Endoscopic-assisted surgical approach for butterfly glioma surgery.

PURPOSE: Gliomas that spread along the white matter tracts of the corpus callosum to both hemispheres have traditionally been considered surgically challenging largely due to the relative complexity of safely achieving complete resections. We present a series of endoscopic-assisted resections of butterfly gliomas with post-operative radiological assessment of EOR and clinical outcome data. METHODS: Retrospective review of patients who underwent surgical resection of a butterfly glioma from 2007 to 2020. Butterfly gliomas were defined as gliomas, which appeared to arise from the corpus callosum with significant bilateral extension. All records were retrospectively reviewed with operative/clinical outcomes and complications recorded. RESULTS: 70 patients who underwent an endoscopic-assisted transcortical or interhemispheric approach for butterfly glioma resection met inclusion criteria. A unilateral transcortical approach was used in 86% of cases and an interhemispheric approach in 14%. The endoscope enhanced the visualization of the contralateral hemisphere and allowed for resection of tumor, not reached by standard microscopic visualization, in 100% of cases. 90% of resections resulted in greater than a 95% resection rate. Neurological deficits mostly consisted of motor (10%) and memory (6%) deficits and were most common with posterior tumors of the splenium. CONCLUSION: The endoscopic-assisted transcortical or interhemispheric approach for butterfly glioma resection is effective in achieving a greater than 95% resection with minimal complications. An angled approach allows careful maneuvering around complex anatomic structures and difficult corners, and should be examined further for its clinical benefits in a prospective manner.

PODNL1 Methylation Serves as a Prognostic Biomarker and Associates with Immune Cell Infiltration and Immune Checkpoint Blockade Response in Lower-Grade Glioma.

Lower-grade glioma (LGG) is a diffuse infiltrative tumor of the central nervous system, which lacks targeted therapy. We investigated the role of Podocan-like 1 (PODNL1) methylation in LGG clinical outcomes using the TCGA-LGG transcriptomics dataset. We identified four PODNL1 CpG sites, cg07425555, cg26969888, cg18547299, and cg24354933, which were associated with unfavorable overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analysis after adjusting for age, gender, tumor-grade, and IDH1-mutation. In multivariate analysis, the OS and DFS hazard ratios ranged from 0.44 to 0.58 (p < 0.001) and 0.62 to 0.72 (p < 0.001), respectively, for the four PODNL1 CpGs. Enrichment analysis of differential gene and protein expression and analysis of 24 infiltrating immune cell types showed significantly increased infiltration in LGGs and its histological subtypes with low-methylation levels of the PODNL1 CpGs. High PODNL1 expression and low-methylation subgroups of the PODNL1 CpG sites were associated with significantly increased PD-L1, PD-1, and CTLA4 expressions. PODNL1 methylation may thus be a potential indicator of immune checkpoint blockade response, and serve as a biomarker for determining prognosis and immune subtypes in LGG.

Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF).

Recurrence in patients with glioblastoma (GBM) is inevitable resulting in short survival times, even in patients with O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation. Other pathways must be activated to escape from temozolomide (TMZ) treatment, however acquired resistance mechanisms to TMZ are not well understood. Herein, frozen tumors from 36 MGMT methylated patients grouped according to overall survival were extracted and proteins were profiled using surface-enhanced laser desorption/ionization (SELDI) with time-of flight (TOF) proteomics to identify low molecular weight proteins that associated with poor survival outcomes. Overexpression of macrophage migration inhibitory factor (MIF) was identified in human GBM specimens that were MGMT methylated but showed poor survival. This correlation was confirmed in an independent cohort of human GBM. MIF overexpression has been reported in several cancer types, including GBM. We repurposed ibudilast, a specific MIF inhibitor, and treated patient derived cell lines. Ibudilast showed modest anti-proliferative activity however, when combined with TMZ, significant synergism was observed, resulting in cell cycle arrest and apoptosis. In vivo, combined ibudilast and TMZ treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.