Germline ALK variations are associated with a poor prognosis in glioma and IDH-wildtype glioblastoma.

BACKGROUND: Glioma is the most common primary brain tumor. Clear classification is crucial for accurate diagnosis and individualized treatment. Histopathological characteristics and genetic alterations have shown to be related to prognosis and treatment response. Germline variants are important components of genetic alterations. However, the distribution of germline variations in glioma patients and their association with survival remain unknown. METHODS: We carried out whole-exome sequencing on 99 cases to explore germline variants in glioma. We also analyzed the association of germline variants with clinicopathological features and other prognostic indicators. RESULTS: All the glioma cases harbored rare germline variants. Germline ALK variants (gALK-Mut) were identified in 12/99 (12.12%) patients. The gALK-Mut patients had significantly shorter overall survival than germline ALK wildtype (gALK-WT) patients in the all glioma group (99 cases) and the subset of patients with IDH-wildtype glioblastoma (IDH-WT-GBM, 39 cases) (P = 0.013 and 0.027, respectively). The gALK-Mut patients also had higher frequency of BIRC5, PIK3CA and RPN1 somatic mutations than the gALK-WT patients in IDH-WT-GBM. Other confounding factors appeared to contribute to patient survival. The subgroup of patients in IDH-WT-GBM with gALK-Mut/TP53-Mut had worse prognosis than the gALK-WT/TP53-Mut subgroup (P = 0.031); The gALK-Mut/TERT-WT and gALK-Mut/TERT-Mut subgroups both had a worse prognosis than the gALK-WT/TERT-Mut subgroup (P = 0.031 and 0.018, respectively). CONCLUSIONS: Our study revealed ALK variation was an independent indicator of poor prognosis in glioma and IDH-WT-GBM. It could be a promising biomarker and tractable therapeutic target for this deadly disease.

Tumor treating fields: a comprehensive overview of the underlying molecular mechanism.

INTRODUCTION: As a novel treatment modality, tumor treating fields (TTFields) exert low-intensity, medium-frequency electric fields on tumor cells. TTFields' effectiveness and safety have been demonstrated clinically and in the real world for treating glioblastoma, the most common and aggressive primary central nervous system tumor. TTFields therapy has also been approved for the management of malignant mesothelioma, and clinical trials are ongoing for NSCLC, gastric cancer, pancreatic cancer, and other solid tumors. AREAS COVERED: This article comprehensively reviews the currently described evidence of TTFields' mechanism of action. TTFields' most evident therapeutic effect is to induce cell death by disrupting mitosis. Moreover, evidence suggests at additional mechanistic complexity, such as delayed DNA repair and heightened DNA replication stress, reversible increase in cell membrane and blood-brain barrier permeability, induction of immune response, and so on. EXPERT OPINION: TTFields therapy has been arising as the fourth anti-tumor treatment besides surgery, radiotherapy, and antineoplastic agents in recent years. However, the precise molecular mechanisms underlying the effects of TTFields are not fully understood and some concepts remain controversial. An in-depth understanding of TTFields' effects on tumor cell and tumor microenvironment would be crucial for informing research aimed at further optimizing TTFields' efficacy and developing new combination therapies for clinical applications.

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued.

BACKGROUND: While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE: To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS: IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS: A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION: Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

SYDE1 Acts as an Oncogene in Glioma and has Diagnostic and Prognostic Values.

Objectives: Gliomas remain one of serious public health problems worldwide which demand further and deeper investigation. The aim of this study was to explore the association between synapse defective protein 1 homolog 1 (SYDE1) and gliomas via public database analysis and in vitro validation to determine the potential diagnostic and prognostic values. Methods and Results: Compared with healthy brain tissues, there was a significant increase in SYDE1 expression in glioma tissues. Additionally, SYDE1 exhibited higher expression levels in glioma patients with unfavorable clinicopathological factors. In vitro knockdown of SYDE1 in glioma cell lines A172 inhibited their migrative and invasive ability but not the proliferative ability. GO and KEGG pathway analysis of the top 100 genes coexpressed with SYDE1 showed enrichments of tumor-associated terms. Further bioinformatic analysis revealed that the SNHG16/hsa-miR-520e/SYDE1 axis might be involved in glioma development. Conclusions: SYDE1 is expressed at higher levels in gliomas than in healthy brains, and can promote metastasis and invasion but not proliferation of gliomas. Furthermore, SYDE1 has values in the diagnosis and prognosis prediction of gliomas.