Search

PurposeUnderstanding the complex bidirectional interactions between neurons and glioma cells could help to identify new therapeutic targets. Herein, the techniques and application of novel neuroscience tools implemented to study the complex interactions between brain and malignant gliomas, their results, and the potential therapeutic opportunities were reviewed.MethodsLiterature search was performed on PubMed between 2001 and 2023 using the keywords "glioma", "glioblastoma", "circuit remodeling", "plasticity", "neuron networks" and "cortical networks". Studies including grade 2 to 4 gliomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas were considered.ResultsGlioma cells are connected through tumour microtubes and form a highly connected network within which pacemaker cells drive tumorigenesis. Unconnected cells have increased invasion capabilities. Glioma cells are also synaptically integrated within neural circuitry. Neurons promote tumour growth via paracrine and direct electrochemical mechanisms, including glutamatergic AMPA-receptors. Increased glutamate release in the tumor microenvironment and loss of peritumoral GABAergic inhibitory interneurons result in network hyperexcitability and secondary epilepsy. Functional imaging, local field potentials and subcortical mapping, performed in awake patients, have defined patterns of malignant circuit remodeling. Glioma-induced remodeling is frequent in language and even motor cortical networks, depending on tumour biological parameters, and influences functional outcomes.ConclusionThese data offer new insights into glioma tumorigenesis. Future work will be needed to understand how tumor intrinsic molecular drivers influence neuron-glioma interactions but also to integrate these results to design new therapeutic options for patients.

Glioma is the most common primary intracranial tumor in adults, with high incidence, recurrence, and mortality rates. Tumor-associated neutrophils (TANs) are essential components of the tumor microenvironment (TME) in glioma and play a crucial role in glioma cell proliferation, invasion and proneural-mesenchymal transition. Besides the interactions between TANs and tumor cells, the multi-dimensional crosstalk between TANs and other components within TME have been reported to participate in glioma progression. More importantly, several therapies targeting TANs have been developed and relevant preclinical and clinical studies have been conducted in cancer therapy. In this review, we introduce the origin of TANs and the functions of TANs in malignant behaviors of glioma, highlighting the microenvironmental regulation of TANs. Moreover, we focus on summarizing the TANs-targeted methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of TANs in the malignant glioma microenvironment. [ABSTRACT FROM AUTHOR]

High-grade glioma (HGG) is one of the most deadly and difficult cancers to treat. Despite intense research efforts, there has not been a significant breakthrough in treatment outcomes since the early 2000's. Anti-glioma gene therapy has demonstrated promise in preclinical studies and is under investigation in numerous clinical trials. This manuscript reviews the current landscape of clinical trials exploring gene therapy treatment of HGG. Using information from clinicaltrials.gov, all trials initiated within the past 5 years (2018–2023) as well as other important trials were cataloged and reviewed. This review discusses trial details, innovative methodologies, and concurrent pharmacological interventions. The review also delves into the subtypes of gene therapy used, trends over time, and future directions. Trials are in the early stages (phase I or II), and there are reports of clinical efficacy in published results. Synergistic effects utilizing immunotherapy within or alongside gene therapy are emerging as a promising avenue for future breakthroughs. Considerable heterogeneity exists across trials concerning administration route, vector selection, drug combinations, and intervention timing. Earlier intervention in newly diagnosed HGG and avoidance of corticosteroids may improve efficacy in future trials. The results from ongoing trials demonstrate promising potential for molding the future landscape of HGG care. [ABSTRACT FROM AUTHOR]

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions. The brain was removed 24 h after the i-PDT and analyzed pathologically. The optical fiber was able to puncture the tumor center in all cases, enabling i-PDT to be performed. Histological analysis showed that tumor necrosis was induced in areas close to the light source, correlating with the irradiation energy dose, whereas apoptosis was induced at some distance from the light source. Irradiation using high energy levels resulted in tissue swelling from strong tumor necrosis, and irradiation at 75 J/cm2 was most suitable for inducing apoptosis. An experimental system of i-PDT using TPS was established using malignant glioma cells transplanted into the rat brain. Tumor cell death, which correlated with the light propagation, was induced in tumor tissue. [ABSTRACT FROM AUTHOR]

Objective: Neurooncological patients are well-known to experience an increased psycho-oncological burden with a negative impact on distress, therapy adherence, quality of life, and finally survival. But still, psycho-oncological screening and support is rare, with ongoing discussion about specific screening time points and impact factors. Therefore, we analysed the psycho-oncologic treatment demand at specific disease-related time points throughout therapy. Methods: In this longitudinal, prospective, single-centre study, patients with malignant brain tumours were screened for increased distress (using the Distress Thermometer), anxiety, depression (Hospital Anxiety and Depression Scale questionnaire), and health-related quality of life interference (EORTC QLQ C30-BN20 questionnaire) at specific longitudinal time points during therapy. The results were correlated with sociodemographic and clinical data. Results: From 2013 to 2017, 2500 prospective screening data points from 512 malignant brain tumour patients were analysed. DT was identified as a significant predictor for psycho-oncological treatment demand (p < 0.001). Particularly significant time points concerning psycho-oncological burden were primary diagnosis and tumour recurrence. Next to these known factors, here, patients < 65 years old and female patients (p = 0.018 and p = 0.017) reflected increased screening results, whereas partnership and professional activity (p = 0.043; p = 0.017) were identified as contributing factors to a significantly decreased treatment demand. Conclusions: The increased need for psycho-oncological support for neurooncological patients is underlined. Psycho-oncological support should particularly be offered at the time points of primary diagnosis and tumour recurrence. To support the positive effect of caregivers, they should be involved at an early stage. [ABSTRACT FROM AUTHOR]

Malignant gliomas make up 25 % of the central nervous system (CNS) tumors in adults and 8–15 % in children. About half of such gliomas have a median localization and are designated by the term "diffuse midline gliomas" (DMG). DMG in children are typically localized in the area of the pons; in 78 % of such cases a heterozygous somatic mutation H3K27M is present. The prognosis of H3K27M-mutant DSG is very unfavorable, with 2-year overall survival rate being less than 10 %. One of the ways of progression of gliomas leading to the death of patients is the spread of the tumor in the form of metastases. Malignant gliomas metastasize mainly into various structures of the CNS (according to autopsies – in about 20 % of patients with glioblastomas), the probability of their metastases to other organs (so-called extraneural metastases), according to some evaluations, is quite rare and doesn’t exceed 2 %. In our practice since 1993, which counts 1700 children with malignant gliomas, including 830 patients with DMG, we’ve observed only one patient with extraneural metastases. The article describes this case of a child who died of the progression of the DMG’s extraneural metastases, despite the fact that chemoradiotherapy had achieved its stabilization in the CNS. This patient with the initial lesion of the pons and cerebellum had massive metastasis to the lymph nodes: supraclavicular, mediastinal, retroperitoneal and inguinal ones, as well as to both pleural cavities, which occurred about one year after treatment of the progression, which had manifested in the form of continued growth of the primary tumor and its dissemination in the central nervous system. The article provides literature data on the frequency, clinical manifestations and possible treatment approaches for extraneural metastasis of brain gliomas. Extraneural metastases of those tumors occur most often to the bones, lymphatic system, lungs, abdominal organs, soft tissues. The effective treatment for extraneural metastases of gliomas has not been developed yet, which makes it urgent to solve this problem through multicenter studies.

Abstract Glioma is the most common primary intracranial tumor in adults, with high incidence, recurrence, and mortality rates. Tumor-associated neutrophils (TANs) are essential components of the tumor microenvironment (TME) in glioma and play a crucial role in glioma cell proliferation, invasion and proneural-mesenchymal transition. Besides the interactions between TANs and tumor cells, the multi-dimensional crosstalk between TANs and other components within TME have been reported to participate in glioma progression. More importantly, several therapies targeting TANs have been developed and relevant preclinical and clinical studies have been conducted in cancer therapy. In this review, we introduce the origin of TANs and the functions of TANs in malignant behaviors of glioma, highlighting the microenvironmental regulation of TANs. Moreover, we focus on summarizing the TANs-targeted methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of TANs in the malignant glioma microenvironment.

Opinion statement: Malignant gliomas are common central nervous system tumors that pose a significant clinical challenge due to the lack of effective treatments. Glioblastoma (GBM), a grade 4 malignant glioma, is the most prevalent primary malignant brain tumor and is associated with poor prognosis. Current clinical trials are exploring various strategies to combat GBM, with oncolytic viruses (OVs) appearing particularly promising. In addition to ongoing and recently completed clinical trials, one OV (Teserpaturev, Delytact®) received provisional approval for GBM treatment in Japan. OVs are designed to selectively target and eliminate cancer cells while promoting changes in the tumor microenvironment that can trigger and support long-lasting anti-tumor immunity. OVs offer the potential to remodel the tumor microenvironment and reverse systemic immune exhaustion. Additionally, an increasing number of OVs are armed with immunomodulatory payloads or combined with immunotherapy approaches in an effort to promote anti-tumor responses in a tumor-targeted manner. Recently completed oncolytic virotherapy trials can guide the way for future treatment individualization through patient preselection, enhancing the likelihood of achieving the highest possible clinical success. These trials also offer valuable insight into the numerous challenges inherent in malignant glioma treatment, some of which OVs can help overcome. [ABSTRACT FROM AUTHOR]

This study analyzed the effectiveness and safety of ultra-low dose fluorescein sodium (FL)-guided malignant glioma resection and its potential to predict the pathological characteristics of glioma. Sixty patients who underwent FL-guided glioma resection were randomly divided into test (1 mg/kg) and control (5 mg/kg) groups. A retrospective analysis included 30 patients with gliomas who did not undergo FL-guided surgery; these patients were included as a blank control group. Surgical outcomes, Karnofsky performance scores (KPS), and progression-free survival (PFS) at 6 months postoperatively were compared between the 3 groups. The sensitivity and specificity of FL and the relationship between the intensity of FL and Glial fibrillary acidic protein (GFAP) or Ki-67 expression were compared. The total tumor resection rates in the test, control, and blank control groups were 90% (27/30), 86.7% (26/30), and 60% (18/30), respectively. There were significant differences (P < 0.05) in the extent of resection, KPS, and PFS at 6 months after surgery between the test and control groups and the blank control group; however, no significant differences (P > 0.05) were observed between the test and control groups. The intensity of FL and the Ki67 positivity rate (P < 0.05) were directly proportional, but this relationship was not observed with GFAP. Ultra-low-dose FL-guided resection of malignant gliomas is safe and effective. The Ki67 positivity rate was directly proportional to the intensity of FL, indicating its potential to predict gliomas during pathological examination. [ABSTRACT FROM AUTHOR]

Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro‐oncology experts convened to provide practical clinical guidance for the off‐label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low‐molecular‐weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT. There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants, specifically in brain tumor patients, but they are widely used for venous thromboembolism in this population. A group of neuro‐oncology experts convened to provide practical clinical guidance for the off‐label use of direct oral anticoagulants in treating venous thromboembolism in patients with brain tumors. [ABSTRACT FROM AUTHOR]

Objective: Malignant gliomas impose a significant symptomatic burden on patients and their families. Current guidelines recommend palliative care for patients with advanced tumors within eight weeks of diagnosis, emphasizing early integration for malignant glioma cases. However, the utilization rate of palliative care for these patients in Germany remains unquantified. This study investigates the proportion of malignant glioma patients who either died in a hospital or were transferred to hospice care from 2019 to 2022, and the prevalence of in-patient specialized palliative care interventions. Methods: In this cross-sectional, retrospective study, we analyzed data from the Institute for the Hospital Remuneration System (InEK GmbH, Siegburg, Germany), covering 2019 to 2022. We included patients with a primary or secondary diagnosis of C71 (malignant glioma) in our analysis. To refine our dataset, we identified cases with dual-coded primary and secondary diagnoses and excluded these to avoid duplication in our final tally. The data extraction process involved detailed scrutiny of hospital records to ascertain the frequency of hospital deaths, hospice transfers, and the provision of complex or specialized palliative care for patients with C71-coded diagnoses. Descriptive statistics and inferential analyses were employed to evaluate the trends and significance of the findings. Results: From 2019 to 2022, of the 101,192 hospital cases involving malignant glioma patients, 6,129 (6% of all cases) resulted in in-hospital mortality, while 2,798 (2.8%) led to hospice transfers. Among these, 10,592 cases (10.5% of total) involved the administration of complex or specialized palliative medical care. This provision rate remained unchanged throughout the COVID-19 pandemic. Notably, significantly lower frequencies of complex or specialized palliative care implementation were observed in patients below 65 years (p < 0.0001) and in male patients (padjusted = 0.016). In cases of in-hospital mortality due to malignant gliomas, 2,479 out of 6,129 cases (40.4%) received specialized palliative care. Conclusion: Despite the poor prognosis and complex symptomatology associated with malignant gliomas, only a small proportion of affected patients received advanced palliative care. Specifically, only about 10% of hospitalized patients with malignant gliomas, and approximately 40% of those who succumb to the disease in hospital settings, were afforded complex or specialized palliative care. This discrepancy underscores an urgent need to expand palliative care access for this patient demographic. Additionally, it highlights the importance of further research to identify and address the barriers preventing wider implementation of palliative care in this context. [ABSTRACT FROM AUTHOR]

Background: Glioma is one of the most drug and radiation-resistant tumors. Gliomas suffer from inter- and intratumor heterogeneity which makes the outcome of similar treatment protocols vary from patient to patient. This article is aimed to overview the potential imaging markers for individual diagnosis, prognosis, and treatment response prediction in malignant glioma. Furthermore, the correlation between imaging findings and biological and clinical information of glioma patients is reviewed. Materials and Methods: The search strategy in this study is to select related studies from scientific websites such as PubMed, Scopus, Google Scholar, and Web of Science published until 2022. It comprised a combination of keywords such as Biomarkers, Diagnosis, Prognosis, Imaging techniques, and malignant glioma, according to Medical Subject Headings. Results: Some imaging parameters that are effective in glioma management include: ADC, FA, Ktrans, regional cerebral blood volume (rCBV), cerebral blood flow (CBF), ve, Cho/NAA and lactate/lipid ratios, intratumoral uptake of 18F-FET (for diagnostic application), RD, ADC, ve, vp, Ktrans, CBFT1, rCBV, tumor blood flow, Cho/ NAA, lactate/lipid, MI/Cho, uptakes of 18F-FET, 11C-MET, and 18F-FLT (for prognostic and predictive application). Cerebral blood volume and Ktrans are related to molecular markers such as vascular endothelial growth factor (VEGF). Preoperative ADCmin value of GBM tumors is associated with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. 2-hydroxyglutarate metabolite and dynamic 18F-FDOPA positron emission tomography uptake are related to isocitrate dehydrogenase (IDH) mutations. Conclusion: Parameters including ADC, RD, FA, rCBV, Ktrans, vp, and uptake of 18F-FET are useful for diagnosis, prognosis, and treatment response prediction in glioma. A significant correlation between molecular markers such as VEGF, MGMT, and IDH mutations with some diffusion and perfusion imaging parameters has been identified. [ABSTRACT FROM AUTHOR]

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Malignant glioma (MG) is the most common type of primary malignant brain tumors. Surgical resection of MG remains the cornerstone of therapy and the extent of resection correlates with patient survival. A limiting factor for resection, however, is the difficulty in differentiating the tumor from normal tissue during surgery. Fluorescence imaging is an emerging technique for real-time intraoperative visualization of MGs and their boundaries. However, most clinical grade neurosurgical operative microscopes with fluorescence imaging ability are hampered by low adoption rates due to high cost, limited portability, limited operation flexibility, and lack of skilled professionals with technical knowledge. To overcome the limitations, we innovatively integrated miniaturized light sources, flippable filters, and a recording camera to the surgical eye loupes to generate a wearable fluorescence eye loupe (FLoupe) device for intraoperative imaging of fluorescent MGs. Two FLoupe prototypes were constructed for imaging of Fluorescein and 5-aminolevulinic acid (5-ALA), respectively. The wearable FLoupe devices were tested on tumor-simulating phantoms and patients with MGs. Comparable results were observed against the standard neurosurgical operative microscope (PENTERO® 900) with fluorescence kits. The affordable and wearable FLoupe devices enable visualization of both color and fluorescence images with the same quality as the large and expensive stationary operative microscopes. The wearable FLoupe device allows for a greater range of movement, less obstruction, and faster/easier operation. Thus, it reduces surgery time and is more easily adapted to the surgical environment than unwieldy neurosurgical operative microscopes. Clinical and Translational Impact Statement—The affordable and wearable fluorescence imaging device developed in this study enables neurosurgeons to observe brain tumors with the same clarity and greater flexibility compared to bulky and costly operative microscopes.

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions. The brain was removed 24 h after the i-PDT and analyzed pathologically. The optical fiber was able to puncture the tumor center in all cases, enabling i-PDT to be performed. Histological analysis showed that tumor necrosis was induced in areas close to the light source, correlating with the irradiation energy dose, whereas apoptosis was induced at some distance from the light source. Irradiation using high energy levels resulted in tissue swelling from strong tumor necrosis, and irradiation at 75 J/cm2 was most suitable for inducing apoptosis. An experimental system of i-PDT using TPS was established using malignant glioma cells transplanted into the rat brain. Tumor cell death, which correlated with the light propagation, was induced in tumor tissue.

Objective: Neurooncological patients are well-known to experience an increased psycho-oncological burden with a negative impact on distress, therapy adherence, quality of life, and finally survival. But still, psycho-oncological screening and support is rare, with ongoing discussion about specific screening time points and impact factors. Therefore, we analysed the psycho-oncologic treatment demand at specific disease-related time points throughout therapy. Methods: In this longitudinal, prospective, single-centre study, patients with malignant brain tumours were screened for increased distress (using the Distress Thermometer), anxiety, depression (Hospital Anxiety and Depression Scale questionnaire), and health-related quality of life interference (EORTC QLQ C30-BN20 questionnaire) at specific longitudinal time points during therapy. The results were correlated with sociodemographic and clinical data. Results: From 2013 to 2017, 2500 prospective screening data points from 512 malignant brain tumour patients were analysed. DT was identified as a significant predictor for psycho-oncological treatment demand (p < 0.001). Particularly significant time points concerning psycho-oncological burden were primary diagnosis and tumour recurrence. Next to these known factors, here, patients < 65 years old and female patients (p = 0.018 and p = 0.017) reflected increased screening results, whereas partnership and professional activity (p = 0.043; p = 0.017) were identified as contributing factors to a significantly decreased treatment demand. Conclusions: The increased need for psycho-oncological support for neurooncological patients is underlined. Psycho-oncological support should particularly be offered at the time points of primary diagnosis and tumour recurrence. To support the positive effect of caregivers, they should be involved at an early stage.

Introduction: Blood–brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). Methods: We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. Results: In mouse GBM model, the survival analysis showed RT-FUS (2 Gy) group was significantly longer than RT (2 Gy) group and control, but not RT (5 Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. Conclusion: Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is one of the most lethal cancers with a poor prognosis. Over the past century since its initial discovery and medical description, the development of effective treatments for this condition has seen limited progress. Despite numerous efforts, only a handful of drugs have gained approval for its treatment. However, these treatments have not yielded substantial improvements in both overall survival and progression-free survival rates. One reason for this is its unique features such as heterogeneity and difficulty of drug delivery because of two formidable barriers, namely the blood-brain barrier and the tumor-blood barrier. Over the past few years, significant developments in therapeutic approaches have given rise to promising novel and advanced therapies. Target-specific therapies, such as monoclonal antibodies (mAbs) and small molecules, stand as two important examples; however, they have not yielded a significant improvement in survival among GBM patients. Gene therapy, a relatively nascent advanced approach, holds promise as a potential treatment for cancer, particularly GBM. It possesses the potential to address the limitations of previous treatments and even newer advanced therapies like mAbs, owing to its distinct properties. This review aims to elucidate the current status and advancements in gene therapy for GBM treatment, while also presenting its future prospects.

Abstract Purpose In the past decade, there has been little progress in the treatment of malignant glioma. Recently, oncolytic virus has made great progress in glioma treatment, and a number of clinical trials have shown their potential of prolonging the survival time of glioma patients. Our objective is to evaluate effectiveness and safety of oncolytic virus (OV) in malignant glioma treatment. Methodology Based upon PRISMA, we collected relevant published clinical trials by searching medical databases up to January 16, 2023, applying the language restrictions in English and Chinese. We cross-searched the terms: ‘glioma’, ‘glioblastoma’, ‘oncolytic viruses’, ‘oncolytic virotherapy’ with filter ‘clinical trial’. Two researchers independently extracted the data regarding case definitions, published years, trial phase, characteristics of patients, administration of drug, overall survival (OS), and adverse events. Results 19 published clinical trials in OV treatment of malignant glioma were included in the further systematic review analysis. None of them induced irresistible adverse effects attributing to OV treatment, median overall survival varied from 3.25 to 20.2 months after treatments. According to trials providing patient’s detailed molecular diagnosis, we find that the effectiveness of OV treatment has no significant difference in patients with different IDH or MGMT status. Conclusions Current clinical trials have initially shown the potential of oncolytic virotherapy as a new treatment for malignant glioma. Besides development of virus types, the strategy of OV use is an urgent problem to be solved in future clinical application, such as repeated administrations, innovative drug delivery systems, and biomarkers.

Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs. [ABSTRACT FROM AUTHOR]

Purpose: In the past decade, there has been little progress in the treatment of malignant glioma. Recently, oncolytic virus has made great progress in glioma treatment, and a number of clinical trials have shown their potential of prolonging the survival time of glioma patients. Our objective is to evaluate effectiveness and safety of oncolytic virus (OV) in malignant glioma treatment. Methodology: Based upon PRISMA, we collected relevant published clinical trials by searching medical databases up to January 16, 2023, applying the language restrictions in English and Chinese. We cross-searched the terms: 'glioma', 'glioblastoma', 'oncolytic viruses', 'oncolytic virotherapy' with filter 'clinical trial'. Two researchers independently extracted the data regarding case definitions, published years, trial phase, characteristics of patients, administration of drug, overall survival (OS), and adverse events. Results: 19 published clinical trials in OV treatment of malignant glioma were included in the further systematic review analysis. None of them induced irresistible adverse effects attributing to OV treatment, median overall survival varied from 3.25 to 20.2 months after treatments. According to trials providing patient's detailed molecular diagnosis, we find that the effectiveness of OV treatment has no significant difference in patients with different IDH or MGMT status. Conclusions: Current clinical trials have initially shown the potential of oncolytic virotherapy as a new treatment for malignant glioma. Besides development of virus types, the strategy of OV use is an urgent problem to be solved in future clinical application, such as repeated administrations, innovative drug delivery systems, and biomarkers. [ABSTRACT FROM AUTHOR]

Malignant glioma is characterized by rapid tumor cell proliferation and high recurrence risk. In terms of its treatment, the therapeutic effects of maximum resection and postoperative radiotherapy with adjuvant chemotherapy as well as many other new therapeutic techniques such as antiangiogenic therapy and immunotherapy remain poor. Glioma recurrence, especially local recurrence, is an important reason of glioma treatment failure. Intraoperative radiotherapy (IORT) enables exclusion of radiation-sensitive normal tissue from the radiation field in operation and then the application of a single high-dose precision irradiation to the residual tumor or tumor bed. IORT has great application potential in the control of local recurrence of malignant tumors. This paper thus aims to review the current status and prospects of IORT's application in malignant glioma treatment. [ABSTRACT FROM AUTHOR]

Cognitive decline is common among patients with low- and high-grade glioma and can significantly impact quality of life. Although cognitive outcomes have been studied after therapeutic interventions such as surgery and radiation, it is important to understand the impact of the disease process itself prior to any interventions. Neurocognitive domains of interest in this disease context include intellectual function and premorbid ability, executive function, learning and memory, attention, language function, processing speed, visuospatial function, motor function, and emotional function. Here, we review oncologic factors associated with more neurocognitive impairment, key neurocognitive tasks relevant to glioma patient assessment, as well as the relevance of the human neural connectome in understanding cognitive dysfunction in glioma patients. A contextual understanding of glioma-functional network disruption and its impact on cognition is critical in the surgical management of eloquent area tumors.

Background: Glioma is one of the most drug and radiation-resistant tumors. Gliomas suffer from inter- and intratumor heterogeneity which makes the outcome of similar treatment protocols vary from patient to patient. This article is aimed to overview the potential imaging markers for individual diagnosis, prognosis, and treatment response prediction in malignant glioma. Furthermore, the correlation between imaging findings and biological and clinical information of glioma patients is reviewed. Materials and Methods: The search strategy in this study is to select related studies from scientific websites such as PubMed, Scopus, Google Scholar, and Web of Science published until 2022. It comprised a combination of keywords such as Biomarkers, Diagnosis, Prognosis, Imaging techniques, and malignant glioma, according to Medical Subject Headings. Results: Some imaging parameters that are effective in glioma management include: ADC, FA, Ktrans, regional cerebral blood volume (rCBV), cerebral blood flow (CBF), ve, Cho/NAA and lactate/lipid ratios, intratumoral uptake of 18F-FET (for diagnostic application), RD, ADC, ve, vp, Ktrans, CBFT1, rCBV, tumor blood flow, Cho/NAA, lactate/lipid, MI/Cho, uptakes of 18F-FET, 11C-MET, and 18F-FLT (for prognostic and predictive application). Cerebral blood volume and Ktrans are related to molecular markers such as vascular endothelial growth factor (VEGF). Preoperative ADCmin value of GBM tumors is associated with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. 2-hydroxyglutarate metabolite and dynamic 18F-FDOPA positron emission tomography uptake are related to isocitrate dehydrogenase (IDH) mutations. Conclusion: Parameters including ADC, RD, FA, rCBV, Ktrans, vp, and uptake of 18F-FET are useful for diagnosis, prognosis, and treatment response prediction in glioma. A significant correlation between molecular markers such as VEGF, MGMT, and IDH mutations with some diffusion and perfusion imaging parameters has been identified.

The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, β-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of β-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the β-elemene structure and designed six series of new generation β-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro, displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and β-elemene is a feasible strategy to improve the in vivo anti-tumour activity of β-elemene.

Glioblastoma (GBM), a highly malignant glioma of the central nervous system, is the most dread and common brain tumor with a high rate of therapeutic resistance and recurrence. Currently, the clinical treatment methods are surgery, radiotherapy, and chemotherapy. However, owning to the highly invasive nature of GBM, it is difficult to completely resect them due to the unclear boundary between the edges of GBM and normal brain tissue. Traditional radiotherapy and the combination of alkylating agents and radiotherapy have significant side effects, therapeutic drugs are difficult to penetrate the blood brain barrier. Patients receiving treatment have a high postoperative recurrence rate and a median survival of less than 2years, Less than 5% of patients live longer than 5years. Therefore, it is urgent to achieve precise treatment through the blood brain barrier and reduce toxic and side effects. Nanotechnology exhibit great potential in this area. This article summarizes the current treatment methods and shortcomings of GBM, and summarizes the research progress in the diagnosis and treatment of GBM using nanotechnology. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastomas are the most common primary malignant brain tumors, with a devastating survival perspective. The treatment concept of interstitial photodynamic therapy (iPDT) enables the light-induced destruction of tumor cells based on the combination of a photosensitizer that selectively accumulates in the tumor and light to activate the photosensitizer. The tumor region is illuminated by minimally invasively inserted optical fibers. Under this approach, prolonged overall survival was observed. An analysis of the patient characteristics and the evolution of the MRI data before treatment and during follow-up was performed to identify potential predictors of an improved survival outcome. It was found that the methylation status of the DNA-repair enzyme MGMT is an important factor regarding survival. Other commonly assessed parameters, such as the tumor volume, necrosis–tumor ratio, and contrast enhancement after therapy, did not seem to significantly affect survival. Overall, the iPDT-treated patients showed very promising results regarding a sustained absence of their tumors and prolonged overall survival. Background: The treatment of glioblastomas, the most common primary malignant brain tumors, with a devastating survival perspective, remains a major challenge in medicine. Among the recently explored therapeutic approaches, 5-aminolevulinic acid (5-ALA)-mediated interstitial photodynamic therapy (iPDT) has shown promising results. Methods: A total of 16 patients suffering from de novo glioblastomas and undergoing iPDT as their primary treatment were retrospectively analyzed regarding survival and the characteristic tissue regions discernible in the MRI data before treatment and during follow-up. These regions were segmented at different stages and were analyzed, especially regarding their relation to survival. Results: In comparison to the reference cohorts treated with other therapies, the iPDT cohort showed a significantly prolonged progression-free survival (PFS) and overall survival (OS). A total of 10 of 16 patients experienced prolonged OS (≥ 24 months). The dominant prognosis-affecting factor was the MGMT promoter methylation status (methylated: median PFS of 35.7 months and median OS of 43.9 months) (unmethylated: median PFS of 8.3 months and median OS of 15.0 months) (combined: median PFS of 16.4 months and median OS of 28.0 months). Several parameters with a known prognostic relevance to survival after standard treatment were not found to be relevant to this iPDT cohort, such as the necrosis–tumor ratio, tumor volume, and posttreatment contrast enhancement. After iPDT, a characteristic structure (iPDT remnant) appeared in the MRI data in the former tumor area. Conclusions: In this study, iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care. [ABSTRACT FROM AUTHOR]

Simple Summary: The preoperative risk estimation of non-enhancing suspected "low-grade" glioma (NEG) is key in determining the optimal timing of diagnosis and treatment to delay malignant progression and avoid undertreatment. The updated 2021 WHO classification brought new facets to glioma grading. Therefore, we sought to identify preoperative risk factors of malignancy in NEG by considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A total of 72 NEG patients were analyzed, and a high prevalence of malignant gliomas was detected considering both the traditional WHO grading (WHO grade 3 + 4) and the integrated molecular classification (IDHwt glioblastoma WHO grade 4 and IDHmut astrocytoma WHO grade 4). Easily determinable preoperative factors (age, T2/FLAIR mismatch sign, and SVZ involvement) were identified by uni- and multivariate analyses and incorporated into a score. The score estimates the probability of an NEG harboring a malignant glioma. Finally, the score was validated in a cohort of 40 NEG patients and proved to be a better prediction model than the Pignatti score or the T2/FLAIR mismatch sign. The preoperative grading of non-enhancing glioma (NEG) remains challenging. Herein, we analyzed clinical and magnetic resonance imaging (MRI) features to predict malignancy in NEG according to the 2021 WHO classification and developed a clinical score, facilitating risk estimation. A discovery cohort (2012–2017, n = 72) was analyzed for MRI and clinical features (T2/FLAIR mismatch sign, subventricular zone (SVZ) involvement, tumor volume, growth rate, age, Pignatti score, and symptoms). Despite a "low-grade" appearance on MRI, 81% of patients were classified as WHO grade 3 or 4. Malignancy was then stratified by: (1) WHO grade (WHO grade 2 vs. WHO grade 3 + 4) and (2) molecular criteria (IDHmut WHO grade 2 + 3 vs. IDHwt glioblastoma + IDHmut astrocytoma WHO grade 4). Age, Pignatti score, SVZ involvement, and T2/FLAIR mismatch sign predicted malignancy only when considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A multivariate regression confirmed age and T2/FLAIR mismatch sign as independent predictors (p = 0.0009; p = 0.011). A "risk estimation in non-enhancing glioma" (RENEG) score was derived and tested in a validation cohort (2018–2019, n = 40), yielding a higher predictive value than the Pignatti score or the T2/FLAIR mismatch sign (AUC of receiver operating characteristics = 0.89). The prevalence of malignant glioma was high in this series of NEGs, supporting an upfront diagnosis and treatment approach. A clinical score with robust test performance was developed that identifies patients at risk for malignancy. [ABSTRACT FROM AUTHOR]

Background/Aim: A recommendation of radiotherapy for patients with malignant gliomas may trigger emotional distress. Frequency and risk factors of this complication were investigated. Patients and Methods: Prevalence of six emotional problems and 11 potential risk factors were evaluated in 103 patients irradiated for grade II-IV gliomas. p-Values <0.0045 were considered significant. Results: Seventy-six patients (74%) had =1 emotional problem. Prevalence of specific emotional problems ranged between 23% and 63%. Associations were found between =5 physical problems and worry (p=0.0010), fear (p=0.0001), sadness (p=0.0023), depression (p=0.0006), and loss of interest (p=0.0006), and Karnofsky performance score =80 and depression (p=0.0002). Trends were found for physical problems and nervousness (p=0.040), age =60 years and depression (p=0.043) or loss of interest (p=0.045), grade IV glioma and sadness (p=0.042), and =2 involved sites and loss of interest (p=0.022). Conclusion: Three-fourths of glioma patients had pre-radiotherapy emotional distress. Psychological support should be offered very soon, particularly for high-risk patients. [ABSTRACT FROM AUTHOR]

Podoplanin (PDPN) is known to induce platelet aggregation via interacting with the C-type lectin-like receptor-2 on platelets and is involved in postoperative venous thromboembolism (VTE) formation. In this study, we investigate the correlation between soluble C-type lectin-like receptor (sCLEC-2) levels and PDPN expression in patients with high grade gliomas and the relationship between sCLEC-2 levels and the occurrence of VTE. Forty-four patients harboring high grade gliomas, treated surgically at the Department of Neurosurgery, Niigata University from April 2018 to August 2020, were included. Patients with high grade gliomas were divided into isocitrate dehydrogenase (IDH)- wildtype and mutant groups, and the presence or absence of VTE and the intensity of PDPN by immunohistochemistry were confirmed. Platelet counts, as well as plasma sCLEC-2 and PDPN were measured in these patients. Furthermore, the levels of sCLEC-2 concentration were divided by the platelet count (C2PAC index) for comparison. IDH-wildtype glioma patients highly expressed PDPN (P < 0.001) compared to IDH-mutant glioma patients. In total, 9 (20.5 %) patients were diagnosed with VTE during the follow-up period, of which 8 patients harbored IDH-wildtype gliomas, and one patient an IDH-mutant glioma. Mean sCLEC-2 levels and C2PAC index in patients with IDH-wildtype gliomas were significantly higher than that of low or no PDPN expression group, which included patients with IDH-mutant gliomas (P = 0.0004, P = 0.0002). In patients with IDH-wildtype gliomas, the C2PAC index in patients with VTE was significantly higher than in patients without VTE (P = 0.0492). The optimal cutoff point of C2PAC for predicting VTE in IDH-wildtype glioma patients was 3.7 with a sensitivity of 87.5 % and specificity of 51.9 %. Platelet activation is strongly involved in the development of VTE in patients with IDH-wildtype high grade gliomas, and C2PAC index is a potential marker to detect VTE formation after surgery. [Display omitted] • Soluble C-type lectin-like receptor (sCLEC-2) levels were correlate with podoplanin (PDPN) expression in patients with high grade gliomas. • IDH-wildtype glioma patients highly expressed PDPN compared to IDH-mutant glioma patients. • Platelet activation is strongly involved in the development of venous thromboembolism (VTE) in patients with IDH-wildtype high grade gliomas. [ABSTRACT FROM AUTHOR]

To evaluate the safety profile of bis-chloroethyl-nitrosourea (BCNU) wafer implantation after malignant glioma resection with or without ventricular opening (VO). This single-center retrospective study included 66 consecutive patients with BCNU wafer implantation after malignant glioma resection between March 2013 and August 2021. The patients were categorized into 2 groups based on whether VO occurred during the malignant glioma resection. Fifty-eight patients had glioblastoma, and 8 had anaplastic astrocytoma or oligodendroglioma. Forty-eight patients underwent an initial treatment, and 18 underwent recurrent surgeries. Infection, hydrocephalus, subcutaneous fluid collection, chronic subdural hematoma, early seizure after surgery within 1 month, symptomatic edema surrounding the resected cavity, cyst formation, and postoperative hemorrhage were defined as adverse events (AEs). Thirty-three patients underwent resection with VO, and 33 without. The median survival time was 28 months in the initial treatment group and 11.5 months in the recurrent treatment group. The with and without VO groups had similar median survival times. Postoperative AEs occurred in 7/33 patients (21.2%) with VO and 10/33 (30.3%) without VO, with no difference between them (P = 0.574). This study showed that VO during surgery with BCNU wafer implantation might not influence the occurrence of postoperative AEs. If VO happens, BCNU wafer implantation can be performed safely with accurate closing of the ventricle. [ABSTRACT FROM AUTHOR]

In spite of substantial progress made in the standard treatment and ancillary therapies that include concurrent chemotherapy, radiotherapy, and surgery, malignant brain tumors – especially high-grade glioma (HGG) and glioblastoma multiforme (GBM) – denote a gloomy prospect. Intrinsic factors associated with the protection of the GBM microenvironment and the challenges of delivering drug across the blood-brain barrier (BBB) primarily hinder the efficient treatment of GBM. Recent advances in nanomedicine have shown potential in overcoming some of these hindrances. The present review examines the merits and demerits of using nanoparticle (NP) drug delivery systems for enhancing the effectiveness of the targeted drug delivery for treating HGG. Recent advances in nanomedicine-based drug delivery strategies that focus on direct and dual-targeting drug deliveries for overcoming the challenges associated with malignant glioma are discussed. Finally, clinical translation of drug delivery strategies, unresolved concerns, and prospects for future development to facilitate the effective treatment of malignant glioma are presented.

Purpose: Epithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor. Methods: Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies. Results: An epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85-90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53. Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts frommyeloid cells as well asM1 andM2macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section. Conclusion: Epithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different. [ABSTRACT FROM AUTHOR]

Background: Individuals caring for patients with malignant gliomas experience high rates of anxiety; however, an in-depth understanding of their distress and evidence-based interventions to target their needs are lacking. Objective: We conducted semistructured interviews with caregivers with elevated anxiety to characterize their drivers of anxiety, identify modifiable intervention targets, and capture their preferences for a psychosocial intervention. Design: From 9/2017 to 3/2019, we conducted semistructured interviews with 21 caregivers of patients with malignant gliomas, at time points following the patient's diagnosis or within one to three months after the patient's death. Setting/Subjects: Eligible caregivers in the United States had clinically significant anxiety as measured by a Hospital Anxiety and Depression Scale-Anxiety score >7. Measurements: Three independent coders employed thematic content analysis to analyze the qualitative data with NVivo 12, achieving high intercoder agreement (Kappa = 0.98). Results: On average, caregivers were 54.81 years old (SD = 10.85) with elevated anxiety (M = 10.90, SD = 3.25). We identified six themes in which caregivers described (1) coping through reassurance seeking or avoidance, (2) changes in their relationship with the patient, (3) challenges with social support, (4) vacillation between certainty and uncertainty regarding the future, (5) devaluation of self-care for the patients' needs, and (6) challenges communicating with the health care team. Caregivers were interested in an intervention soon after the patient's diagnosis, yet expressed concern about finding the time to participate. Conclusions: Emergent themes characterized the distress experienced by caregivers of patients with malignant gliomas and provided insight into their psychosocial intervention preferences. We identified evidence-based intervention components based on the modifiable factors arising from these themes. [ABSTRACT FROM AUTHOR]

Cerebral vein thrombosis is a unique and rare type of cerebrovascular disease. The main challenge in identifying cerebral vein thrombosis is the presence of vague signs and symptoms that can resemble a variety of other intracranial pathologies. Our goal is to present the unique case of a young patient whose MRI scan revealed an abnormally enhancing tumor-like brain lesion that was heterogeneous in intensity and whose intraoperative view and histopathological findings were consistent with the vein of Labbe thrombosis, with ipsilateral transverse and sigmoid sinus involvement. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-invasion efficacy of the ethanol extract of Oldenlandia diffusa Will. (EEOD) on a three-dimensional (3D) human malignant glioma (MG) cell invasion and perfusion model based on microfluidic chip culture and the possible mechanism of action of Oldenlandia diffusa Will. (OD). Methods: The comprehensive pharmacodynamic analysis method in this study was based on microfluidic chip 3D cell perfusion culture technology, and the action mechanism of Chinese medicine (CM) on human MG cells was investigated through network pharmacology analysis. First, the components of EEOD were analyzed by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Then, cell viability and apoptosis were assessed to determine the optimum concentration of EEOD for invasion experiments, and two-dimensional (2D) migration and invasion abilities of U87 and U251 MG cells were evaluated using scratch wound and Transwell assays. The possible mechanism underlying the effects of EEOD on glioma was analyzed through a network pharmacology approach. Results: Thirty-five compounds of EEOD were detected by UPLC-Q-TOF/MS. EEOD suppressed the viability of MG cells, promoted their apoptosis, and inhibited their migratory and invasive potentials (all P<0.05). Network pharmacology analysis showed that OD inhibited the invasion of MG cells by directly regulating MAPK and Wnt pathways through MAPK, EGFR, MYC, GSK3B, and other targets. The anti-invasion effect of OD was also found to be related to the indirect regulation of microtubule cytoskeleton organization. Conclusions: ]EEOD could inhibit the invasion of human MG cells, and the anti-invasion mechanism of OD might be regulating MAPK and Wnt signaling pathways and microtubule cytoskeleton organization. [ABSTRACT FROM AUTHOR]

Abstract Background Antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65) are biomarkers of autoimmune disorders and are more common in non-neurological autoimmune diseases than in neurological disorders. As for the central nervous system (CNS), it is well known that GAD65 is primarily associated with stiff-person syndrome, cerebellar ataxia, epilepsy, and paraneoplastic neurological syndrome. However, GAD65 antibodies have not been reported in patients with brain tumors. Case presentation This study presents the case of a 62-year-old man who manifested rapidly progressive dizziness with gradually worsening physical disturbance and unstable gait in the 2 months prior to consultation. Antibodies against GAD65 were detected in his serum. Brain magnetic resonance imaging (MRI) showed abnormal signals in the corpus callosum, the semi-oval center in both hemispheres, and the area below the frontal cortex, along with enhanced intracranial lesions in the same regions. Positron emission tomography–computed tomography (PET–CT) showed high metabolism in the corpus callosum, which protruded into both ventricles. Due to signs of malignancy, the patient was diagnosed with a malignant glioma. Conclusions This case raises awareness on the fact that anti-GAD65 antibodies may be associated with CNS neoplastic lesions. Early recognition of anti-GAD antibodies could be of great importance for the early diagnosis and targeted treatment of neoplastic lesions, and could lead to better prognosis.

Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs.

Abstract Background Long non-coding RNA (LncRNA) HOTAIR was amplified and overexpressed in many human carcinomas, which could serve as a useful target for cancer early detection and treatment. The 99mTc radiolabeled antisense oligonucleotides (ASON) could visualize the expression of HOTAIR and provide a diagnostic value for malignant tumors. The aim of this study was to evaluate whether liposome-coated antisense oligonucleotide probe 99mTc-HYNIC-ASON targeting HOTAIR can be used in in vivo imaging of HOTAIR in malignant glioma xenografts. Methods The ASON targeting LncRNA HOTAIR as well as mismatched ASON (ASONM) were designed and modified. The radiolabeling of 99mTc with two probes were via the conjugation of bifunctional chelator HYNIC. Then probes were purified by Sephadex G25 and tested for their radiolabeling efficiency and purity, as well as stability by ITLC (Instant thin-layer chromatography) and gel electrophoresis. Then the radiolabeled probes were transfected with lipofectamine 2000 for cellular uptake test and the next experimental use. Furthermore, biodistribution study and SPECT imaging were performed at different times after liposome-coated 99mTc-HYNIC-ASON/ASONM were intravenously injected in glioma tumor-bearing mice models. All data were analyzed by statistical software. Results The labeling efficiencies of 99mTc-HYNIC-ASON and 99mTc-HYNIC-ASONM measured by ITLC were (91 ± 1.5) % and (90 ± 0.6) %, respectively, and both radiochemical purities were more than 89%. Two probes showed good stability within 12 h. Gel electrophoresis confirmed that the oligomers were successfully radiolabeled no significant degradation were found. Biodistribution study demonstrated that liposome-coated antisense probes were excreted mainly through the kidney and bladder and has higher uptake in the tumor. Meanwhile, the tumor was clearly shown after injection of liposome coated 99mTc-HYNIC-ASON, and its T/M ratio was higher than that in the non-transfection group and mismatched group. No tumor was seen in mismatched and blocking group. Conclusion The liposome encapsulated 99mTc-HYNIC-ASON probe can be used in the in vivo, real-time imaging of LncRNA HOTAIR expression in malignant glioma.

PurposeEpithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor.MethodsWhole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies.ResultsAn epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85–90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53. Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts from myeloid cells as well as M1 and M2 macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section.ConclusionEpithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different.

Paediatric high-grade gliomas are an almost universally fatal form of childhood cancer. While radiotherapy combined with temozolomide has had a pivotal role in the standard care of adult high-grade gliomas, this has not translated to the paediatric population, where its precise role remains undefined. The effectiveness of this treatment approach and continued use in paediatric high-grade glioma (including diffuse midline glioma) is questionable and we argue that it's time for paediatric neuro-oncologists to consider alternative approaches. [ABSTRACT FROM AUTHOR]

The ORBEYE (ORB), an innovative 3-dimensional digital exoscope, is an equipped system for fluorescence-guided surgery with 5-aminolevulinic acid. Therefore, this study aimed to verify the characteristics of fluorescence-guided surgery with 5-aminolevulinic acid and excitation light source with ORB. The same operative field of glioblastoma was recorded under blue light (BL) excitation using a conventional microscope (MS) and ORB. For in vitro studies, the energy of 405-nm wavelength light in white light and BL modes of each scope was examined in various focal lengths. To examine the degree of photobleaching with BL for each scope, protoporphyrin IX–soaked filter papers were continuously exposed with BL of an MS and ORB, and the video-recorded red fluorescence intensity was analyzed. The color tone of tumor-induced red fluorescence was remarkably different under each scope. Furthermore, nonfluorescent normal structures without red fluorescence were well recognized under ORB. The energy of 405-nm wavelength light in BL was significantly higher in ORB than that in an MS, especially in the short focal length. With continuous BL excitation to filter papers, the relative red fluorescence intensity of filter papers was significantly decreased over time in ORB than in an MS. In low protoporphyrin IX concentration, the difference was more significant. With ORB, the good visibility due to BL energy as compared with an MS might improve the surgical manipulation even in BL mode. However, the weak fluorescent tissue and short focal length should be carefully considered because photobleaching might be critical for FGS. [ABSTRACT FROM AUTHOR]

Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment.