Temozolomide (TMZ), an oral alkylating agent, is a cornerstone of standard-of-care multimodality therapy for glioblastoma. In spite of significant efforts to treat this disease, the tumor carries a poor prognosis and is considered incurable largely due to the development of chemoresistance. One of the main mechanisms for this phenomenon is the activation of tumor DNA repair systems, such as O-6-methylguanine-DNA methyltransferase, that removes TMZ-induced DNA adducts and restores genomic integrity. Recent advances in the understanding of TMZ resistance oncobiology have introduced several novel independent molecular mechanisms involving epigenetic, transcriptomic, proteomic aberrations as well as alterations in apoptosis-autophagy processes, receptor tyrosine kinase activity, the tumor microenvironment, and the emergence of glioma stem cells. This article describes a multifaceted summary of the latest proposed causes for TMZ resistance and their complex interactions. It is believed that only by comprehending this growing network of interdependent mechanisms can effective combinatorial oncologic therapeutic strategies be developed to improve patient overall survival.

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Glioblastoma multiforme (GBM) is the most devastating and common primary malignant brain tumor in adults. Angiogenesis as a hallmark in glioblastoma has attracted more and more attention of the research community. Over the past years, several systematic studies have provided vital results in this field discovering alterations in unanticipated number of genes and other regulatory factors and the associated signaling pathways. Recent discoveries about such genes and signaling pathway associated with angiogenesis in GBM provide a picture of the genomic routes in angiogenesis and antiangiogenesis pathways and may lay the foundation for improved antiangiogenesis therapy and clinical care. In this review, we discuss several such recent progresses in the genes associated with GBM angiogenesis/antiangiogenesis pathways and explore the potential new targets for GBM treatment.

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Background: Molecular markers including isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion have been incorporated into the World Health Organization (WHO) 2016 classification of diffuse gliomas for integrated diagnostic reporting. The prognostic relevance of BRAF mutation among the newly established molecularly defined entities of gliomas remained relatively unexplored. Materials and Methods: We examined BRAF mutation in 578 adult diffuse gliomas and examined the clinical significance of the mutation in five histomolecular subgroups, namely oligodendrogliomas, IDH-mutant and 1p/19q-codeleted (Group I), astrocytomas, IDH- mutant (Group II), astrocytomas, IDH-wild-type (Group III), glioblastoma, IDH-mutant (Group IV), and glioblastoma, IDH-wild type (Group V). Results: Mutation rate of BRAF was 5.9% across the whole cohort and was 4.9%, 7.5%, and 7.0% in Group II, Group III, and Group V gliomas, respectively. Univariate analysis revealed a trend of poor overall survival in BRAF-mutant tumors among Group II gliomas, a trend which was also demonstrated by multivariable analysis. Among Group III and Group V gliomas, BRAF-mutant tumors seemed to exhibit more favorable survival in univariate analysis. Multivariable analysis further demonstrated the favorable prognostic significance of BRAF mutation in Group III (hazard ratio [HR] = 0.31, 95% confidence interval [CI] = 0.10–0.95, P = 0.04) and Group V gliomas (HR = 0.44, 95% CI = 0.18–1.09, P = 0.077). Conclusion: BRAF mutation appears to mark out a small subset of adult infiltrative gliomas with the distinct clinical outcome. Mutational analysis of BRAF can potentially contribute to the clinical risk stratification in the management of glioma patients in the context of the WHO 2016 classification.

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High-grade gliomas (HGGs) in pediatric age have the same bad prognosis as those arising in adults. Approximately one-half of HGGs in children occur in the brain stem, most frequently within the pons as diffuse intrinsic pontine glioma or other midline structures. Although they have the same histological appearance of adult malignant gliomas, in recent years, the extensive use of molecular profiling techniques has demonstrated significant molecular differences between the two age groups. These data have led to a major reclassification of pediatric HGG (pHGG) based on molecular subgrouping with significant clinical correlations in terms of age at presentation, anatomical location, and prognosis. The most important molecular groups are: (1) the histone mutations related pHGG, that is, H3.K27-mutated midline and H3.G34-mutated hemispheric pHGG; (2) the rare isocitrate dehydrogenase (IDH)-mutated pHGG occurring mainly in adolescents; and (3) the H3-/IDH wild type, a heterogenous group of pHGG still object of further molecular stratification. Another important group of pHGG is that occurring in patients with cancer predisposition syndromes such as Li-Fraumeni syndrome, constitutional mismatch repair deficiency, and neurofibromatosis-1 (NF1). In this review, the different subgroups of pHGG and their major driver molecular alterations will be discussed.

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The prognosis of patients with cerebral gliomas remains noticeably poor. Total surgical resection is almost unachievable due to considerable infiltrative ability of glial cells. Furthermore, adjuvant treatments are burdened by considerable limitations. Angiogenesis is the mechanism by which new blood vessels are formed from preexisting ones, thus supporting neoplasm progression. Gliomas are characterized by extensive microvascular proliferation. The extent of neovascularization in brain tumor correlates directly with the biological aggressiveness, degree of malignancy, and clinical recurrence of the tumor. Although a plethora of molecules can act as inducers of angiogenesis, the major growth factors include members of the vascular endothelium growth factor family. The new therapeutic approaches envisage the identification of specific biomarkers involved in this process and try to inhibit them, thus slowing down the neoplastic progression. Nanoparticles (NPs) show the ability to pass the blood–brain barrier, and moreover, when suitably modified, they can bind to specific overexpressed receptors in the glial cells. As carriers, they are able to protect the therapeutic agent and allow their sustained release. In this review, we describe some NP delivery systems which target specific biomarkers to intervene in the process of angiogenesis.

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Background: The alkylating agent temozolomide (TMZ) is widely used in glioblastoma multiforme (GBM) therapy. Unfortunately, TMZ-resistance frequently occurs in recurrent GBM and is the major cause of treatment failure. The anti-malarial drug quinacrine (QC) harbors antitumor and chemosensitivity properties, but its interactions with TMZ in GBM remain unclear. This study aimed to investigate whether QC would sensitize TMZ in TMZ-sensitive and TMZ-resistant GBM cells as well as the underlying mechanisms. Materials and Methods: The cytotoxicity of QC and TMZ in TMZ-sensitive and TMZ-resistant GBM cells was evaluated using in vitro cell viability assay and colony formation assay. Cellular apoptosis and protein expression levels were determined using TUNEL assay and immunoblotting, respectively. Results: QC substantially enhanced TMZ cytotoxicity in both TMZ-sensitive and TMZ-resistant cells. Such cytotoxic effect was accompanied by changes in the expression levels of LC3II, p62 and cleaved caspase 3, and increased cellular apoptosis. The results suggested that QC could sensitize GBM cells to TMZ at least partially through apoptosis induction, in which autophagy inhibition might be involved. Conclusion: The antimalarial drug QC may hold promise as a potentiation of TMZ treatment in GBM, especially in cases of TMZ-resistance.

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Background: YKL-40 has been reported to be associated with the prognosis of glioma patients. However, expression of YKL-40 was detected at protein or mRNA level in different studies. This may result in conclusion bias. This study is to investigate the prognostic value of increased YKL-40 protein versus mRNA expression in glioma patients. Methods: A comprehensive systematic search and review were performed using PubMed, EMBASE, and NKI databases to identify literature (published before May 1, 2018) that evaluated the association between YKL-40 and survival in glioma patients. Results: Thirteen relevant studies, involving 2139 patients, were included in this study. Elevated YKL-40 expression was associated with worse overall survival (OS) in glioma patients (hazard ratio [HR] = 1.44, 95% confidence interval [CI]: 1.27–1.63, P < 0.001), especially in high-grade glioma (anaplastic glioma: HR = 1.37, 95% CI: 1.09–1.74, P = 0.008; glioblastoma multiform: HR = 1.52, 95% CI: 1.33–1.73, P < 0.001). The increased YKL-40 protein level in serum (detected by ELISA) or in tumor tissues (detected by immunohistochemistry) was associated with worse OS (ELISA: HR = 1.43, 95% CI: 1.29–1.59, P < 0.001; immunohistochemistry: HR = 1.52, 95% CI: 1.20–1.93, P = 0.001). However, the association between elevated YKL-40 mRNA level (detected by real-time PCR) with worse OS was not significant (HR = 1.44, 95% CI: 0.73–2.83, P = 0.29, I² = 68.3%). In addition when status of IDH1 mutation or/and O⁶-methylguanine-DNA methyltransferase promoter was incorporated as multivariate, increased expression level of YKL-40 was not associated with poorer survival (HR = 1.39, 95% CI: 0.99–1.93, P = 0.055). Conclusion: YKL-40 protein level, rather than mRNA level, may be a valuable biomarker to assess the prognosis in glioma patients.

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The 2016 updated World Health Organization Classification of Tumors of the Central Nervous System shows an increasing number of entities under the classification of neuronal and mixed neuronal-glial tumors. Despite being a biogenetically heterogeneous group of tumors, the members frequently display some overlapping histological and clinical features, leading to diagnostic dilemmas among neuropathologists, especially when the aid of advanced molecular and immunohistochemical tools is not available. Nonetheless, meticulous assessment of the morphological features with careful interpretation of the immunophenotypes can be rewarding often without the investment of an expensive molecular investigation. We propose a method of approaching the neuronal-glial tumors based on pattern recognition. We briefly discuss the key histological features that are helpful in narrowing down the differentials, with the aid of immunohistochemistry or available molecular information, directing the pathologist toward the correct diagnosis.

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Background: Glioma, notably glioblastoma multiforme, is characterized by extensive inter-and intra-tumoral heterogeneity. Surprisingly, the potential for differentiation of glioma cells has not been systematically analyzed and included in patient stratification methods. In the current study, retinoic acid (RA), a neuronal differentiation agent, was assessed for the pro-differentiative and anti-proliferative effects on glioma cells. Methods: Using RA-responsive glioma culture as an experimental paradigm, we analyzed the differentiation process both by videomicroscopy and at the mRNA (RNA-seq and reverse transcription-quantitative-polymerase chain reaction) and proteomic levels. Results: Glioma cells can differentiate into neurons in response to RA by (i) extending ultra-long cytoplasmic extensions, (ii) using these extensions to move from cell to cell either by perikaryal translocation or in a "spider-flight" like process, (iii) slowing their cell cycling, (iv) acquiring several neuronal differentiation markers such as MAPT, GAP43, DCX, NRCAM, NeuroD2, NeuroG2, and NeuN, and (v) decreasing the expression of several genes associated with glioma aggressiveness. Conclusion: These results indicate the existence of a subgroup of patients harboring RA-responsive glioma cells amenable to differentiation therapy, and stratifying such patients with a functional test is easily achievable. This provides the first step to reassess the potential of RA in the context of personalized medicine.

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Background: Venous thromboembolism is a common complication in patients with glioma. The clotting factor von Willebrand factor (VWF) is a highly adhesive procoagulant molecule that mediates platelet adhesion to endothelial and subendothelial surfaces. In the current analysis, we examined The Cancer Genome Atlas (TCGA) data to assess the effect of VWF gene expression on prognosis in patients with lower grade gliomas (LGGs). Methods: For newly diagnosed gliomas, we evaluated the association between VWF and overall survival in the genomic data commons TCGA LGG dataset in TCGA. Survival data of the glioma subgroup were extracted for analysis and generation of Kaplan–Meier curves for overall survival. Results: Lower grade gliomas with less VWF gene expression had significantly better survival than those with more VWF gene expression (hazard ratio 0.64, 95% confidence interval 0.44–0.92, P = 0.015 log rank test). The effect of VWF gene expression on survival was even more evident when the sample was analyzed as three groups (P = 0.00019). IDH1, TP53, and ATRX mutations are present in 40% or more adult LGGs. Conclusion: The deleterious prognostic effect of VWF expression in LGGs is not surprising, given its role in other cancers. Therefore, VWF gene expression may be a clinically important risk marker in LGG.

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Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m² per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m² per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.

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Myeloid-derived suppressor cells (MDSCs) are a subgroup of immunosuppressive heterogeneous cells derived from bone marrow (BM) stem cells. They not only strongly inhibit T cell-mediated antitumor immune response but also directly induce tumorigenesis and promote tumor growth and metastasis. Besides, the nonresolving inflammation (NRI), a prime cause of tumor development, is present in the glioma microenvironment. However, the relationship between MDSCs and NRI, especially in the view of relevant molecular regulatory networks, has not been fully elucidated in gliomas. In the present study, the MDSC- and NRI-associated molecular regulatory network and key regulatory points are reviewed, and the targeted therapeutic strategies against gliomas are further discussed.

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Background: Vasculogenic mimicry (VM) describes the functional plasticity of aggressive tumor cells to form newly recognized microcirculation, lined by tumor cells rather than endothelial cells, in solid tumors. The presence of VM in glioma is significantly associated with high tumor grade and poor prognosis. However, whether VM is a regular feature or only a temporary phenomenon during glioma growth is unknown. This study was designed to observe VM during the growth of subcutaneous and orthotopic xenograft glioma in Balb/c nude mice. Methods: The human glioblastoma cell line (U87) was used as xenografts in Balb/c nude mice models. The xenografts were obtained at different stages of tumor growth, and evaluated for VM and endothelium-dependent vessels by dual staining for endothelial marker CD34 and periodic acid-Schiff (PAS). Results: It was found that the PAS-positive patterns which were identified as VM were persistent during tumor growth of both subcutaneous and orthotropic xenografts. Further analysis showed that the microvessel density (MVD) of endothelium-dependent vessels was positively correlated with the tumor size of subcutaneous xenograft (r = 0.406, P = 0.009), while no significant correlation was found between VM density (VMD) and the tumor size (r = 0.107, P = 0.512). Furthermore, VMD was negatively correlated with MVD (r = −0.404, P = 0.010). Conclusion: The study results revealed that both VM and endothelium-dependent vessels coexist persistently during glioblastoma xenograft growth, indicating that VM may complement microcirculation in gliomas.

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Background and Aim: Mechanisms of glioma progression are poorly understood. Upregulation of calcium-activated potassium channel subunit alpha-1 (KCNMA1), which encodes the α-subunit of maxi-calcium-activated potassium (BK_Ca) channels, is shown to be a novel mechanism for the malignant phenotype of brain tumor cells. The aim of this study was to establish the functional role of KCNMA1 in glioma biology. Materials and Methods: U-87-MG (U-87) cells were transfected to increase BK_Ca channel expression and activity. Glioma cell proliferation, invasiveness, and transendothelial migration were then measured. BK_Ca channels were blocked with iberiotoxin or short hairpin RNA (shRNA), which significantly inhibited K+ currents and growth of U-87 cells. It was tested whether KCNMA1 overexpression enhanced tumorogenecity in glioma xenograft mouse models by injecting wild-type and KCNMA1- overexpressing U87-MG cells. In parallel experiment, it was studied whether shRNA KCNMA1-expressing U-87 cells show attenuated glioma growth in mice. The study protocol was approved by the Institutional Animal Care and Use Committee, Mercer University (A0706007_01), Atlanta, GA, USA on July 20, 2007. Results: The effect of KCNMA1 overexpression in glioma growth as well as on associated cell biology functions such as proliferation, invasion, and migration was presented in this study. Messenger RNA and protein analyses revealed that KCNMA1 was amplified in 90% of high-grade gliomas and in high-grade glioma cell line U-87. In contrast, KCNMA1 amplification was not found in normal brain tissues. These data indicate that KCNMA1 plays critical role in glioma biology by interacting with several cellular processes. The data demonstrate that KCNMA1 amplification drives glioma cell proliferation and growth, which can be attenuated by its downregulation. Conclusion: KCNMA1 is a regulator of glioma cell proliferation and growth and thus qualifies as a promising diagnostic and therapeutic target in the treatment of glioma.

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Background and Aim: Brain tumors are a fairly common neurological problem in Nigeria and associated with a relatively low morbidity and mortality rate. Magnetic resonance imaging is the best imaging modality revealing precisely the tumor's location, patterns, and to some extent, the tumor characterization; however, only computed tomography (CT) is readily available in the study locality. In this study, we assessed the patterns of CT findings among patients diagnosed with a brain tumor using CT. Materials and Methods: This was a retrospective study, in which brain CT records of 40 cases of brain tumor diagnosed between January 2016 and August 2018 were reviewed, irrespective of patient age, sex, or clinical information. This study was approved by the Human Research Ethical Committee of the Federal Neuro-Psychiatric Hospital, Maiduguri (approval No. FNPH/GEN/092/VOLII) on December 22, 2015. Results: Of the 40 brain tumors diagnosed during the study, 17 (42%) cases were male and 23 (58%) were female. Their age range was 2–70 years (28.4 ± 20.2 years). About 22% of cases were extra-axial, whereas 31 (78%) were intra-axial. Twenty-seven (68%) patients had definitive diagnosis, with eight (20%) cases being meningioma, whereas 13 (32%) had nonspecific findings (a longer differential diagnosis). Conclusion: Meningioma was the most common type of brain tumor in this study despite the limitation of histopathology facility within the immediate locality. The low rate of glioma was probably due to few old adults included in the study.

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Background and Aim: The standard-of-care for patients with glioblastoma (GBM) is surgery followed by concurrent chemotherapy with temozolomide and radiotherapy. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is commonly assessed in GBM as a predictive marker of response to temozolomide. Although MGMT methylation status has been shown to change between primary and recurrent GBM, no indication exists on retesting MGMT in recurrent GBM. In addition, what causes the change in MGMT methylation has yet to be identified. In this study, we aimed to investigate whether MGMT promoter methylation in recurrent GBM was influenced by intratumor heterogeneity in the initial GBM tumor. Materials and Methods: We investigated the status of MGMT promoter methylation in different samples taken from concentric layers of 24 GBMs and in 11-paired surgically resected recurrences. The neoplastic nature of samples submitted for methylation analysis was preliminary verified through histological examination; the fragments were accurately chosen to have adequate cellularity and minimal amount of nontumor contaminants. Results: About 27% (3 out of 11) of the recurrences had changed MGMT methylation status compared to the initial tumor. Initial tumor heterogeneity might play a role in this change, as all three cases had intratumor heterogeneity (with the central part of the tumor methylated and the peripheral part unmethylated) in the primary GBM. Conclusion: This study suggests that MGMT methylation variation in recurrent GBM may depend on intratumor heterogeneity in the initial tumor. Intratumor heterogeneity and possible changes in the recurrence should be taken into account when testing MGMT promoter methylation status as a predictive factor orienting therapeutic decisions in patients with GBM.

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Glioma is the most common primary tumor of the central nervous system. In addition to traditional anticancer drugs, some common nonchemotherapeutic drugs have been considered by some scholars, such as nonsteroidal anti-inflammatory drugs, metformin, and statins. These drugs are often used for the treatment of noncancerous diseases. However, it was found that those drugs could be considered for the clinical treatment of glioma, especially in combination with chemotherapy drugs, which may improve the treatment effect. This process is called “repurposing.” Here, we aim to review these drugs and the literature. These “old drugs” have been used clinically for many years, and their safety and feasibility are high. Such combinations are expected to become a new strategy in chemotherapy for glioma in the clinic.

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Gliomas are the most common primary central nervous system malignancy and have an overall poor prognosis, despite aggressive treatment. Understanding the immune microenvironment of these fatal tumors will advance discovery of immune-related therapeutic targets. Natural killer (NK) cells are innate lymphoid cells that constitute the first line of host-tumor immune responses since these cells do not require prior sensitization or tumor antigen recognition to kill. NK cells kill tumor cells by recognizing stress-induced ligands expressed on tumor cells, thereby providing an efficient path to early tumor cytolysis. Dysregulation of NK-mediated immunity plays a prominent role in immune escape for glioblastoma (World Health Organization Grade IV gliomas) and for various low-grade diffuse gliomas. Thus, the biology of NK cells is fertile ground for identifying novel immunotherapeutic targets in glioma. This review discusses the biology of NK cells as well as the potential applications for immunotherapy in the treatment of gliomas.

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To date, information on the management of specific neurosurgical tumors, such as glioma, in Pakistan remains scattered and scarce. Our review synthesizes the predicaments of glioma management routinely presented to the neurosurgery, medical oncology, radiation oncology, and radiology departments in Pakistan. Expert opinions were integrated from each of the relevant fields in the form of personal citations. The data presented in our review were collected from various PubMed and non-PubMed indexed articles, coupled with various health reports from the Government of Pakistan along with the World Health Organization. Through these data, it was postulated that the utilization of innovative and instrumental technologies is a constant struggle for neurosurgeons in Pakistan, considering the cost-effectiveness. Hence, this results in significant limitations for surgeons to provide the best outcome for their patients. As most Pakistanis (74%) pay out of pocket, measuring cost-effectiveness is extremely crucial. It was found that significant differences in intra-operative and postoperative care existed among various centers. Public sector institutions fared much worse. The role of diagnostics in glioma surgery is severely limited across centers in Pakistan and as such, research and training need to be addressed promptly. In order to achieve success in glioma management, the data in our article demonstrate various facets of health care that need to be addressed simultaneously and swiftly. Surgical access needs to be improved; only then, optimal management of glioma can be accomplished in Pakistan.

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Glioblastoma is associated with poor prognosis with a mean survival of 15 months after diagnosis. The current standard of care includes surgery, radiation, and temozolomide with the use of tumor-treating fields in select patient population. The past decade has witnessed a convergence in our understanding of tumor biology and the role of the immune system in fighting cancer. The highly immunosuppressive tumor microenvironment exerted by glioblastoma cells has contributed to the lack of success of novel immunotherapies till date (including checkpoint inhibitors). Oncolytic viral-based approaches are of renewed interest given advances in tumor cell tropism, pathogenicity, and immunogenicity. More importantly, oncolytic viruses have been shown to initiate a broad immune response through various mechanisms including dual activation of the innate and adaptive arms of the host immune system. Because the initial clinical studies with monotherapy checkpoint inhibition in glioblastoma have failed to demonstrate a survival advantage, most trials in glioblastoma are testing combinations that seek to augment the immune response through mutually reinforcing approaches that can overcome the immunosuppressive milieu. Preclinical data in glioblastoma models with combined oncolytic viruses therapy and checkpoint blockade are favorable and provide rationale to initiate first-in-human trials. Even though the number of clinical trials testing this combination in glioblastoma is limited, more studies are expected in the future.

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Conventional immunotherapy in the treatment of glioblastoma (GBM) has essentially produced no significant advantage over the use of chemotherapeutic drugs. A strongly immunosuppressive tumor microenvironment and lack of antigen-presenting major histocompatibility expression on tumor cells have made GBM a poor immunological target. Molecular heterogeneity of GBMs, both within the tumor and across patients, results in the immunological escape of tumors that do not express target antigens. Therefore, the development of nonconventional immunotherapy for GBM is continuously being sought. γδ T cells are a minor subset of the human T-cell repertoire with unique antitumor properties that have been shown to be functionally superior to conventional αβ T-cell receptor expressing T cell-based immunotherapy for cancer, including GBM. Unlike, the more abundant αβ T cells, γδ T cells do not require major histocompatibility proteins for activation. In addition to the γδ T-cell receptor, these cells express a plethora of other antigenic receptors that recognize external stimuli, as well as several self-peptides, which make these cells a strong candidate for the development of cancer immunotherapeutics. A higher threshold of activation-induced cell death and resistance to inducing graft-versus-host disease are also characteristics of these T cells. In this review, we discuss the biology and immunological characteristics of γδ T cells and review current research using γδ T cells in GBM immunotherapy to explore whether these cells can be the potential next-gen immunotherapeutic candidate for this dreadful disease.

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The investigation and development of recently introduced agents or radiological measurements caused emergent misunderstandings to the response assessment of glioma. To date, the classical Macdonald criteria and the response assessment of neuro-oncology (RANO) criteria have been used successively for the evaluation of glioma outcome. However, ongoing efforts on complementary assessments are necessary to combat this malignancy. In this review, we highlight the shortcomings of the current criteria and introduce the initiative effort of RANO guideline and its offspring. We also discuss some future barriers for accurate assessment of treatment response in glioma.

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Glioblastoma (GBM) is the most common and fatal type of malignant central nervous system tumor with high invasion. The median overall survival of GBM is only around 14 months by standard treatment, which conventionally consists of surgical resection, followed by radiotherapy and adjuvant chemotherapy with temozolomide (TMZ). Currently, TMZ, carmustine, lomustine, and bevacizumab are the therapeutic drugs for GBM approved by the US Food and Drug Administration. Due to the progress of molecular genetics in tumor therapy, new targeted therapy drugs are continuously emerging for GBM. Meanwhile, immunotherapies, such as immune checkpoint inhibitors, tumor vaccines, and chimeric antigen receptor T (CAR-T) cell therapy, have also made great achievements in clinical trials. The combination of molecular targeted therapy and immunotherapy of GBM has become the focus of current research. It shows promise in GBM treatment and gives new hope to patients. This review focuses on recent advances in targeted therapy and immunotherapy and discusses their combined treatment of GBM.

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Midline astrocytic neoplasms have distinct molecular characteristics, quite different from astrocytic neoplasms with similar morphology but not located in the midline. It is imperative that neuropathologists should be aware of the existence of these tumors, so they can be correctly diagnosed. Here, we discuss the case of a 14-year-old boy who presented with acute onset of vomiting followed by loss of consciousness. Subsequent magnetic resonance imaging revealed an ill-defined exophytic lesion arising from the brainstem and extending into the left cerebellopontine angle, with areas of hemorrhage and patchy restricted diffusion. The tumor was resected. Microscopy revealed medium-sized tumor cells in diffuse sheets, having round nuclei, granular chromatin, and scant cytoplasm. Microvascular and endothelial cell proliferation in small necrotic areas were seen. Mitosis was 0–1 per high-power field. By routine histopathological analysis, all features were consistent with the diagnosis of glioblastoma. Tumor cells were immunopositive for glial fibrillary acidic protein and isocitrate dehydrogenase-1 mutation (R132H), immunonegative for p53, and retained alpha thalassemia/mental retardation syndrome X-linked. It also showed a strong immunopositivity for H3-K27M mutation. A diagnosis of a diffuse midline glioma with H3-K27M mutation corresponding to the World Health Organization Grade IV was made. This case highlights the importance of exploring signature mutations in well-defined tumor categories such as H3-K27M-mutant diffuse midline glioma.

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