKDC axis enhances DNA repair and promotes chemoresistance in glioblastoma. Cell death & disease\| PubMed ID: 41271669	2025

Rafal Chojak

Biography

JoVE Journal Publications

Other Publications