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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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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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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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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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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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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Gliomas are the most common primary brain tumors, the grading of which is associated with biological behavior and prognosis. With rapid advances in our understanding of glioma biology and a move toward personalized medicine, it is important to obtain a greater understanding of these tumors, beyond that provided by conventional neuroimaging. “Imaging genomics” is an emerging field which has an immense potential to greatly expand our understanding of glioma behavior. This article reviews the relationship between the radiologic and genomic features of gliomas, which may aid in personalizing patient treatment.

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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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The newly released World Health Organization Classification of Tumors of the Central Nervous System 2016 has implemented molecular information in the classification of brain tumors. A number of large-scale retrospective studies have indicated that molecular data are of diagnostic and prognostic relevance in neuro-oncology. Incorporation of molecular studies has become a prerequisite in standard-of-care practice of neuro-oncology. Next-generation sequencing (NGS) or massively parallel sequencing allows simultaneously sequencing millions of DNA fragments in an acceptable period. The technique allows examination of a number of genes and gene regions simultaneously and is capable of detecting a wide variety of molecular alterations. NGS has been rapidly adopted in cancer studies to identify mutational landscape, copy number variation, novel fusion genes, and others. With its rapidly declining cost, NGS is slowly replacing conventional molecular techniques in cancer diagnosis. In this review, we will review the development of NGS and common sequencing strategies in oncology laboratories. We will then discuss the application of NGS in detecting genetic aberrations in neuro-oncology.

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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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Historically, brainstem gliomas have been one of the most difficult types of neoplasms to treat. They comprise 10%–20% of pediatric tumors of the central nervous system. The average age of diagnosis is 7–9 years, without a predilection for gender. The advent of magnetic resonance imaging and radiotherapy has significantly aided in the diagnosis and treatment of brainstem gliomas.

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Glioblastoma (GBM) is the most common primary central nervous system tumor, and despite advances made in traditional chemotherapy and radiation, it continues to carry a poor prognosis. The discovery of the profound immunosuppressive microenvironment created by GBM has given insight on the aggressiveness of this recalcitrant disease. This has led many to believe that immune therapy may yield the improvement in survival that the neuro-oncology community is seeking. In other cancers, the targeting of immune checkpoints has been the most promising immunotherapeutic strategy to date. Immune checkpoints modulate the function of the immune system by increasing or decreasing immune activity. Checkpoint inhibitors and more recently agonists target molecules that regulate immune response to increase immune function either directly or by removal of inhibitory signals. These molecules modulate immunity in the physiologic state to maintain homeostasis, but they are co-opted by cancer to avoid immune detection and attack. The use of checkpoint inhibition to improve cancer therapy has revolutionized the field of oncology, leading to unprecedented improvements in survival from many systemic malignancies. Utilizing PubMed and ClinicalTrials.gov to compile published findings and ongoing trials, we review immune checkpoints and their modulators from bench to bedside over several decades. In this review, the discovery of different checkpoint molecules and the development of drugs used to target them are addressed. In addition, the current state of checkpoint inhibition in GBM, presenting completed and ongoing preclinical and clinical studies utilizing these therapies, is discussed. Finally, we conclude by reviewing the current limitations and potential future directions for the use of checkpoint blockade in the treatment of GBM.

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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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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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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: 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 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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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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Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median survival rate of GBM patients is approximately 14 months and tumor recurrence is almost inevitable. With the increased use of immunotherapy, immune response and edema found on posttreatment magnetic resonance imaging (MRI) may be misinterpreted as tumor progression. Distinguishing the true radiographic progression from pseudo-progression by MRI is often difficult. Peripheral biomarkers are needed to identify the true tumor recurrence and evaluate therapy response. Exosomes isolated from both blood and cerebrospinal fluid are cargo containers utilized by eukaryotic cells to exchange biomolecules such as proteins, mRNA, and microRNA (miRNA). These biomolecules participate in cell-cell communication, cell migration, angiogenesis, and tumor growth. Isolation of RNA (including miRNA) from exosomes can yield a greater concentration compared with circulating mRNA directly taken from body fluid as molecules within exosomes are not degraded by nucleases and proteases. Not only are exosomes a novel approach to biomarker detection, but they may also provide potential therapeutic interventional targets. In addition, exosomes are critical in miRNA replacement therapy as they can act as a carrier for anticancer drug delivery. This review focuses on the advances in basic research of exosome-related potential biomarkers and discusses their potential application in the diagnosis, prognosis, and treatment of GBM.

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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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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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Glioblastoma (GBM, WHO Grade IV) is the most aggressive form of primary brain cancer in adults, and as with other cancers, clinical investigations to use immunotherapy as a possible therapeutic option for GBM are underway. One form of immunotherapy is immune checkpoint inhibition that targets the programmed cell death-1 (PD-1) receptor on lymphocytes. While PD-1 receptor inhibitors, such as pembrolizumab, are often tolerable, there can be dose-limiting immune-related adverse effects, which have the potential to result in impaired health-related quality of life. This case report discusses one patient with recurrent GBM who received pembrolizumab and developed refractory drug-induced arthritis.

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Background: Cytoplasmic activation/proliferation-associated protein-1 (caprin-1) is a newly discovered RNA-binding protein and is now recognized as one of the putative oncogenes. This study was performed to reveal its presence in human gliomas and its oncogenic functions in human glioblastoma-derived Denver brain tumor research group 05 (DBTRG-05MG) cells. Materials and Methods: Clinical glioma samples were cumulatively collected for the identification of caprin-1 using immunoblot analysis and immunofluorescence detection. DBTRG cells transfected with caprin-1-specific small interfering RNA (siRNA) were used to verify caprin-1's oncogenic function using a real-time cell analyzer (RTCA) and scratch assay. Results: Seven of eight collected glioma samples were identified as positive for caprin-1 expression. siRNA dose-responsive inhibition of cell proliferation was observed in DBTRG cells with RTCA, and cell migration rate was significantly reduced by siRNA transfection (P < 0.05). Conclusion: The present study identified the higher expression of caprin-1 in human glioblastoma-derived DBTRG cells. Its oncogenic functions, mainly enhanced cell proliferation and promoted cell migration capacity, were also verified in these cells. This study provided fundamentals for developing caprin-1 as a therapeutic target for the treatment of gliomas.

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Background: Spinal cord glioblastoma multiforme (SCGBM) is an extremely rare malignant tumor. The study aims to present the clinical and imaging features of SCGBM. Methods: The clinical and magnetic resonance imaging (MRI) characteristics of 12 pathologically proven SCBGM patients were retrospectively analyzed. Results: Three major MRI findings are as follows: (1) Mixed hypo-isointense signal on T1-weighted image (T1WI) and hyper-isointense signal on T2WI in all cases, (2) All except two patients demonstrated slight syringomyelia at upper or lower side of the lesion, and (3) Post-gadolinium-diethylenetriamine pentaacetic acid, a heterogeneously enhanced lesion with the crab foot-like shape on the map was seen in 11/12 cases. Clinically, pain in neck and waist was reported in 7 cases (58%) and progressive weakness of both lower extremities in 6 patients (50%). Gross total resection in 3 cases (25%) and subtotal resection in 9 cases (75%) were achieved. The most common postoperative complication was spinal instability, developed in 3 patients. The progress-free survival of surgery, surgery + temozolomide (TMZ), and surgery + TMZ + radiation treated patients was 2.50, 7.75, and 12.66 months, respectively. The overall survival of surgery, surgery + TMZ, and surgery + TMZ + radiation treated patients was 5.50, 15.25, and 24.00 months, respectively. Conclusion: The study reported MRI features in a large series of SCGBM. The trimodal therapy could provide longer survival for SCGBM patients.

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Treatment-related lymphopenia is a poor prognostic factor for overall survival in patients with high-grade glioma and predicts suboptimal response to immune therapies. Immunotherapy is conceptually an appealing approach in adults with high-grade glioma given that effector lymphocytes are capable of penetrating the blood–brain barrier. However, 40% of these patients develop severe lymphopenia (CD4 counts <200) following concurrent radiation and temozolomide. These low lymphocyte counts are associated with inferior survival. Research suggests that this iatrogenic immunosuppression is attributed to the inadvertent radiation of circulating lymphocytes as they traverse the irradiated field. Lymphocyte subtypes are universally affected by this radiation toxicity. These findings have been reproduced in animal studies, and clinical correlations have been demonstrated in patients with various malignancies. This lymphopenia has been linked with failure to respond to immunologic interventions. Recent insights into the etiology of this radiation-induced lymphopenia have triggered a variety of novel approaches to prevent or restore immunologic function in this patient population. These include altering radiation plans, reducing the number of lymphocytes passing through the radiation field, harvesting lymphocytes before and reinfusing them after radiation, and using growth factors to restore lymphocyte counts. This manuscript reviews critical relationships between treatment-related lymphopenia and immunotherapy outcomes in patients with high-grade gliomas and novel approaches to these issues.

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