High-grade Glioblastoma Research Articles

TMIC-86. THE ROLE AND THERAPEUTIC RESEARCH OF NETS IN PROMOTING TMZ RESISTANCE IN GLIOBLASTOMA

Abstract OBJECTIVE This study aims to investigate the issue of resistance to temozolomide (TMZ) treatment in high-grade glioblastoma (GBM), specifically the association between TMZ resistance, the tumor microenvironment (TME), and neutrophil activity. The research hypothesis posits that changes in neutrophils induced by TMZ treatment, particularly the formation of neutrophil extracellular traps (NETs), may lead to TMZ resistance in GBM cells. METHODS The study utilized clinical data analysis and animal model research to evaluate changes in neutrophils during TMZ treatment and their impact on treatment efficacy. Proteomics analysis and high-throughput sequencing were employed to investigate the effect of TMZ on cytokine secretion by GBM cells and how these cytokines stimulate the release of NETs. Additionally, gene ontology (GO) analysis and bioinformatics methods were used to study how NETs promote the epithelial-mesenchymal transition (EMT) process and TMZ resistance by activating specific signaling pathways such as Jak-Stat3. RESULTS The study found that TMZ treatment led to increased neutrophil infiltration, which was associated with poor prognosis in GBM patients. TMZ treatment altered the levels of cytokines secreted by GBM cells, particularly IL-6, promoting the release of NETs by neutrophils. The formation of NETs was closely related to the activation of Stat3 signaling and the promotion of the EMT process in tumor cells, thereby enhancing TMZ resistance. Magnesium-based micromotors were found to improve TMZ efficacy by scavenging ROS production in neutrophils, inhibiting the release of NETs. CONCLUSION This study confirms the association between TMZ resistance and neutrophil activity, particularly the role of NETs in promoting EMT and resistance. These findings provide new insights into the treatment of GBM and offer a theoretical basis for the development of therapeutic strategies targeting NETs, which may improve the response of glioblastoma to TMZ treatment by inhibiting ROS production. The development of this novel therapeutic approach offers new treatment options for postoperative chemotherapy in GBM.

CNSC-41. DABRAFENIB AND TRAMETINIB AS A PROMISING TREATMENT OPTION FOR PEDIATRIC POPULATION WITH LOW-GRADE GLIOMAS THAT HAVE BRAF V600E MUTATION:A BREAKTHROUGH IN THE FIELD OF NEURO- ONCOLOGY

Abstract Two-thirds of all pediatric malignant central nervous tumors, including high-grade (glioblastoma, anaplastic astrocytoma) and low-grade (ganglioglioma, pilocytic astrocytoma) carcinomas, are gliomas. Low-grade glioma(LGG) exhibits genetic alterations caused by the BRAF kinase mutation, such as replacing glutamic acid (E) in place of valine (V) at the 600 positions, known as the V600E point mutation. Pediatric low-grade gliomas (PLGGs) also comprise around one-third of juvenile brain tumors and are the most frequent central nervous system tumors. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). Where possible, complete surgical removal is the mainstay of treatment for progressing or symptomatic PLGG.Radiation therapy has historically been used to treat PLGG in both up-front and salvage scenarios. To delay or avoid the necessity for radiation therapy in young children with advancing or incompletely resected PLGG, chemotherapy was created in 1980. On March 16, 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from low-grade glioma (LGG) who require systemic therapy and are at least one year old. Nevertheless, early-stage clinical trials have produced encouraging results that may revolutionize the treatment of LGG in the near future.

CSIG-06. BRAF GERMLINE MUTATIONS AND PREDISPOSITION TO BRAIN TUMORS

Abstract We report on two BRAF-mutated children and discuss genetic counseling regarding predisposition to brain tumors. Molecular analysis of the PTPN11 gene and twelve other genes in the RAS-MAPK pathway was carried out in a series of 54 dysmorphic patients with suspected Rasopathies. Two heterozygous BRAF germline mutations were detected in two 7-year-old girls, at exon 6 and 12 respectively. Both patients had the distinctive facial appearance of cardio-facio-cutaneous syndrome (CFC) type 1. Patients with CFC are rare and characterized by phenotypic and genetic heterogeneity, with overlaps with Noonan syndrome. While nearly 75% of CFC cases have germline BRAF mutations, the frequency of BRAF mutations is inferior in Noonan and LEOPARD syndromes. BRAF mutations in CFC are often found in the cysteine-rich domain of the BRAF protein (exons 6, 11, 12, 13, 14, 15 and 16). Conversely, somatic BRAF mutations are more common, grouped into classes according to their kinase activity level, and have been associated with a variety of malignancies, including pediatric and adult brain tumors (low- and high-grade gliomas, glioblastomas and low-grade astrocytomas). BRAF V600E is the most common somatic mutation, but other mutations are currently being identified. Many of these mutations are within the kinase domain, while others are located across the gene and have less well-understood functional consequences. Germinal V600E mutation has been described once, in a CFC patient having a severe phenotype. Nevertheless, it seems that patients with germline BRAF mutations and gliomas have not yet been reported. Given the rarity of CFC, it is unclear whether there is a high risk of brain tumors. Further molecular studies will enable us to refine recommendations for the prevention, monitoring and care of people with germline BRAF mutations, given the success of BRAF inhibitors in certain cancers, with encouraging results in gliomas.

Primary murine high-grade glioma cells derived from RCAS/tv-a diffuse glioma model reprogram naive T cells into immunosuppressive regulatory T lymphocytes

High-grade gliomas (HGGs) and glioblastomas (GBMs) are the most aggressive and lethal brain tumors. The current standard of care (SOC) includes gross safe surgical resection followed by chemoradiotherapy. The main chemotherapeutic agents are the DNA-alkylating agent temozolomide (TMZ) and adjuvants. Due to the outdated therapeutic protocols and lack of specific treatments, there is an urgent and rising need to improve ourunderstanding of tumor biology and design more effective therapeutic strategies. Invitro models are essential for investigating glioma biology and testing novel therapeutic approaches. While using commercially available and patient-derived glioma cell lines for invitro studies is common practice, they exhibit several limitations, including failing to maintain the genetic and phenotypic diversity of primary tumors, undergo genetic drift over time, and often lacking the invasive and stem-like characteristics of patient tumors. These limitations can lead to inconsistent and non-reproducible results, hampering translational research progress. In this study, we established a novel primary murine HGG cell line, isolated from an immunocompetent HGG-bearing RCAS/T-va mouse. We characterized the transcriptome and phenotype to ensure that this cell line resembles the nature of HGGs and retains the ability to reprogram primary murine T lymphocytes.

The CCL2-CCR4 axis promotes Regulatory T cell trafficking to canine glioma tissues

PurposeSpontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high-grade glioma and human glioblastomas share many molecular similarities, including the accumulation of immunosuppressive regulatory T cells (Tregs) that inhibit anti-tumor immune responses. Identifying in dog mechanisms responsible for Treg recruitment may afford to target the cellular population driving immunosuppression, the results providing a rationale for translational clinical studies in human patients. Our group has previously identified C-C motif chemokine 2 (CCL2) as a glioma-derived T-reg chemoattractant acting on chemokine receptor 4 (CCR4) in a murine orthotopic glioma model. Recently, we demonstrated a robust increase of CCL2 in the brain tissue of canine patients bearing high-grade glioma.MethodsWe performed a series of in vitro experiments using canine Tregs and patient-derived canine glioma cell lines (GSC 1110, GSC 0514, J3T-Bg, G06A) to interrogate the CCL2-CCR4 signaling axis in the canine.ResultsWe established a flow cytometry gating strategy for identifying and isolating FOXP3+ Tregs in dogs. The canine CD4 + CD25high T-cell population was highly enriched in FOXP3 and CCR4 expression, indicating they are bona fide Tregs. Canine Treg migration was enhanced by CCL2 or by glioma cell line-derived supernatant. Blockade of the CCL2-CCR4 axis significantly reduced migration of canine Tregs. CCL2 mRNA was expressed in all glioma cell lines, and expression increased when exposed to Tregs but not CD4 + helper T-cells.ConclusionOur study validates CCL2-CCR4 as a bi-directional Treg-glioma immunosuppressive and tumor-promoting axis in canine high-grade glioma.

Fractional tumor burden maps increase the confidence of reading brain MR perfusion

Rationale and objectivesVarious methods exist to perform and post-process perfusion weighted MR imaging in the post-treatment imaging of glioma patients to differentiate tumor progression from tumor-related abnormalities. One of these post-processing methods produces ‘fractional tumor burden’ maps. This multi-reader study investigated the clinical feasibility of fractional tumor burden maps on real world data from radiological follow-up of high-grade astrocytoma patients. MethodsFive readers with background in radiology and varying levels of experience were tasked with assessing 30 astrocytoma and glioblastoma patients during one reader session. First, they were provided with a dataset of conventional MRI sequences, including perfusion MRI with regional cerebral blood volume maps. Then the dataset was expanded with a corresponding fractional tumor burden maps. Diagnostic accuracy, duration of post-processing, duration of the assessment of the fractional tumor burden maps, the diagnostic confidence reported by the readers and their diagnoses were recorded. Final diagnosis was determined by clinical and radiological follow-up and/or histopathological data used as gold standard. ResultsA mean sensitivity of 83.3 % and mean specificity of 55.1 % was obtained without the use of fractional tumor burden maps, whereas their additional of fractional tumor burden maps resulted in a mean sensitivity and specificity of 79.5 % and 54.2 %, respectively. Diagnostic accuracies with and without fractional tumor burden maps were not significantly different (Z = 0.76, p = 0.450). The median time spent post-processing was 313 s, while the median duration of the assessment of the FTB maps was 19 s. Interestingly, reader confidence increased significantly after adding the fractional tumor burden-maps to the assessment (Z = 454, p < 0.01). ConclusionsWhile the use of fractional tumor burden maps does not carry additional value in the radiological follow-up of post-operative high-grade astrocytoma and glioblastoma patients, it does give readers more confidence in their diagnosis.

NFS-08. CLINICAL AND MOLECULAR FEATURES OF HIGH-GRADE GLIOMA IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS TYPE 1: A PRELIMINARY ANALYSIS

Abstract BACKGROUND Individuals with neurofibromatosis type 1 (NF1) are at increased risk for developing high-grade glioma (HGG) relative to the general population. Despite the elevated incidence in NF1, adequately powered studies of HGG have not been performed to date, limiting understanding of the clinical course, prevalent treatment approaches, recurrent molecular features, and outcomes. METHODS Patients with NF1 and pathologic or molecularly confirmed high grade glioma and high-grade astrocytoma with piloid features at Children’s Hospital of Philadelphia, University of California San Francisco, Washington University, and Cincinnati Children’s Hospital Medical Center diagnosed between 2005 to 2021 were included. Retrospective clinical, molecular, treatment, and imaging data were collated and analyzed. RESULTS Thirty-four patients met eligibility criteria, 13 (38%) were female. The median age at diagnosis was 22.7 years; 10 were pediatric (children &amp;lt;18 years of age). The most common diagnoses included high-grade astrocytoma (7), anaplastic astrocytoma (8), glioblastoma multiforme (5), and high-grade astrocytoma with piloid features (5). Fifteen (44%) of tumors underwent biopsy only and 4 (12%) were gross totally resected. Nine tumors (26%) were considered to have transformed from a pre-existing low-grade lesion. In the 22 cases with molecular testing, the most prevalent genetic variants involved the NF1, CDKN2A/B, ATRX, TP53, and SUZ12 genes. Frontline treatment approach varied; however, 26 individuals (76%) received radiation as part of their initial therapy. Overall survival at 2 years was 52% (95% CI 33-67) across all ages and 70% (95% CI 33-89) in children. There was no significant difference in overall survival at 2 years by extent of tumor resection at diagnosis. CONCLUSIONS High grade glioma in individuals with NF1 demonstrate a high prevalence of alterations in the CDKN2A/B and ATRX genes, with a poor overall survival despite radiation-inclusive treatment regimens. Collection of additional patient data from collaborating institutions is ongoing to support further analyses.

Unveiling the Pharmacological Role of Human Deubiquitinating Enzymes in Temozolomide Response of Glioblastoma Cells.

Temozolomide (TMZ) stands as the primary chemotherapeutic drug utilized in clinical glioma treatment, particularly for high-grade glioblastoma (GBM). However, the emergence of TMZ resistance in GBM poses a significant hurdle to its clinical efficacy. Our objective was to elucidate the role of deubiquitinating enzymes (DUBs) in GBM cell resistance to TMZ. We employed the broad-spectrum DUBs inhibitor G5 to investigate the function of DUBs in TMZ cytotoxicity against GBM cells. Eighty-two GBM cell lines with specified DUBs knockout were generated and subjected to CCK-8 assays to assess cell proliferation and TMZ resistance. Furthermore, the association between DUBs and TMZ resistance in GBM cells, along with the modulation of autophagic flux, was examined. The pan-DUBs inhibitor G5 demonstrated the ability to induce cell death and enhance TMZ toxicity in GBM cells. Subsequently, we identified potential DUBs involved in regulating GBM cell proliferation and TMZ resistance. The impact of DUBs knockout on TMZ cytotoxicity was found to be associated with their regulation of TMZ-induced autophagy. In summary, our study provides primary insights into the role of DUBs in GBM cell proliferation and TMZ resistance, and contributes to a deeper understanding of the complex function of DUBs genes underlying TMZ resistance in GBM cells.

Spectrum of [18F]FDG PET/CT Findings in Primary Central Nervous System Lymphoma - A Pictorial Essay.

Primary central nervous system lymphoma (PCNSL) is a rare, aggressive variant of extranodal non-Hodgkin's lymphoma. Although gadolinium-enhanced magnetic resonance imaging remains the initial imaging modality of choice, a whole-body F-18 fluorodeoxyglucose (FDG) positron emission tomography-computed tomography is imperative to exclude systemic lymphomatous involvement. Furthermore, the metabolic parameter, maximum standardized uptake value (SUVmax) of the lesion, tumor-to-normal cerebral tissue SUVmax ratio, and FDG uptake patterns help in differentiating intracranial lymphomas from High-grade Glioblastoma Multiforme (HGM) and infectious lesions, and hence, consolidating the diagnosis. In this pictorial essay, we present a series of PCNSL cases, representing the different imaging characteristics and metabolic uptake patterns.

Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases

Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma.

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.

Abstract 2834: Establishment of orthotopic high grade glioma xenograft model using zebrafish embryos

Abstract High grade glioma (HGG) is the most common malignant brain tumor in adults. These tumors represent a lethal group of brain tumors characterized by a remarkable level of genetic, epigenetic, and environmental heterogeneity, which can significantly affect therapy response and patient outcomes. Patient-derived xenograft (PDX) models of glioma are a central tool for neuro-oncology research and drug development, enabling the detection of patient-specific differences in growth and drug response. Mouse xenografts of HGG are well-established, but the time required to generate these models is not practical for integration into clinical paradigms. Patient derived organoids cannot mimic the physiologic aspects of an in vivo system, such as the blood-brain barrier or metabolism of drugs, which can affect how tumor cells respond to treatment. In this context, zebrafish are emerging as a time-efficient and cost-effective in vivo model. We investigated a rapid zebrafish-based PDX model that can recapitulate key aspects of different gliomas and enable treatment response evaluation within 8 days. We engrafted one GBM cell line (U-87), two patient-derived glioblastoma (GBM) cells, and one patient-derived IDH mutant grade 4 astrocytoma into the midbrain region of 2-day-old zebrafish embryos. Survival of transplanted larvae were monitored over 8 days post-transplantation and the engraftment was analyzed. Therapy response was evaluated through tumor size. One day post-transplantation, animals received 10 and 25 Gy radiation with or without 50 and 100 µM of temozolomide, a common GBM therapeutic, and tumor size was measured after 3 days by imaging. Results showed that GBM and astrocytoma cells had 100% and 80% of engraftment, respectively. GBM cell induced a median survival of 7 days in transplanted animals while 87 % of astrocytoma-injected animals were alive 8 days post transplantation. GBMs also varied in their drug and radiation response. Although both samples were classified as high-grade GBM and MGMT unmethylated, PDX derived from a younger patient with no alterations in PTEN and MDM2 genes responded better to temozolomide and radiation. Tumor responsiveness to therapy is often a combination of genetic and non-genetic factors that are difficult to clinicians to predict. By combining tumor-specific models and drug testing, a patient’s treatment plan could be tailored based on the sensitivity of each sub-clone to targeted therapeutics. In conclusion, we showed that the zebrafish-based PDX model provides a novel, high throughput avenue to assess the impact of tumor heterogeneity on drug response. Citation Format: Evelyn Winter da Silva, Annick De Loose, Yelena Chernyavskaya, Analiz Rodriguez, Jessica Blackburn. Establishment of orthotopic high grade glioma xenograft model using zebrafish embryos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2834.

Intraoperative ultrasound for surgical resection of high-grade glioma and glioblastoma: a meta-analysis of 732 patients.

Here, we conducted a meta-analysis to explore the use of intraoperative ultrasound (iUS)-guided resection in patients diagnosed with high-grade glioma (HGG) or glioblastoma (GBM). Our aim was to determine whether iUS improves clinical outcomes compared to conventional neuronavigation (CNN). Databases were searched until April 21, 2023 for randomized controlled trials (RCTs) and observational cohort studies that compared surgical outcomes for patients with HGG or GBM with the use of either iUS in addition to standard approach or CNN. The primary outcome was overall survival (OS). Secondary outcomes include volumetric extent of resection (EOR), gross total resection (GTR), and progression-free survival (PFS). Outcomes were analyzed by determining pooled relative risk ratios (RR), mean difference (MD), and standardized mean difference (SMD) using random-effects model. Of the initial 867 articles, only 7 articles specifically met the inclusion criteria (1 RCT and 6 retrospective cohorts). The analysis included 732 patients. Compared to CNN, the use of iUS was associated with higher OS (SMD = 0.26,95%CI=[0.12,0.39]) and GTR (RR = 2.02; 95% CI=[1.31,3.1]) for both HGG and GBM. There was no significant difference in PFS or EOR. The use of iUS in surgical resections for HGG and GBM can improve OS and GTR compared to CNN, but it did not affect PFS. These results suggest that iUS reduces mortality associated with HGG and GBM but not the risk of recurrence. These results can provide valuable cost-effective interventions for neurosurgeons in HGG and GBM surgery.

Classification of high-grade glioblastoma and single brain metastases using a new SCAT-inception model trained with MRI images.

Glioblastoma (GBM) and brain metastasis (MET) are the two most common intracranial tumors. However, the different pathogenesis of the two tumors leads to completely different treatment options. In terms of magnetic resonance imaging (MRI), GBM and MET are extremely similar, which makes differentiation by imaging extremely challenging. Therefore, this study explores an improved deep learning algorithm to assist in the differentiation of GBM and MET. For this study, axial contrast-enhanced T1 weight (ceT1W) MRI images from 321 cases of high-grade gliomas and solitary brain metastasis were collected. Among these, 251 out of 270 cases were selected for the experimental dataset (127 glioblastomas and 124 metastases), 207 cases were chosen as the training dataset, and 44 cases as the testing dataset. We designed a new deep learning algorithm called SCAT-inception (Spatial Convolutional Attention inception) and used five-fold cross-validation to verify the results. By employing the newly designed SCAT-inception model to predict glioblastomas and brain metastasis, the prediction accuracy reached 92.3%, and the sensitivity and specificity reached 93.5 and 91.1%, respectively. On the external testing dataset, our model achieved an accuracy of 91.5%, which surpasses other model performances such as VGG, UNet, and GoogLeNet. This study demonstrated that the SCAT-inception architecture could extract more subtle features from ceT1W images, provide state-of-the-art performance in the differentiation of GBM and MET, and surpass most existing approaches.

Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice.

Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.

Regnase-2 inhibits glioblastoma cell proliferation

Regnase-2 (Reg-2/MCPIP2/ZC3H12B) is uniquely expressed at a high level in the healthy brain and down-regulated in samples from patients with glioma, reaching the lowest level in high-grade glioblastoma multiforme (GBM). This RNase is involved in the regulation of neuroinflammation through the degradation of IL-6 and IL-1 mRNAs, key pro-inflammatory cytokines for GBM pathology. Reg-2 is a strong inhibitor of the proliferation of human glioblastoma cell lines and blocks their potential to form colonies. Here, we describe that overexpression of Reg-2 stalls glioblastoma cells in the G1 phase of the cell cycle and reduces the level of transcripts implicated in cell cycle progression. These newly identified targets include CCND1, CCNE1, CCNE2, CCNA2, CCNB1, and CCNB2, encoding the cyclins as well as AURKA and PLK1, encoding two important mitosis regulators. By RNA immunoprecipitation we confirmed the direct interaction of Reg-2 with the investigated transcripts. We also tested mRNA regions involved in their interaction with Reg-2 on the example of CCNE2. Reg-2 interacts with the 3’UTR of CCNE2 in a dose-dependent manner. In conclusion, our results indicate that Reg-2 controls key elements in GBM biology by restricting neuroinflammation and inhibiting cancer cell proliferation.

EMP3 as a prognostic biomarker correlates with EMT in GBM

BackgroundGlioblastoma (GBM) is the most aggressive malignant central nervous system tumor with a poor prognosis.The malignant transformation of glioma cells via epithelial-mesenchymal transition (EMT) has been observed as a main obstacle for glioblastoma treatment. Epithelial membrane protein 3 (EMP3) is significantly associated with the malignancy of GBM and the prognosis of patients. Therefore, exploring the possible mechanisms by which EMP3 promotes the growth of GBM has important implications for the treatment of GBM.MethodsWe performed enrichment and correlation analysis in 5 single-cell RNA sequencing datasets. Differential expression of EMP3 in gliomas, Kaplan–Meier survival curves, diagnostic accuracy and prognostic prediction were analyzed by bioinformatics in the China Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) database. EMP3-silenced U87 and U251 cell lines were obtained by transient transfection with siRNA. The effect of EMP3 on glioblastoma proliferation was examined using the CCK-8 assay. Transwell migration assay and wound healing assay were used to assess the effect of EMP3 on glioblastoma migration. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect the mRNA and protein expression levels of EMT-related transcription factors and mesenchymal markers.ResultsEMP3 is a EMT associated gene in multiple types of malignant cancer and in high-grade glioblastoma. EMP3 is enriched in high-grade gliomas and isocitrate dehydrogenase (IDH) wild-type gliomas.EMP3 can be used as a specific biomarker for diagnosing glioma patients. It is also an independent prognostic factor for glioma patients' overall survival (OS). In addition, silencing EMP3 reduces the proliferation and migration of glioblastoma cells. Mechanistically, EMP3 enhances the malignant potential of tumor cells by promoting EMT.ConclusionEMP3 promotes the proliferation and migration of GBM cells, and the mechanism may be related to EMP3 promoting the EMT process in GBM; EMP3 may be an independent prognostic factor in GBM.

Dabrafenib and trametinib as a promising treatment option for pediatric population with low-grade gliomas that have BRAF V600E mutation; a breakthrough in the field of neuro-oncology

Two-thirds of all pediatric malignant central nervous tumors, including high-grade (glioblastoma, anaplastic astrocytoma) and low-grade (ganglioglioma, pilocytic astrocytoma) carcinomas, are gliomas. Low-grade glioma (LGG) exhibits genetic alterations caused by the BRAF kinase mutation, such as replacing glutamic acid (E) in place of valine (V) at the 600 positions, known as the V600E point mutation. Pediatric low-grade gliomas (PLGGs) also comprise around one-third of juvenile brain tumors and are the most frequent central nervous system tumors. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). Where possible, complete surgical removal is the mainstay of treatment for progressing or symptomatic PLGG. Radiation therapy has historically been used to treat PLGG in both up-front and salvage scenarios. To delay or avoid the necessity for radiation therapy in young children with advancing or incompletely resected PLGG, chemotherapy was created in 1980. On 16 March 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from LGG who require systemic therapy and are at least one year old. Nevertheless, early-stage clinical trials have produced encouraging results that may revolutionize the treatment of LGG in the near future.

The Curious Case of a Glioblastoma Disguised as Lumbar Pathology in Orthopaedic Physical Therapy Practice

BACKGROUND: Glioblastoma is a primary brain tumor that shares symptoms with orthopaedic conditions like low back pain with radiating pain. The purpose of this case study was to describe a patient referred to physical therapy (PT) and subsequently diagnosed with a glioblastoma. CASE PRESENTATION: A 64-year-old male was referred to PT with right foot numbness and lower back pain. Initially, the patient was diagnosed with chronic low back pain with radiating pain (International Classification of Diseases and Related Health Problems, 10th Revision) related to lumbar spinal stenosis, and initial treatment resulted in significant reduction of foot numbness. After initial improvement, he reported an insidious onset of fasciculations and lacked response to therapy interventions, which warranted referral for imaging. OUTCOME AND FOLLOW-UP: Magnetic resonance imaging of the brain revealed high-grade glioblastomas, and the patient underwent a craniotomy for tumor resection with subsequent chemotherapy and radiation. DISCUSSION: Glioblastoma is an underreported condition in PT literature, and increased awareness of symptoms can improve recognition and appropriate referral. JOSPT Cases 2023;3(4):219-226. Epub 25 September 2023. doi:10.2519/josptcases.2023.11913

Primary Tumours of The Optic Disc and The Optic Disc Sheath

Primary optic nerve and optic nerve sheath tumors constitute approximately 8% of intraorbital tumors and although most of them are benign, they are manifested by findings that significantly affect visual function such as vision loss, visual field defect and proptosis. Tumors originating from the optic nerve trunk are mostly benign optic nerve glioma, but rarer tumors such as ganglioglioma, medulloepithelioma, hemangioblastoma, melanocytoma and high-grade glioblastomas such as malignant optic nerve glioma can also be detected. Tumors originating from the optic nerve sheath usually have optic nerve sheath meningioma (ONSM), of those with intraorbital and intracanalicular origin are classified as primary and intracranial ONSMs are classified as secondary tumors. Optic glioma, ONSM, and hemangioblastomas can be seen sporadically or as a component of Type 1 and Type 2 Neurofibromatosis (NF) and Von Hippel-Lindau (VHL) syndromes, respectively. Treatment with systemic chemotherapy, surgical resection and radiotherapy methods should be considered when progressive vision loss, visual field defect and cosmetically intolerable proptosis develop in optic nerve and nerve sheath tumors, which can have a quiet course for years in terms of visual function. While systemic chemotherapy is accepted as the main treatment method in optic gliomas, more successful results are obtained with specialized treatment methods such as stereotactic fractionated radiotherapy in ONSMs.