Glioblastoma is a fatal brain tumor with a bleak prognosis. The use of chemotherapy, primarily the alkylating agent temozolomide, coupled with radiation and surgical resection, has provided some benefit. Despite this multipronged approach, average patient survival rarely extends beyond 18 months. Challenges to glioblastoma treatment include the identification of functional pharmacologic targets as well as identifying drugs that can cross the blood-brain barrier. To address these challenges, current research efforts are examining metabolic differences between normal and tumor cells that could be targeted. Among the metabolic differences examined to date, the apparent addiction to exogenous methionine by glioblastoma tumors is a critical factor that is not well understood and may serve as an effective therapeutic target. Others have proposed this property could be exploited by methionine dietary restriction or other approaches to reduce methionine availability. However, methionine links the tumor microenvironment with cell metabolism, epigenetic regulation, and even mitosis. Therefore methionine depletion could result in complex and potentially undesirable responses, such as aneuploidy and the aberrant expression of genes that drive tumor progression. If methionine manipulation is to be a therapeutic strategy for glioblastoma patients, it is essential that we enhance our understanding of the role of methionine in the tumor microenvironment.

/pdf/glioblastoma-and-methionine-addiction-2mtllkk2.pdf

Glioblastoma and Methionine Addiction

Background: Studies have suggested that glioblastoma (GBM) cells originate from the subventricular zone (SVZ) and that GBM contact with the SVZ correlated with worse prognosis and higher recurrence. However, research on differentially expressed genes (DEGs) between GBM and the SVZ is lacking. Methods: We performed deep RNA sequencing on seven SVZ-involved GBMs and paired tumor-free SVZ tissues. DEGs and enrichment were assessed. We obtained GBM patient expression profiles and clinical data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. The least absolute shrinkage and selection operator Cox regression model was utilized to construct a multigene signature in the CGGA cohort. GBM patient data from TCGA cohort were used for validation. Results: We identified 137 (97 up- and 40 down-regulated) DEGs between GBM and healthy SVZ samples. Enrichment analysis revealed that DEGs were mainly enriched in immune-related terms, including humoral immune response regulation, T cell differentiation, and response to tumor necrosis factor, and the MAPK, cAMP, PPAR, PI3K-Akt, and NF-κb signaling pathways. An eight-gene (BCAT1, HPX, NNMT, TBX5, RAB42, TNFRSF19, C16orf86, and TRPC5) signature was constructed. GBM patients were stratified into two risk groups. High-risk patients showed significantly reduced overall survival compared with low-risk patients. Univariate and multivariate regression analyses indicated that the risk score level represented an independent prognostic factor. High risk score of GBM patients negatively correlated with 1p19q codeletion and IDH1 mutation. Immune infiltration analysis further showed that the high risk score was negatively correlated with activated NK cell and monocyte counts, but positively correlated with macrophage and activated dendritic cell counts and higher PD-L1 mRNA expression. Conclusion: Here, a novel gene signature based on DEGs between GBM and healthy SVZ was developed for determining GBM patient prognosis. Targeting these genes may be a therapeutic strategy for GBM.

https://www.frontiersin.org/articles/10.3389/fgene.2022.912227/pdf

Identifying Differential Expression Genes and Prognostic Signature Based on Subventricular Zone Involved Glioblastoma

Glioblastoma (GBM) is associated with a poorer prognosis when leptomeningeal dissemination (LMD) occurs. Recently, the role of both ventricular entry (VE) during surgery and subventricular zone localization of tumors in promoting LMD in GBM patients has been debated. This article investigates the role of VE in causing LMD in GBM patients.We conducted a retrospective analysis of GBMs operated on at our Institution between March 2018 and December 2020. We collected pre- and post-surgical images, anamnestic information, and surgical reports.Two hundred cases were collected. The GBM localization was periventricular in 69.5% of cases, and there was a VE during the surgical procedure in 51% of cases. The risk of post-surgical LMD in the case of VE was 16%. The rate of LMD was higher in the case of VE than not-VE (27.4% vs. 4%, p < 0.0001). The rate of LMD in periventricular GBM was 19% (p = 0.1131).According to our data, VE is an independent factor associated with a higher rate of post-surgical LMD, and the periventricular localization is not independently correlated to this negative outcome. Neurosurgeons should avoid VE when possible. The correct surgical strategy should be founded on balancing the need for maximal EOR and the risks associated with VE. 

/pdf/ventricular-entry-during-surgical-resection-is-associated-hc7r1f2j.pdf

Ventricular entry during surgical resection is associated with intracranial leptomeningeal dissemination in glioblastoma patients

Abstract Background Glioblastoma is one of the most common and aggressive adult brain tumors. The conventional treatment strategy, surgery combined with chemoradiotherapy, did not change the fact that the recurrence rate was high and the survival rate was low. Over the years, accumulating evidence has shown that the subventricular zone has an important role in the recurrence and treatment resistance of glioblastoma. The human adult subventricular zone contains neural stem cells and glioma stem cells that are probably a part of reason for therapy resistance and recurrence of glioblastoma. Main body Over the years, both bench and bedside evidences strongly support the view that the presence of neural stem cells and glioma stem cells in the subventricular zone may be the crucial factor of recurrence of glioblastoma after conventional therapy. It emphasizes the necessity to explore new therapy strategies with the aim to target subventricular zone to eradicate neural stem cells or glioma stem cells. In this review, we summarize the recent preclinical and clinical advances in targeting neural stem cells in the subventricular zone for glioblastoma treatment, and clarify the prospects and challenges in clinical application. Conclusions Although there remain unresolved issues, current advances provide us with a lot of evidence that targeting the neural stem cells and glioma stem cells in subventricular zone may have the potential to solve the dilemma of glioblastoma recurrence and treatment resistance. 

/pdf/targeting-the-neural-stem-cells-in-subventricular-zone-for-2vb9k446.pdf

Targeting the neural stem cells in subventricular zone for the treatment of glioblastoma: an update from preclinical evidence to clinical interventions

BACKGROUND
As the largest concentration of neural stem cells in adult brain, the subventricular zone (SVZ) is considered to be a potential source of glioblastoma (GBM) occurrence in recent years.


METHODS
In this study, 116 patients with glioblastoma treated at PLA General Hospital were retrospectively reviewed. The features of SVZ contacting glioblastoma were analyzed in terms of MR imaging and MGMT promoter methylation. We also evaluated the prognostic value of SVZ contacting in GBM patients.


RESULTS
GBM with SVZ involvement on MRI is more likely to grow across the midline(36.8% vs 6.9%,P=0.002), more often multifocal lesion(35.6% vs. 6.9%,P=0.003) and have a lower proportion of MGMT promoter methylation (36.8% vs. 69.0%, P=0.003). The median overall survival and progression-free survival of patients in the SVZ contacting group were 12 months and 7 months, while 25 months and 17 months in the non-contacting group(P<0.001, respectively). There was no significant difference in overall survival (P=0.229) and progression-free survival (P=0.808) between patients with different SVZ contacting regions. Multivariate survival analysis indicated that patients with MRI SVZ involvement showed worse overall survival (HR=2.060, 95%CI 1.195-3.550，P=0.009) and progression-free survival (HR=3.021, 95%CI 1.788-5.104，P＜0.001).


CONCLUSION
This study suggested that MRI SVZ involvement at diagnosis is an independent risk factor for overall survival and progression-free survival in IDH wild-type glioblastoma patients. Based on MR imaging, we also found that SVZ contacting glioblastomas had a larger proportion of crossing midline tumors and multifocal lesions. In addition, patients with SVZ contact in our research presented a lower proportion of MGMT promoter methylation.

MR Imaging, MGMT Promoter Methylation Features and Prognostic Analysis of Subventricular Zone Contacting IDH Wild-type Glioblastoma.

There is growing evidence that the subventricular zone (SVZ) may be involved in both the initiation and progression of glioblastoma (GB). We aimed to assess tumor proximity to the SVZ as a potential prognostic factor in GB. Retrospective study of 133 patients diagnosed with primary GB who underwent surgery followed by temozolomide-based chemoradiation between 2010 and 2016. All lesions were classified according to their anatomic relation with the SVZ. We determined the effect of tumor contact with the SVZ on progression-free survival (PFS), overall survival (OS), type, and patterns of recurrence. At a median follow-up of 18.6 months (95% CI 15.9–21.2), PFS and OS were 7.5 (95% CI 6.7–8.3) and 13.9 (95% CI 10.9–16.9) months, respectively. On the univariate analyses, initial contact with the SVZ was a factor for poor prognosis for both PFS (6.1 vs. 8.7 months; p = 0.006) and OS (10.6 vs. 17.9 months; p = 0.037). On the multivariate analysis, tumor contact with the SVZ remained statistically significant for PFS, but not OS. Patients with SVZ-contacting tumors presented a higher rate of aggressive clinical progression (30.9% vs. 11.3%; p = 0.007) and contralateral relapse patterns (23.4% vs. 9.1%; p = 0.048). Our results suggest that glioblastoma contact with the SVZ appears to be an independent prognostic factor for poor PFS. The presence of an SVZ-contacting tumor was associated with more aggressive recurrences and a higher rate of contralateral relapses. These findings suggest that this variable may be a new prognostic factor in glioblastoma.

Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns.

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Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns.