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Pyruvate carboxylase (PC) is an enzyme catalyzing the carboxylation of pyruvate to oxaloacetate. The enzymatic generation of oxaloacetate, an intermediate of the Krebs cycle, could provide the cancer cells with the additional anaplerotic capacity and promote their anabolic metabolism. Recent studies revealed that several types of cancer cells express PC. The gained anaplerotic capability of cells mediated by PC correlates with their expedited growth, higher aggressiveness, and increased metastatic potential. By immunohistochemical staining and immunoblotting analysis, we investigated PC expression among samples of different types of human brain tumors. Our results show that PC is expressed by the cells in glioblastoma, astrocytoma, oligodendroglioma, and meningioma tumors. The presence of PC in these tumors suppose that PC could support the anabolic metabolism of their cellular constituents by its anaplerotic capability. [ABSTRACT FROM AUTHOR]

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Pineal region glioma histologies are fibrillary astrocytoma, pilocytic astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, ependymoma, and choroid plexus papilloma. Malignant tumors of the pineal region are difficult to manage. Glioblastomas are rare aggressive tumors that can cause acute hydrocephalus and life-threatening complications in this area. We present a case of pineal region glioblastoma, who diagnosed and treated with neuroendoscopy as well as radiotherapy and chemotherapy. We also provided a literature review specifically focused on neuroendoscopic treatment of the disease with a comparison between those with and without surgical resection. [ABSTRACT FROM AUTHOR]

Purpose: Magnetic resonance image (MRI) guided radiation therapy has the potential to improve outcomes for glioblastoma by adapting to tumor changes during radiation therapy. This study quantifies interfraction dynamics (tumor size, position, and geometry) based on sequential magnetic resonance imaging scans obtained during standard 6-week chemoradiation.Methods and Materials: Sixty-one patients were prospectively imaged with gadolinium-enhanced T1 (T1c) and T2/FLAIR axial sequences at planning (Fx0), fraction 10 (Fx10), fraction 20 (Fx20), and 1 month after the final fraction of chemoradiation therapy (P1M). Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured at all time points. Target dynamics were quantified by absolute volume (V), volume relative to Fx0 (Vrel), and the migration distance (dmigrate; the linear displacement of the GTV or CTV relative to Fx0). Temporal changes were assessed using a linear mixed-effects model.Results: Median volumes at Fx0, Fx10, Fx20, and P1M for the GTV were 18.4 cm3 (range, 1.1-110.5 cm3), 14.7 cm3 (range, 0.9-115.1 cm3), 13.7 cm3 (range, 0.6-174.2 cm3), and 13.0 cm3 (range, 0.9-76.3 cm3), respectively, with corresponding median Vrel of 0.88 at Fx10, 0.77 at Fx20, and 0.71 at P1M relative to Fx0 (P < .001 for all). The GTV (CTV) migration distances were greater than 5 mm in 46% (54%) of patients at Fx10, 50% (58%) of patients at Fx20, and 52% (57%) of patients at P1M. Dynamic tumor morphologic changes were observed, with 40% of patients exhibiting a decreased GTV (Vrel ≤1) with a dmigrate >5 mm during chemoradiation therapy.Conclusions: Clinically meaningful tumor dynamics were observed during chemoradiation therapy for glioblastoma, supporting evaluation of daily MRI guided radiation therapy and treatment plan adaptation. [ABSTRACT FROM AUTHOR]

Myeloid cells are an inherent part of the microenvironment of glioblastoma multiforme (GBM). There is growing evidence for their participation in mechanisms of tumor escape, especially in the development of resistance following initially promising anti‐VEGF/VEGFR treatment. Thus, we sought to define the capability of myeloid cells to contribute to the expression of proangiogenic molecules in human GBM. We investigated GBM specimens in comparison with anaplastic astrocytoma (WHO grade III) and epilepsy patient samples freshly obtained from surgery. Flow cytometric analyses revealed two distinct CD11b+CD45+ cell populations in GBM tissues, which were identified as microglia/macrophages and granulocytes. Due to varied granulocyte influx, GBM samples were subdivided into groups with low (GBM‐lPMNL) and high (GBM‐hPMNL) numbers of granulocytes (polymorphonuclear leukocytes; PMNL), which were related to activation of the microglia/macrophage population. Microglia/macrophages of the GBM‐lPMNL group were similar to those of astrocytoma specimens, but those of GBM‐hPMNL tissues revealed an altered phenotype by expressing high levels of CD163, TIE2, HIF1α, VEGF, CXCL2 and CD13. Although microglia/macrophages represented the main source of alternative proangiogenic factors, additionally granulocytes participated by production of IL8 and CD13. Moreover, microglia/macrophages of the GBM‐hPMNL specimens were highly associated with tumor blood vessels, accompanied by remodeling of the vascular structure. Our data emphasize that tumor‐infiltrating myeloid cells might play a crucial role for limited efficacy of anti‐angiogenic therapy bypassing VEGF‐mediated pathways through expression of alternative proangiogenic factors. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and malignant Grade IV primary craniocerebral tumor caused by glial cell carcinogenesis with an extremely poor median survival of 12–18 months. The current standard treatments for GBM, including surgical resection followed by chemotherapy and radiotherapy, fail to substantially prolong survival outcomes. Adeno-associated virus (AAV)-mediated gene therapy has recently attracted considerable interest because of its relatively low cytotoxicity, poor immunogenicity, broad tissue tropism, and long-term stable transgene expression. Furthermore, a range of gene therapy trials using AAV as vehicles are being investigated to thwart deadly GBM in mice models. At present, AAV is delivered to the brain by local injection, intracerebroventricular (ICV) injection, or systematic injection to treat experimental GBM mice model. In this review, we summarized the experimental trials of AAV-based gene therapy as GBM treatment and compared the advantages and disadvantages of different AAV injection approaches. We systematically introduced the prospect of the systematic injection of AAV as an approach for AAV-based gene therapy for GBM. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is a highly malignant brain tumor with poor survival and prognosis. Randomized trials have demonstrated that chemotherapy improves survival in patients with GBM. This study aims to examine the clinical characteristics that are potentially associated with the efficacy of chemotherapy and the risk factors of GBM.Methods: A total of 25,698 patients diagnosed with GBM were identified between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER). The clinical and demographic variables between groups were examined by Student's t-test and Pearson's chi-square test. GBM-specific survival (GBMSS) and overall survival (OS) were evaluated using the Kaplan-Meier method with the log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazards model to identify statistically significant prognostic factors.Results: Patients who received chemotherapy had better overall survival (median OS 13 vs. Three months, HR = 1.9224, 95%CI 1.8571-1.9900, p < 0.0001) and better GBMSS (median GBMSS of 12 vs. Three months, HR = 1.9379, 95%CI 1.8632-2.0156, p < 0.0001), compared to patients who did not. Further subgroup analysis revealed that among patients who underwent chemotherapy, those who were younger, with a supratentorial tumor, received surgery, or radiotherapy had both improved OS and GBMSS. Age, race, tumor location, tumor size, and treatments were identified as independent prognostic factors by multivariable analyses for patients with glioblastoma.Conclusion: Patients with GBM who were younger (< 65 years), underwent surgery, or radiotherapy can benefit more from chemotherapeutic regimens. Age, race, tumor size, tumor location, surgery, radiotherapy, and chemotherapy were factors associated with the prognosis of patients with GBM. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a very aggressive primary malignant brain tumor and finding effective therapies is a pharmaceutical challenge and an unmet medical need. Photothermal therapy may be a promising strategy for the treatment of GBM, as it allows the destruction of the tumor using heat as a non-chemical treatment for disease bypassing the GBM heterogeneity limitations, conventional drug resistance mechanisms and side effects on peripheral healthy tissues. However, its development is hampered by the distinctive features of this tumor. Photoabsorbing agents such as nanoparticles need to reach the tumor site at therapeutic concentrations, crossing the blood-brain barrier upon systemic administration. Subsequently, a near infrared light irradiating the head must cross multiple barriers to reach the tumor site without causing any local damage. Its power intensity needs to be within the safety limit and its penetration depth should be sufficient to induce deep and localized hyperthermia and achieve tumor destruction. To properly monitor the therapy, imaging techniques that can accurately measure the increase in temperature within the brain must be used. In this review, we report and discuss recent advances in nanoparticle-mediated plasmonic photothermal therapy for GBM treatment and discuss the preclinical challenges commonly faced by researchers to develop and test such systems. [ABSTRACT FROM AUTHOR]

Abnormal RAS/RAF signaling plays a critical role in glioma. Although it is known that the V600E mutation of v-raf murine viral oncogene homolog B1 (BRAF V600E) and BRAF amplification (BRAF AMP) both result in constitutive activation of the RAS/RAF pathway, whether BRAF V600E and BRAF AMP have different effects on the survival of glioma patients needs to be clarified. Using cBioPortal, we retrieved studies of both mutations and copy number variations of the BRAF gene in CNS/brain tumors and investigated data from 69 nonredundant glioma patients. The BRAF mutation group had significantly more male patients (64.00% vs. 36.84%; P = 0.046) and a higher occurrence of glioblastoma multiforme (66.00% vs. 31.58%; P = 0.013) compared to those in the other group. The BRAF AMP group had significantly more patients with the mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) (73.68% vs. 18.00%; P = 0.000), tumor protein p53 (TP53) (73.68% vs. 30.00%; P = 0.002), and alpha thalassemia/mental retardation syndrome X linked (ATRX) (63.16% vs. 18.00%; P = 0.001) than the mutation group. The BRAF AMP and IDH1/2 WT cohort had lower overall survival compared with the BRAF AMP and IDH1/2 MT groups (P = 0.001) and the BRAF mutation cohort (P = 0.019), including the BRAF V600E (P = 0.033) and BRAF non-V600E (P = 0.029) groups, using Kaplan–Meier survival curves and the log rank (Mantel–Cox) test. The BRAF AMP and IDH1/2 WT genotype was found to be an independent predictive factor for glioma with BRAF mutation and BRAF AMP using Cox proportional hazard regression analysis (HR = 0.138, P = 0.018). Our findings indicate that BRAF AMP frequently occurs with IDH1/2 , TP53 , and ATRX mutations. Adult patients with glioma with BRAF AMP and IDH1/2 WT had worse prognoses compared with those with BRAF mutation and BRAF AMP and IDH1/2 MT. This suggests that the assessment of the status of BRAF AMP and IDH1/2 in adult glioma/glioblastoma patients has prognostic value as these patients have relatively short survival times and may benefit from personalized targeted therapy using BRAF and/or MEK inhibitors. [ABSTRACT FROM AUTHOR]

Introduction The infiltrative margin of glioblastomas (GBM) contains proliferative tumor cells difficult to estimate radiologically as they are included in the hyperintense signal of T2 sequences and they remain in the cavity margin after tumor resection. The amount of these cells could determine overall survival (OS) of these patients. Material and Methods From October 2007 to January 2010, patients whose MRI were suggestive of newly diagnosed, resectable high-grade glioma were operated using fluorescence-guided surgery (FGS). Separate samples were selectively taken from nonfluorescent white matter areas just adjacent to the border of the pale fluorescence and staining was made for Ki-67. OS was analyzed with Kaplan–Meier and Cox regression. Multivariate analysis included the following prognosis variables: age, extent of resection (EOR), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and performance status index. Results Sample included 65 patients, comprising 37 men and 28 women, with a median Karnofsky Performance Score (KPS) of 80 (40–100) and mean age of 60 (34–78) years. Mean preoperative tumor volume was 35.8 mL. EOR was 100% in 52 patients (80%), with the lower EOR being 88%. For Ki-67, 39 patients had <5% and 26 had ≥5%. OS was 26.8 months (95% confidence interval [CI]: 18.9–28.2) for the Ki-67 low group versus 15.8 months (95% CI: 7.7–18.2) for the Ki-67 high group (p = 0.002). Conclusion Proliferative activity in the normal-looking brain around the resection cavity measured with Ki-67 immunostaining is an important independent prognostic factor for GBM cases with complete resection of enhancing tumor. When complete resection is not reached, this factor is not relevant for prognosis. [ABSTRACT FROM AUTHOR]

Aim: Glioma stem cells (GSCs) have been shown to contribute to tumor development and recurrence, therapeutic resistance, and cellular heterogeneity of glioblastoma multiforme (GBM). Recently, it has been reported that GSCs lose their self-renewal ability and tumorigenic potential upon differentiation. In this study, we identified Regulatory Factor X4 (RFX4) gene to regulate GSCs' survival and self-renewal activity in the GBM patients samples. Materials and methods: We utilized public datasets from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Ivy Glioblastoma Atlas Project, and The Human Protein Atlas to screen candidate genes which are associated with the development of GBM and poor patients survival. Small hairpin RNA (shRNA) lentivirus was applied to knockdown RFX4 gene in GSCs. Results: We found that RFX4 mRNA expression among the RFX family was particularly reduced during GSC differentiation. RT-qPCR analysis revealed significant downregulation of RFX4 and stem cell markers (CD15 and CD133) mRNA expressions in primary human GBM-derived GSCs cultured under serum condition. Consistently, GSCs showed significantly elevated RFX4 mRNA expression levels compared to normal astrocytes, NHA, whereas glioma cells did not. Furthermore, analysis of the TCGA data set revealed that RFX4 is highly expressed in GBM, and contributes to the lowering of patient survival. Depletion of RFX4 using shRNA lentivirus in patient GBM-derived GSCs decreased neurosphere formation and cell viability. Conclusion: These results suggest that RFX4 is a potential risk factor for maintaining the stemness of GSCs and making glioma more malignant, and thus, could be a promising target of GBM treatment. [ABSTRACT FROM AUTHOR]

Despite the anti-proliferative and survival benefits from tumor treating fields (TTFields) in human glioblastoma (hGBM), little is known about the effects of this form of alternating electric fields therapy on the aberrant glycolysis of hGBM. [18F]FDG is the most common radiotracer in cancer metabolic imaging, but its utility in hGBM is impaired due to high glucose uptake in normal brain tissue. With TTFields, radiochemistry, Western blot, and immunofluorescence microscopy, we identified pyruvate kinase M2 (PKM2) as a biomarker of hGBM response to therapeutic TTFields. We used [18F]DASA-23, a novel radiotracer that measures PKM2 expression and which has been shown to be safe in humans, to detect a shift away from hGBM aberrant glycolysis in response to TTFields. Compared to unexposed hGBM, [18F]DASA-23 uptake was reduced in hGBM exposed to TTFields (53%, P < 0.05) or temozolomide chemotherapy (33%, P > 0.05) for 3 d. A 6-d TTFields exposure resulted in a 31% reduction (P = 0.043) in 60-min uptake of [18F]DASA-23. [18F]DASA-23 was retained after a 10 but not 30-min wash-out period. Compared to [18F]FDG, [18F]DASA-23 demonstrated a 4- to 9-fold greater uptake, implying an improved tumor-to-background ratio. Furthermore, compared to no-TTFields exposure, a 6-d TTFields exposure caused a 35% reduction in [18F]DASA-23 30-min uptake compared to only an 8% reduction in [18F]FDG 30-min uptake. Quantitative Western blot analysis and qualitative immunofluorescence for PKM2 confirmed the TTFields-induced reduction in PKM2 expression. This is the first study to demonstrate that TTFields impairs hGBM aberrant glycolytic metabolism through reduced PKM2 expression, which can be non-invasively detected by the [18F]DASA-23 radiotracer. [ABSTRACT FROM AUTHOR]

Primary spinal cord tumors represent 2%-10% of all central nervous system tumors and mainly comprise astrocytoma, ependymoma, ganglioglioma, oligodendroglioma and subependymoma. Only 1%-3% of all spinal cord tumors show primary glioblastoma multiforme pathology. Methods: Spinal glioblastoma multiforme was diagnosed as a result of MRI findings of the patient (The thoracic spinal MR revealed an intramedullary nodular expansile lesion), who had numbness in lower extremities. Maximum safe resection was performed our patient. The lesion reported as GBM. Adjuvant radiotherapy and chemotherapy including temozolomide was applied subsequently. The primary treatment of spinal glioblastoma multiforme includes surgery, radiotherapy and chemotherapy. Despite multidisciplinary approaches available to treat spinal glioblastoma multiforme, the prognosis remains poor, with survival rates of 10-12 months. Total resection is nevertheless the main therapy for spinal glioblastoma multiforme in spite of current developments. Although spinal intramedullary glioblastoma multiforme particularly is quite rare, its treatment is very difficult. [ABSTRACT FROM AUTHOR]

Gliomas are one of the most aggressive primary brain tumors arising from neural progenitor cells. Delayed diagnosis, invasive biopsy, and diagnostic challenges stems the need for specific, minimally-invasive, and early diagnostic biomarkers. Tumor-associated (TA) autoantibodies are measurable in the biofluids long before the onset of the symptoms, suggesting their role in early diagnosis and clinical management of the patients. In the current study, cerebrospinal fluid (CSF) samples from patients with low-grade glioma (LGG) and the Glioblastoma multiforme (GBM) that characterizes advanced disease were compared with healthy control samples to identify putative TA autoantibodies, using protein microarrays. The CSF samples from LGGs (n = 10), GBM (n = 7) were compared with the control CSF samples (n = 6). Proteins showing significant antigenic response were cross-verified. Proteins NOL4 (a cancer-testis antigen) and KALRN showed an antigenic response in the CSF of GBM patients, whereas, UTP4 and CCDC28A showed an antigenic response in low grade gliomas when compared with the control samples. TA autoantibodies identified in this study from the CSF of the patients could supplement current screening modalities. Further validation of these TA autoantibodies on a larger clinical cohort could provide cues towards relevance of these proteins in early diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Glioblastoma is a malignant brain cancer with limited treatment options and high mortality rate. While established glioblastoma cell line models provide valuable information, they ultimately lose most primary characteristics of tumors under long-term serum culture conditions. Therefore, established cell lines do not necessarily recapitulate genetic and morphological characteristics of real tumors. In this study, in line with the growing interest in using primary cell line models derived from patient tissue, we generated a primary glioblastoma cell line, KUGBM8 and characterized its genetic alterations, long term growth ability, tumor formation capacity and its response to Temozolomide, the front-line chemotherapy utilized clinically. In addition, we performed a drug repurposing screen on the KUGBM8 cell line to identify FDA-approved agents that can be incorporated into glioblastoma treatment regimen and identified Topotecan as a lead drug among 1,200 drugs. We showed Topotecan can induce cell death in KUGBM8 and other primary cell lines and cooperate with Temozolomide in low dosage combinations. Together, our study provides a new primary cell line model that can be suitable for both in vitro and in vivo studies and suggests that Topotecan can offer promise as a therapeutic approach for glioblastoma. [ABSTRACT FROM AUTHOR]

Objective: To determine the relationship between survival and glioblastoma distance from the ventricular-subventricular neural stem cell niche (VSVZ). Methods: 502 pre-operative gadolinium-enhanced, T1-weighted MRIs with glioblastoma retrieved from an institutional dataset (n = 252) and The Cancer Imaging Atlas (n=250) were independently reviewed. The shortest distance from the tumor contrast enhancement to the nearest lateral ventricular wall, the location of the VSVZ, was measured (GBM-VSVZDist). The relationship of GBM-VSVZDist with the proportion of glioblastomas at each distance point and overall survival was explored with a Pearson's correlation and Cox regression model, respectively, adjusting for the well-established glioblastoma prognosticators. Results: 244/502 glioblastomas had VSVZ contact. The proportion of non-VSVZ-contacting glioblastomas correlated inversely with GBM-VSVZDist (partial Pearson's correlation adjusted for tumor volume R=-0.79, p=7.11x10-7). A fit of the Cox regression model adjusted for age at diagnosis, Karnofsky performance status score, post-operative treatment with temozolomide and/or radiotherapy, IDH1/2 mutation status, MGMT promoter methylation status, tumor volume, and extent of resection demonstrated a significantly decreased overall survival only when glioblastoma contacted the VSVZ. Overall survival did not correlate with GBM-VSVZDist. Conclusions: In the two independent cohorts analyzed, glioblastomas at diagnosis were found in close proximity or in contact with the VSVZ with a proportion that decreased linearly with GBM-VSVZDist. Patient survival was only influenced by the presence or absence of a gadolinium-enhanced glioblastoma contact with the VSVZ. These results may guide analyses to test differential effectiveness of VSVZ radiation in VSVZ-contacting and non-contacting glioblastomas and/or inform patient selection criteria in clinical trials of glioblastoma radiation. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma is the most common primary malignant brain tumor. Recent studies have shown that hematological biomarkers have become a powerful tool for predicting the prognosis of patients with cancer. However, most studies have only investigated the prognostic value of unilateral hematological markers. Therefore, we aimed to establish a comprehensive prognostic scoring system containing hematological markers to improve the prognostic prediction in patients with glioblastoma. Patients and Methods: A total of 326 patients with glioblastoma were randomly divided into a training set and external validation set to develop and validate a hematological-related prognostic scoring system (HRPSS). The least absolute shrinkage and selection operator Cox proportional hazards regression analysis was used to determine the optimal covariates that constructed the scoring system. Furthermore, a quantitative survival-predicting nomogram was constructed based on the hematological risk score (HRS) derived from the HRPSS. The results of the nomogram were validated using bootstrap resampling and the external validation set. Finally, we further explored the relationship between the HRS and clinical prognostic factors. Results: The optimal cutoff value for the HRS was 0.839. The patients were successfully classified into different prognostic groups based on their HRSs (P < 0.001). The areas under the curve (AUCs) of the HRS were 0.67, 0.73, and 0.78 at 0.5, 1, and 2 years, respectively. Additionally, the 0.5-, 1-y, and 2-y AUCs of the HRS were 0.51, 0.70, and 0.79, respectively, which validated the robust prognostic performance of the HRS in the external validation set. Based on both univariate and multivariate analyses, the HRS possessed a strong ability to predict overall survival in both the training set and validation set. The nomogram based on the HRS displayed good discrimination with a C-index of 0.81 and good calibration. In the validation cohort, a high C-index value of 0.82 could still be achieved. In all the data, the HRS showed specific correlations with age, first presenting symptoms, isocitrate dehydrogenase mutation status and tumor location, and successfully stratified them into different risk subgroups. Conclusions: The HRPSS is a powerful tool for accurate prognostic prediction in patients with newly diagnosed glioblastoma. [ABSTRACT FROM AUTHOR]

Objective: To construct a glycolysis-related prognostic model to predict individualized survival in patients with glioblastoma (GBM). Methods: Clinical data for patients with GBM, including expression levels of glycolysis-related genes (GRGs), were extracted from The Cancer Genome Atlas. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were then carried out and protein-protein interactions were investigated. Univariate and multivariate Cox regression analyses were performed on the GRGs to identify the best prognosis-related genes. We then established and verified a novel prognostic model, based on the expression of differentially expressed GRGs that were significantly associated with overall survival in GBM patients. Results: ALDH3B1, CHPF, FBP1, ISG20 and STC1 were chosen to establish the prognostic risk score model. Patients with high risk scores had significantly poorer overall survival than patients with low risk scores. Conclusion: The glycolysis-related model has significant value in performing individualized survival predictions for GBM patients and could suggest better treatment options for GBM patients. Our results may help to elucidate GBM pathogenesis and contribute to clinical decision-making and individualized treatment. [ABSTRACT FROM AUTHOR]

On brain magnetic resonance imaging, both diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) are used to evaluate cerebral tumors. The purpose of this meta-analysis was to evaluate and compare the diagnostic performance of DWI and PWI in differentiating between pseudoprogression and true tumor progression of glioblastoma. We performed a systematic review of the PubMed database from January 2000 to December 2019 for relevant studies. After application of specific inclusion and exclusion criteria, the eligible articles were evaluated for methodologic quality and risk of bias using the updated Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool. From the published study results, the pooled sensitivity, pooled specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio and their corresponding confidence intervals (% CI), and the area under the curve, were calculated individually for DWI and PWI. The meta-analysis included 24 studies, with a total of 900 patients. DWI was found to be slightly superior in terms of sensitivity and specificity, 0.88 (% CI 0.83–0.92) and 0.85 (% CI 0.78–0.91), respectively, compared with the respective values of PWI, 0.85 (% CI 0.81–0.89) and 0.79 (% CI 0.74–0.84). On comparison of the overall diagnostic accuracy of the MRI modalities using their respective area under the curve values (0.9156 for DWI, 0.9072 for PWI), no significant difference was demonstrated between the 2. Both DWI and PWI provided optimal diagnostic performance in differentiating pseudoprogression from true tumor progression in cerebral glioblastoma, and neither technique proved to be superior. [ABSTRACT FROM AUTHOR]

Pediatric giant cell glioblastoma, a highly malignant and lethal tumor, can only be distinguished from glioblastoma multiforme histologically. Though it is said to have a better prognosis, adequate evidence in favor is lacking. Early diagnosis with gross total resection and adjuvant chemotherapy might increase the survival period. [ABSTRACT FROM AUTHOR]

Background: The extent of resection of non-contrast enhancing tumors (EOR-NCEs) has been shown to be associated with prognosis in patients with newly diagnosed glioblastoma (nGBM). This study aimed to develop and independently validate a nomogram integrated with EOR-NCE to assess individual prognosis. Methods: Data for this nomogram were based on 301 patients hospitalized for nGBM from October 2011 to April 2019 at the Beijing Tiantan Hospital, Capital Medical University. These patients were randomly divided into derivation (n=181) and validation (n=120) cohorts at a ratio of 6:4. To evaluate predictive accuracy, discriminative ability, and clinical net benefit, concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were calculated for the extent of resection of contrast enhancing tumor (EOR-CE) and EOR-NCE nomograms. Comparison between these two models was performed as well. Results: The Cox proportional hazards model was used to establish nomograms for this study. Older age at diagnosis, Karnofsky performance status (KPS)<70, unmethylated O6-methylguanine-DNA methyltransferase (MGMT) status, wild-type isocitrate dehydrogenase enzyme (IDH), and lower EOR-CE and EOR-NCE were independent factors associated with shorter survival. The EOR-NCE nomogram had a higher C-index than the EOR-CE nomogram. Its calibration curve for the probability of survival exhibited good agreement between the identical and actual probabilities. The EOR-NCE nomogram showed superior net benefits and improved performance over the EOR-CE nomogram with respect to DCA and ROC for survival probability. These results were also confirmed in the validation cohort. Conclusions: An EOR-NCE nomogram assessing individualized survival probabilities (12-, 18-, and 24-month) for patients with nGBM could be useful to provide patients and their relatives with health care consultations on optimizing therapeutic approaches and prognosis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant diseases and requires more effective prevention and treatment strategies. Mutations or overexpression of endoplasmic reticulum (ER) proteins have been frequently identified in a solid tumor, suggesting that ER proteins play an important role in tumor development. SEC61G, a component of Sec61 complex located in the membrane of the human ER, has been revealed a potential relevance in glioblastoma multiforme. Analyses from TCGA database showed that SEC61G was overexpressed in HCC. Additionally, the expression of SEC61G mRNA was associated with the survival time of HCC patients. We verified that the higher expression of SEC61G in HCC tissues than paracancerous tissues. Moreover, knockdown of SEC61G inhibited cell proliferation and induced cell apoptosis in vitro. Besides, SEC61G was required for cell migration and invasion, conferring a potential role for SEC61G in tumor transfer. Taken together, our results revealed the role of SEC61G in HCC cells. Further detailed understanding of the signaling networks underlying SEC61G involvement in HCC cells would make SEC61G as a viable therapeutic target for pharmaceutical intervention of HCC. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a highly malignant and aggressive primary brain tumor mostly prevalent in adults and is associated with a very poor prognosis. Moreover, only a few effective treatment regimens are available due to their rapid invasion of the brain parenchyma and resistance to conventional therapy. However, the fast development of cancer immunotherapy and the remarkable survival benefit from immunotherapy in several extracranial tumor types have recently paved the way for numerous interventional studies involving GBM patients. The recent success of checkpoint blockade therapy, targeting immunoinhibitory proteins such as programmed cell death protein-1 and/or cytotoxic T lymphocyte-associated antigen-4, has initiated a paradigm shift in clinical and preclinical investigations, and the use of immunotherapy for solid tumors, which would be a potential breakthrough in the field of drug therapy for the GBM treatment. However clinical trial showed limited benefits for GBM patients. The main reason is drug resistance. This review summarizes the clinical research progress of immune checkpoint molecules and inhibitors, introduces the current research status of immune checkpoint inhibitors in the field of GBM, analyzes the molecular resistance mechanism of checkpoint blockade therapy, proposes corresponding re-sensitive strategies, and describes a reference for the design and development of subsequent clinical studies on immunotherapy for GBM. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM) is the most common and aggressive form of intracranial tumors with poor prognosis. In recent years, tumor immunotherapy has been an attractive strategy for a variety of tumors. Currently, most immunotherapies take advantage of the adaptive anti-tumor immunity, such as cytotoxic T cells. However, the predominant accumulation of tumor-associated microglia/macrophages (TAMs) results in limited success of these strategies in the glioblastoma. To improve the immunotherapeutic efficacy for GBM, it is detrimental to understand the role of TAM in glioblastoma immunosuppressive microenvironment. In this review, we will discuss the roles of CD47-SIRPα axis in TAMs infiltration and activities and the promising effects of targeting this axis on the activation of both innate and adaptive antitumor immunity in glioblastoma. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered "undruggable" ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma. [ABSTRACT FROM AUTHOR]

Background: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to methylguanin‐O6-methyltransferase promoter (MGMT) promoter hypermethylated tumors. Further resistance markers are largely unknown and would help for better stratification. Methods: Clinical data and methylation profiles from the NOA‐08 (104, elderly glioblastoma) and the EORTC 26101 (297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg Neuro‐Oncology center have been analyzed focused on the predictive effect of DNA damage response (DDR) gene methylation. Candidate genes were validated in vitro. Results: Twenty‐eight glioblastoma 5'‐cytosine‐phosphat‐guanine‐3' (CpGs) from 17 DDR genes negatively correlated with expression and were used together with telomerase reverse transcriptase (TERT) promoter mutations in further analysis. CpG methylation of DDR genes shows highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) II glioblastoma subgroup. MES tumors have lower tumor purity compared to RTK I and II subgroup tumors. CpG hypomethylation of DDR genes TP73 and PRPF19 correlated with worse patient survival in particular in MGMT promoter unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival. Primary glioma cells show methylation patterns that resemble RTK I and II glioblastoma and long term established glioma cell lines do not match with glioblastoma subtypes. Silencing of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide in vitro. Conclusion: Hypomethylation of DDR genes and TERT promoter mutations is associated with worse tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in IDH wild‐type glioblastoma. [ABSTRACT FROM AUTHOR]

Background: Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and highdose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect. Methods: To investigate LCD's effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients. This study involved 29 individuals and evaluated, over a period of 1 year, the adjuvant effect of LCD associated with POH therapy in terms of toxicity, extent of peritumoral edema, reduced corticosteroid use, seizure frequency, and overall survival. POH group (n = 14) received solely intranasal POH without specific diet regimen, whereas POH/LCD group (n = 15) received intranasal POH in combination with nutritional intervention. Patients' assessment was based on clinical reviews and magnetic resonance data. Results: In the 1-year follow-up, the POH/LCD group showed a 4.4-fold decrease in the proportion of patients who needed treatment with corticosteroids, as well as a reduction in tumor size and peritumoral edema, as compared to the POH group. While 75% of patients undergoing POH treatment experienced seizures, this fraction was reduced to 56% in the POH/LCD group. A 2.07-fold increase in the proportion of patients with stable disease, along with a 2.8-fold decrease in the proportion of patients with TP, was seen in the POH/LCD group. Conclusion: The results presented in this study show that the LCD associated with intranasal POH therapy may represent a viable option as adjunctive therapy for rGB to improve survival without compromising patients' quality of life. Prospective cohort studies are needed to confirm these findings and validate the efficacy of this novel therapeutic strategy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a highly aggressive glioma with an extremely poor prognosis after conventional treatment. Recent advances in immunotherapy offer hope for these patients with incurable GBM. Our present review aimed to provide an overview of immunotherapy for GBM, especially chimeric antigen receptor T-cell (CAR T) therapy. CAR T-cell immunotherapy, which involves the engineering of T cells to kill tumors by targeting cell surface-specific antigens, has been successful in eliminating B-cell leukemia by targeting CD19. IL-13Rα2, EGFRvIII, and HER2-targeted CAR T cells have shown significant clinical efficacy and safety in phase 1 or 2 clinical trials conducted in patients with GBM; these findings support the need for further studies to examine if this therapy can ultimately benefit this patient group. However, local physical barriers, high tumor heterogeneity, and antigen escape make the use of CAR T therapy, as a treatment for GBM, challenging. The potential directions for improving the efficacy of CAR T in GBM are to combine the existing traditional therapies and the construction of multi-target CAR T cells. [ABSTRACT FROM AUTHOR]

Spinal metastasis of cerebral glioblastoma (GBM) is rare, with some reports suggesting a prevalence of 1%−2%. Herein, we present 2 unique cases of spinal metastasis of cerebral GBM, 1 of which was histologically proven to be a drop spinal GBM metastasis. The first case was a 25-year-old female who presented with a spinal intradural intramedullary spinal lesion a few months after resection of a left temporal lobe GBM (isocitrate dehydrogenase wild type). The patient underwent surgical resection of the new lesion, and subsequent histopathologic examination proved that the intramedullary spinal lesion was GBM. The patient experienced full recovery postoperatively, and then a few months later, she presented again with widespread drop metastasis of the spinal cord. The second case is a middle-aged male with right temporal GBM who developed spinal metastasis 10 months after his diagnosis. We are reporting these 2 cases due to the rarity of spinal metastasis in GBM. We reviewed the current literature and included genetic and molecular profiles in the discussion. Currently, there are no established treatment guidelines for GBM spinal metastasis. The Stupp protocol after initial brain surgery for GBM did not appear to have beneficial effects on prolonging survival in these patients with spinal metastasis. The goal of treatment was primarily to alleviate pain and neurologic deficits with no effect on overall outcome. Prognosis following the diagnosis of spinal metastasis is poor. [ABSTRACT FROM AUTHOR]

The major difficulty in treating glioblastoma stems from the intrinsic privileged nature of the brain. This complicates therapy, as many traditionally potent chemotherapeutics cannot access their target sites in the brain. Several techniques have been investigated to overcome this barrier and facilitate drug delivery. However, these techniques have inherent shortcomings related to the delivery system, the drug itself, or its bioactivity. Periosteal flaps and temporoparietal fascial flaps (TPFFs) are widely used options because they have predictable vasculature and a wide rotational arc. These flaps are not restricted by the blood-brain barrier, as they derive their vascular supply from branches of the external carotid artery, which can be readily identified with Doppler ultrasound. We hypothesized that transposition of a vascularized TPFF to the walls of a resected tumor surgical cavity may bring autologous tissue not restricted by the blood-brain barrier in close vicinity of the resected tumor bed microenvironment. This offers a nonselective, long-lasting gateway to target the residual tumor cells nesting in the brain adjacent to the tumor. A 47-year-old, right-handed woman with newly diagnosed multifocal glioblastoma underwent excision of the tumor and TPFF placement. This illustrative case report represents the first case of the use of this novel surgical technique with radiologic follow-up. The blood-brain barrier is identified as a major barrier for effective drug delivery in glioblastoma. This study demonstrates the feasibility of the TPFF technique to bypass this barrier and help facilitate the goal of improving drug delivery. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most common tumors of the central nervous system, which is the most lethal brain cancer. GBM treatment is based primarily on surgical resection, combined with radiotherapy and chemotherapy. Despite the positive treatment, progression free survival and overall survival were not significantly prolonged because GBM almost always recurs. We are always looking forward to some new and effective treatments. In recent years, a novel treatment method called tumor treating fields (TTFields) for cancer treatment has been proposed. TTFields devices were approved by the Food and Drug Administration (FDA) for adjuvant treatment of recurrent and newly diagnosed GBMs in 2011 and 2015, respectively. This became the first breakthrough treatment for GBM in the past 10 years after the FDA approved bevacizumab for patients with relapsed GBM in 2009. This paper summarized the research results of TTFields in recent years and elaborated the mechanism of action of TTFields on GBM, including cell and animal experimental research, clinical application and social benefits. [ABSTRACT FROM AUTHOR]

Purpose: Precision medicine has been most successful in targeting single mutations, but personalized medicine using broader genomic tumor profiles for individual patients is less well developed. We evaluate a genomics-informed computational biology model (CBM) to predict outcomes from standard treatments and to suggest novel therapy recommendations in glioblastoma (GBM).Methods and Materials: In this retrospective study, 98 patients with newly diagnosed GBM undergoing surgery followed by radiation therapy and temozolomide at a single institution with available genomic data were identified. Incorporating mutational and copy number aberration data, a CBM was used to simulate the response of GBM tumor cells and generate efficacy predictions for radiation therapy (RTeff) and temozolomide (TMZeff). RTeff and TMZeff were evaluated for association with overall survival and progression-free survival in a Cox regression model. To demonstrate a CBM-based individualized therapy strategy, treatment recommendations were generated for each patient by testing a panel of 45 central nervous system-penetrant US Food and Drug Administration-approved agents.Results: High RTeff scores were associated with longer survival on univariable analysis (P < .001), which persisted after controlling for age, extent of resection, performance status, MGMT, and IDH status (P = .017). High RTeff patients had a longer overall survival compared with low RTeff patients (median, 27.7 vs 14.6 months). High TMZeff was also associated with longer survival on univariable analysis (P = .007) but did not hold on multivariable analysis, suggesting an interplay with MGMT status. Among predictions of the 3 most efficacious combination therapies for each patient, only 2.4% (7 of 294) of 2-drug recommendations produced by the CBM included TMZ.Conclusions: CBM-based predictions of RT and TMZ effectiveness were associated with survival in patients with newly diagnosed GBM treated with those therapies, suggesting a possible predictive utility. Furthermore, the model was able to suggest novel individualized monotherapies and combinations. Prospective evaluation of such a personalized treatment strategy in clinical trials is needed. [ABSTRACT FROM AUTHOR]

Although malignant glioblastoma (GBM) treatment has significantly improved in the past few decades, the prognosis of GBM remains unsatisfactory. MicroRNA (miR)-138-5p has been reported as a tumor suppressor in several types of human cancer; however, little is known about the function of miR-138-5p in GBM. The present study aimed to investigate the role of miR-138-5p in GBM as well as the underlying molecular mechanisms. The present study performed bioinformatics analysis, reverse transcription-quantitative (RT-q) PCR, western blotting, cell viability assays, colony formation assays, invasion assays and cell cycle analysis to investigate the biological function of miR-138-5p in both patient tissues and cell lines. In addition, miR-138-5p targets in GBM were predicted using Gene Expression Omnibus website and further validated by a dual luciferase reporter gene assay. The results revealed that miR-138-5p expression levels in patients with GBM from a Gene Expression Omnibus dataset were significantly downregulated. RT-qPCR analysis of miR-138-5p expression levels also revealed similar results in GBM tissues and cell lines. The upregulation of miR-138-5p expression levels using a mimic significantly inhibited the cell viability, colony formation and the G0/G1 to S progression in GBM cell lines, suggesting that miR-138-5p may be a tumor suppressor. Moreover, miR-138-5p was discovered to directly target cyclin D3 (CCND3), a protein that serves an important role in the cell cycle, and inhibited its expression. Finally, silencing CCND3 using small interfering RNA suppressed the viability of GBM cells. In conclusion, the results of the present study suggested that miR-138-5p may function as a tumor suppressor in GBM by targeting CCND3, indicating that miR-138-5p may be a novel therapeutic target for patients with GBM. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma is the most aggressive form of brain tumors. A better understanding of the molecular mechanisms leading to its evolution is essential for the development of treatments more effective than the available modalities. Here, we aim to identify molecular drivers of glioblastoma development and recurrence by analyzing DNA CpG methylation patterns in sequential samples. Methods: DNA was isolated from 22 pairs of primary and recurrent formalin-fixed, paraffin-embedded glioblastoma specimens, and subjected to reduced representation bisulfite sequencing. Bioinformatic analyses were conducted to identify differentially methylated sites and pathways, and biostatistics was used to test correlations among clinical and pathological parameters. Results: Differentially methylated pathways likely involved in primary tumor development included those of neuronal differentiation, myelination, metabolic processes, synapse organization and endothelial cell proliferation, while pathways differentially active during glioblastoma recurrence involved those associated with cell processes and differentiation, immune response, Wnt regulation and catecholamine secretion and transport. Conclusion: DNA CpG methylation analyses in sequential clinical specimens revealed hypomethylation in certain pathways such as neuronal tissue development and angiogenesis likely involved in early tumor development and growth, while suggested altered regulation in catecholamine secretion and transport, Wnt expression and immune response contributing to glioblastoma recurrence. These pathways merit further investigations and may represent novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma (GBM) is the most lethal primary cancer in adult central nervous system, and new strategies are desperately needed. The secretory pathway kinase or kinase-like proteins (SPKKPs) have been shown to mediate multiple physiological functions by phosphorylating extracellular proteins and proteoglycans. However, their roles in cancers, especially GBM, remain poorly defined. Methods: The least absolute shrinkage and selection operator (LASSO) regression was employed for establishing the SPKKPs signature for IDH wild type (wt) GBM prognosis. Integrative analyses with multiple datasets were employed to identify the core member of this gene family in glioma. The receiver operator characteristic (ROC) curves and immunohistochemistry were further used for evaluating its association with progressive malignancy in glioma and GBM patients' survival, respectively. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to interpret its functions in GBM, which were further verified in vitro. Results: A SPKKPs classifier was constructed with 3 genes of this family. This signature could effectively distinguish IDH wt GBM survival. Family with sequence similarity 20 C (FAM20C) was further identified as the core member of this family in glioma. Elevated FAM20C expression was not only closely correlated with glioma malignancy progression and the mesenchymal subtype of GBM but also indicated unfavorable survival of GBM patients. FAM20C was also found to be associated with the disrupted immune response in GBM microenvironment and was required for the migration of glioma and immune cells. Conclusion: These data indicate that the potential of FAM20C serving as a predictive molecule and a therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

The utility of diffusion kurtosis imaging (DKI) for assessing intra‐tumor heterogeneity was evaluated in a rat model of glioblastoma multiforme. Longitudinal MRI including T2‐weighted and diffusion‐weighted MRI (DWI) was performed on six female Fischer rats 8, 11 and 14 days after intracranial transplantation of F98 cells. T2‐weighted images were used to measure the tumor volumes and DWI images were used to compute diffusion tensor imaging (DTI) and DWI based parametric maps including mean diffusivity (MD), mean kurtosis (MK), axial diffusivity (AD), axial kurtosis, radial diffusivity, radial kurtosis, fractional anisotropy (FA) and kurtosis fractional anisotropy (KFA). Median values from the segmented normal contralateral cortex, tumor and edema from the diffusion parameters were compared at the three imaging time points to assess any changes in tumor heterogeneity over time. ex vivo DKI was also performed in a representative sample and compared with histology. Significant differences were observed between normal cortex, tumor and edema in both the DTI and DKI parameters. Notably, at the earliest time point MK and KFA were significantly different between normal cortex and tumor in comparison with MD or FA. Although a decreasing trend in MD, AD and FA values of the tumor were observed as the tumor grew, no significant changes in any of the DTI or DKI parameters were observed longitudinally. While DKI was equally sensitive to DTI in differentiating tumor from edema and normal brain, it was unable to detect longitudinal increases in intra‐tumoral heterogeneity in the F98 model of glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

Background/Aim: Glioblastoma is the most malignant form of astrocytoma. The purpose of this study was to analyze the genetic characteristics of primary and recurrent glioblastomas using targeted sequencing and investigate the differences in mutational profiles between the locations of tumor recurrence. Materials and Methods: Fourteen glioblastoma patients who developed local (n=10) or distal (n=4) recurrence were included in the study. Targeted sequencing analysis was performed using the primary (n=14) and corresponding recurrent (n=14) tumor tissue samples. Results: The local and distal recurrence groups showed different genetic evolutionary patterns. Most of the locally recurrent glioblastomas demonstrated concordant mutational profiles between the primary and recurrent tumors, suggesting a linear evolution. In contrast, all cases of distally recurrent glioblastomas showed changes in mutational profiles with newly acquired mutations when compared to the corresponding primary tumors, suggesting a branching evolution. Conclusion: Locally and distally recurrent glioblastomas exhibit different evolutionary patterns. [ABSTRACT FROM AUTHOR]

Background/Aim: Better diagnostic and prognostic markers are required for a more accurate diagnosis and an earlier detection of glioma progression and for suggesting better treatment strategies. This retrospective study aimed to identify actionable gene variants to define potential markers of clinical significance. Materials and Methods: 56 glioblastomas (GBM) and 44 grade 2-3 astrocytomas were profiled with next generation sequencing (NGS) as part of routine diagnostic workup and bioinformatics analysis was used for the identification of variants. CD34 immunohistochemistry (IHC) was used to measure microvessel density (MVD) and Log-rank test to compare survival and progression in the presence or absence of these variants. Results: Bioinformatic analysis highlighted frequently occurring variants in genes involved in angiogenesis regulation (KDR, KIT, TP53 and PIK3CA), with the most common ones being KDR (rs1870377) and KIT (rs3822214). The KDR variant was associated with increased MVD and shorter survival in GBM. We did not observe any correlation between the KIT variant and MVD; however, there was an association with tumour grade. Conclusion: This study highlights the role of single-nucleotide variants (SNVs) that may be considered non-pathogenic and suggests the prognostic significance for survival of KIT rs3822214 and KDR rs1870377 and potential importance in planning new treatment strategies for gliomas. [ABSTRACT FROM AUTHOR]

Gliomas, particularly high-grade gliomas including glioblastoma (GBM), represent the most common and malignant types of primary brain cancer in adults, and carry a poor prognosis. GBM has been classified into distinct subgroups over the years based on cellular morphology, clinical characteristics, biomarkers, and neuroimaging findings. Based on these classifications, differences in therapeutic response and patient outcomes have been established. Recently, the identification of complex molecular signatures of GBM has led to the development of diverse targeted therapeutic regimens and translation into multiple clinical trials. Chemical-, peptide-, antibody-, and nanoparticle-based probes have been designed to target specific molecules in gliomas and then be visualized with multimodality molecular imaging (MI) techniques including positron emission tomography (PET), single-photon emission computed tomography (SPECT), near-infrared fluorescence (NIRF), bioluminescence imaging (BLI), and magnetic resonance imaging (MRI). Thus, multiple molecules of interest can now be noninvasively imaged to guide targeted therapies with a potential survival benefit. Here, we review developments in molecular-targeted diagnosis and therapy in glioma, MI of these targets, and MI monitoring of treatment response, with a focus on the biological mechanisms of these advanced molecular probes. MI probes have the potential to noninvasively demonstrate the pathophysiologic features of glioma for diagnostic, treatment, and response assessment considerations for various targeted therapies, including immunotherapy. However, most MI tracers are in preclinical development, with only integrin αVβ3 and isocitrate dehydrogenase (IDH)-mutant MI tracers having been translated to patients. Expanded international collaborations would accelerate translational research in the field of glioma MI. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most malignant form of astrocytoma with short survival and a high recurrence rate and remains a global problem. Currently, surgery, chemotherapy, radiotherapy, and other comprehensive treatments are the main treatment modalities, but patients still have a poor prognosis mainly due to the infiltrative growth of GBM and the protective effect of the blood–brain barrier on tumor cells. Therefore, immunotherapy is expected to be a good option for GBM. In the immune system, different cells play varying roles in the treatment of GBM, so understanding the roles played by various immune cells in treating GBM and considering how to combine these effects to maximize the efficacy of these cells is important for the selection of comprehensive and optimal treatment plans and improving GBM prognosis. Therefore, this study reviews the latest research progress on the role of various types of immune cells in the treatment of GBM. [ABSTRACT FROM AUTHOR]

Introduction: Traditional classification that divided gliomas into glioblastoma multiformes (GBM) and lower grade gliomas (LGG) based on pathological morphology has been challenged over the past decade by improvements in molecular stratification, however, the reproducibility and diagnostic accuracy of glioma classification still remains poor. This study aimed to establish and validate a novel nomogram for the preoperative diagnosis of GBM by using integrated data combined with feasible baseline characteristics and preoperative tests. Material and method: The models were established in a primary cohort that included 259 glioma patients who had undergone surgical resection and were pathologically diagnosed from March 2014 to May 2016 in the First Affiliated Hospital of Xi'an Jiaotong University. The preoperative data were used to construct three models by the best subset regression, the forward stepwise regression, and the least absolute shrinkage and selection operator, and to furthermore establish the nomogram among those models. The assessment of nomogram was carried out by the discrimination and calibration in internal cohorts and external cohorts. Results and discussion: Out of all three models, model 2 contained eight clinical-related variables, which exhibited the minimum Akaike Information Criterion (173.71) and maximum concordance index (0.894). Compared with the other two models, the integrated discrimination index for model 2 was significantly improved, indicating that the nomogram obtained from model 2 was the most appropriate model. Likewise, the nomogram showed great calibration and significant clinical benefit according to calibration curves and the decision curve analysis. Conclusion: In conclusion, our study showed a novel preoperative model that incorporated clinically relevant variables and imaging features with laboratory data that could be used for preoperative prediction in glioma patients, thus providing more reliable evidence for surgical decision-making. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive tumor of the central nervous system. Prognosis is poor, even in the presence of a methylated state of MGMT gene promoter, which represents the biomarker with the highest prognostic/predictive value for the standard treatment of patients. Among patients with a methylated MGMT status, we identified an intermediate range of methylation above the standard 9% cut-off (gray zone) in which the predictive strength of the marker was lost. In an effort to improve the evaluation of the biomarker in clinical decision-making, we are carrying out a retrospective study, performing an in-depth analysis of samples used for diagnosis to understand how molecular heterogeneity, a hallmark of glioblastoma, impacts the evaluation of MGMT gene promoter methylation. Preliminary data from samples belonging to the "gray zone" tend to confirm the hypothesis of a mismatch between methylation values used for clinical decision-making and those included in our in-depth analysis. Confirmation of these data would help to better define the predictive power of MGMT promoter methylation status and greatly facilitate clinical decision-making. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) are the most common tumors of the central nervous system and among the deadliest cancers in adults. GBM overall survival has not improved over the last decade despite optimization of therapeutic standard-of-care. While immune checkpoint inhibitors (ICI) have revolutionized cancer care, they unfortunately have little therapeutic success in GBM. Here, we elaborate on normal brain and GBM-associated immune landscapes. We describe the role of microglia and tumor-associated macrophages (TAMs) in immune suppression and highlight the impact of energy metabolism in immune evasion. We also describe the challenges and opportunities of immunotherapies in GBM and discuss new avenues based on harnessing the anti-tumor activity of myeloid cells, vaccines, chimeric antigen receptors (CAR)-T and -NK cells, oncolytic viruses, nanocarriers, and combination therapies. [ABSTRACT FROM AUTHOR]

Pseudogenes, which are long noncoding RNAs that originate from protein-coding genes, have been suggested to play important roles in disease. Although studies have revealed high expression of legumain (LGMN) in many types of tumors, the regulation of LGMN remains largely unknown. Here, we found that a novel LGMN pseudogene (LGMNP1) was upregulated in glioblastoma (GBM) tissues and high LGMNP1 expression in GBM cells enhanced proliferation and invasion. Biochemical analysis showed that cytoplasmic LGMNP1 functionally targeted miR-495-3p in a manner involving an RNA-induced silencing complex. Dual-luciferase reporter assays demonstrated that LGMN was a target of miR-495-3p, and LGMN was upregulated and positively correlated with LGMNP1 in GBM. Moreover, miR-495-3p was downregulated and negatively correlated with LGMNP1 in GBM tissues. Notably, the tumor-promoting effects of LGMNP1 upregulation could be alleviated by miR-495-3p mimics. Furthermore, GBM cells overexpressing LGMNP1 exhibited more aggressive tumor progression and elevated LGMN expression in vivo. Thus, our data illustrate that LGMNP1 exerts its oncogenic activity, at least in part, as a competitive endogenous RNA (ceRNA) that elevates LGMN expression by sponging miR-495-3p. CeRNA-mediated miRNA sequestration might be a novel therapeutic strategy in GBM. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary brain tumor and is highly aggressive with a median survival of 15 months. We have previously shown that residual cells of GBM form multinucleated giant cells (MNGCs) showing a senescent phenotype, but eventually escape from therapy induced senescence (TIS), resulting in GBM recurrence. Here we demonstrate the role of PARP-1 in TIS and its recovery. We show that genetic and pharmacological inhibition of PARP-1 has an anti-proliferative effect on GBM cell lines and primary cultures derived from patient samples. Furthermore, the PARP-1 inhibitor olaparib, in combination with radiation increased MNGCs formation and senescence as assessed by β-galactosidase activity, and macroH2A1 levels in residual cells. Additionally, we found that reduced PARP-1 activity and not protein levels in residual cells was crucial for MNGCs formation and their maintenance in the senescent state. PARP-1 activity was restored to higher levels in recurrent cells that escaped from TIS. Importantly, olaparib + radiation treatment significantly delayed recurrence in vitro as well in vivo in orthotopic GBM mouse models with a significant increase in overall survival of mice. Overall, this study demonstrates that sustained inhibition of PARP-1 activity during radiation treatment significantly delays GBM recurrence. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) stem cells are resistant to cancer therapy, and therefore responsible for tumor progression and recurrence after conventional therapy. However, the molecular mechanisms driving the maintenance of stemness and dedifferentiation are poorly understood. In this study, we identified plant homeodomain finger-containing protein 20 (PHF20) as a crucial epigenetic regulator for sustaining the stem cell-like phenotype of GBM. It is highly expressed in GBM and tightly associated with high levels of aggressiveness of tumors and potential poor prognosis in GBM patients. Knockout of PHF20 inhibits GBM cell proliferation, as well as its invasiveness and stem cell-like traits. Mechanistically, PHF20 interacts with WDR5 and binds to the promoter regions of WISP1 for its expression. Subsequently, WISP1 and BGN act in concert to regulate the degradation of β-Catenin. Our findings have identified PHF20 as a key driver of GBM malignant behaviors, and provided a potential target for developing prognosis and therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60–70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide. [ABSTRACT FROM AUTHOR]

Background Antidepressant drugs have shown antitumor activity in preclinical glioblastoma studies. Antidepressant drug use, as well as its association with survival, in glioblastoma patients has not been well characterized on a population level. Methods Patient characteristics, including the frequency of antidepressant drug use, were assessed in a glioblastoma cohort diagnosed in a 10-year time frame between 2005 and 2014 in the Canton of Zurich, Switzerland. Cox proportional hazards regression models were applied for multivariate analysis. Kaplan-Meier survival curves were used to estimate overall survival (OS) data and the log-rank test was performed for comparisons. Results A total of 404 patients with isocitrate dehydrogenase wild-type glioblastoma were included in this study. Sixty-five patients (16.1%) took antidepressant drugs at some point during the disease course. Patients were most commonly prescribed selective serotonin reuptake inhibitors at any time (N = 46, 70.8%). Nineteen patients (29.2%) were on antidepressant drugs at the time of their tumor diagnosis. No differences were observed in OS between those patients who had taken antidepressants at some point in their disease course and those who had not (P  = .356). These data were confirmed in a multivariate analysis including age, Karnofsky Performance Scale (KPS), sex, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and first-line treatment as cofounders (P  = .315). Also, there was no association of use of drugs modulating voltage-dependent potassium channels (citalopram; escitalopram) with survival (P  = .639). Conclusions This signal-seeking study does not support the hypothesis that antidepressants have antitumor efficacy in glioblastoma on a population level. [ABSTRACT FROM AUTHOR]

Objectives: Targeted immunotherapies such as chimeric antigen receptor (CAR)‐T cells are emerging as attractive treatment options for glioblastoma, but rely on identification of a suitable tumor antigen. We validated a new target antigen for glioblastoma, fibroblast activation protein (FAP), by undertaking a detailed expression study of human samples. Methods: Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datasets. Short‐term cultures of glioma neural stem (GNS) cells were compared to cultures of healthy astrocytes and neurons using flow cytometry. Glioblastoma tissues were dissociated and analysed by high‐parameter flow cytometry and single‐cell transcriptomics (scRNAseq). Results: Compared to normal brain, FAP was overexpressed at the gene and protein level in a large percentage of glioblastoma tissues, with highest levels of expression associated with poorer prognosis. FAP was also overexpressed in several paediatric brain cancers. FAP was commonly expressed by cultured GNS cells but absent from normal neurons and astrocytes. Within glioblastoma tissues, the strongest expression of FAP was around blood vessels. In fact, almost every tumor vessel was highlighted by FAP expression, whereas normal tissue vessels and cultured endothelial cells (ECs) lacked expression. Single‐cell analyses of dissociated tumors facilitated a detailed characterisation of the main cellular components of the glioblastoma microenvironment and revealed that vessel‐localised FAP is because of expression on both ECs and pericytes. Conclusion: Fibroblast activation protein is expressed by multiple cell types within glioblastoma, highlighting it as an ideal immunotherapy antigen to target destruction of both tumor cells and their supporting vascular network. [ABSTRACT FROM AUTHOR]

Glioblastomas [also called glioblastoma multiforme (GBM)] are malignant grade-IV tumors. The tumors consist predominantly of abnormal astrocytic cells but contain a mix of cell types. Glioblastomas are the most common and most malignant of the glial tumors. While GBM is not the most common brain tumor, it is the deadliest. Median survival time with standard therapy is 14-15 months after diagnosis. In a disease with poor prognosis and rapid progression, early tumor detection is necessary for making timely treatment decisions. Optometrists are in a position to detect early signs of tumors such as GBM and improve the survival rate. Clinical evaluation -- thorough review of symptoms including seizures, headaches, weight loss, dizziness, muscle weakness and visual field loss -- is crucial for these patients. New or worsening visual field defects may indicate the presence or progression of glioblastoma and should prompt further testing and investigation. We identify a case, previously misdiagnosed as glaucoma, in which careful history and Humphrey visual field testing predated neuroimaging findings of glioblastoma located in an unusual part of the brain. [ABSTRACT FROM AUTHOR]