Non-traditional cognitive brain network involvement in insulo-Sylvian gliomas: a case series study and clinical experience using Quicktome.

BACKGROUND: Patients with insulo-Sylvian gliomas continue to present with severe morbidity in cognitive functions primarily due to neurosurgeons' lack of familiarity with non-traditional brain networks. We sought to identify the frequency of invasion and proximity of gliomas to portions of these networks. METHODS: We retrospectively analyzed data from 45 patients undergoing glioma surgery centered in the insular lobe. Tumors were categorized based on their proximity and invasiveness of non-traditional cognitive networks and traditionally eloquent structures. Diffusion tensor imaging tractography was completed by creating a personalized brain atlas using Quicktome to determine eloquent and non-eloquent networks in each patient. Additionally, we prospectively collected neuropsychological data on 7 patients to compare tumor-network involvement with change in cognition. Lastly, 2 prospective patients had their surgical plan influenced by network mapping determined by Quicktome. RESULTS: Forty-four of 45 patients demonstrated tumor involvement (< 1 cm proximity or invasion) with components of non-traditional brain networks involved in cognition such as the salience network (SN, 60%) and the central executive network (CEN, 56%). Of the seven prospective patients, all had tumors involved with the SN, CEN (5/7, 71%), and language network (5/7, 71%). The mean scores of MMSE and MOCA before surgery were 18.71 ± 6.94 and 17.29 ± 6.26, respectively. The two cases who received preoperative planning with Quicktome had a postoperative performance that was anticipated. CONCLUSIONS: Non-traditional brain networks involved in cognition are encountered during surgical resection of insulo-Sylvian gliomas. Quicktome can improve the understanding of the presence of these networks and allow for more informed surgical decisions based on patient functional goals.

Structural alterations of the salience network in patients with insular glioma.

OBJECTIVE: The structural alteration that occurs within the salience network (SN) in patients with insular glioma is unclear. Therefore, we aimed to investigate the changes in the topological network and brain structure alterations within the SN in patients with insular glioma. METHODS: We enrolled 46 patients with left insular glioma, 39 patients with right insular glioma, and 21 demographically matched healthy controls (HCs). We compared the topological network, gray matter (GM) volume, and fractional anisotropy (FA) between HCs and patients after controlling for the effects of age and gender. RESULTS: Patients with insular glioma showed topological network decline mainly in the insula, basal ganglia region, and anterior cingulate cortex (ACC). Compared with HCs, patients primarily showed GM volume increased in the ACC, inferior temporal gyrus (ITG), superior temporal gyrus (STG), temporal pole: middle temporal gyrus (TPOmid), insula, middle temporal gyrus (MTG), middle frontal gyrus, and superior occipital gyrus (SOG), but decreased in TPOmid, ITG, temporal pole: superior temporal gyrus, and SOG. FA declined mainly in the STG, MTG, ACC, superior frontal gyrus, and SOG, and also showed an increased cluster in SOG. CONCLUSIONS: FA represents the integrity of the white matter. In patients with insular glioma, decreased FA may lead to the destruction of the topological network within the SN, which in turn may lead to the decrease of network efficiency and brain function, and the increase of GM volume may compensate for these changes. Overall, this pattern of structural changes provides new insight into the compensation model of insular glioma.

MEX3A Impairs DNA Mismatch Repair Signaling and Mediates Acquired Temozolomide Resistance in Glioblastoma.

MutS protein homolog 2 (MSH2) is a key element involved in the DNA mismatch repair (MMR) system, which is responsible for recognizing and repairing mispaired bases. Simultaneously, MSH2 identifies DNA adducts induced by temozolomide (TMZ) and triggers apoptosis and autophagy in tumor cells. Previous work has revealed that reduced MSH2 expression is often observed in patients with glioblastoma (GBM) who relapse after chemotherapy. Elucidation of the mechanism behind TMZ-mediated reduction of MSH2 could help improve GBM treatment. Here, we report significant upregulation of Mex-3 RNA binding family member A (MEX3A) in GBM tissues and cell lines following TMZ treatment. MEX3A bound to the MEX3 recognition element (MRE) of MSH2 mRNA, which in turn recruited CCR4-NOT complexes to target MSH2 mRNA for deadenylation and degradation. In addition, ectopic expression of MEX3A significantly decreased cellular DNA MMR activities and reduced the chemosensitivity of GBM cells via downregulation of MSH2, while depletion of MEX3A sensitized GBM cells to TMZ. In MGMT-deficient patients with GBM, MEX3A expression correlated with MSH2 levels, and high MEX3A expression was associated with poor prognosis. Overall, these findings reveal a potential mechanism by which MSH2 expression is reduced in post-TMZ recurrent GBM. SIGNIFICANCE: A MEX3A/CCR4-NOT/MSH2 axis plays a crucial role in promoting temozolomide resistance, providing new insights into the function of MEX3A and suggesting MEX3A as a potential therapeutic target in therapy-resistant glioblastoma.

Diverse Macrophages Constituted the Glioma Microenvironment and Influenced by PTEN Status.

The glioma immune microenvironment (GIM), consisting of glioma cells, stromal cells, and immune cells, accelerates the initiation, development, immune evasion, chemoresistance, and radioresistance of glioblastoma (GBM), whereas the immunosuppressive mechanisms of GBM have not been thoroughly elucidated to date. The glioma data downloaded from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were used to evaluate the composition of tumor-infiltrating immune cells (TICs) by the CIBERSORT algorithm. RNA-seq datasets from the TCGA and CGGA were used to analyze the relationship between immune scores with patients' characteristics and TICs, which showed higher ratios of tumor-inhibiting/tumor-promoting signatures (M2/M1 macrophages) along with higher immune scores. The distribution of TICs among different glioma patients and the correlation with hazard ratio (HR) analysis suggested that M2 macrophages were abundant in malignant gliomas and indicated an unfavorable prognosis. We further analyzed TCGA cases with available mutation and copy-number alteration information, which showed that the status of PTEN could influence the immune microenvironment of glioma patients. Tissue microarrays of 39 GBM patients were carried out to confirm the clinical significance of PTEN and macrophage markers. We found that the high expression of PTEN was associated with a more extended survival period of glioma patients, positively correlated with M2 macrophages and negatively with M1 macrophages. Transwell and flow cytometry analyses demonstrated that PTEN status could prevent M1 to M2 polarization and M2 macrophage recruitment of gliomas in vitro. The newly discovered immunoregulatory activity of PTEN opens innovative avenues for investigations relevant to counteracting cancer development and progression.