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Diffuse gliomas are the most common type of adult primary brain tumors, and they have been recently classified into three types: astrocytoma IDH-mutant, oligodendroglioma, and glioblastoma IDH-wildtype. Molecular testing is now used to diagnose these tumors, but imaging still plays a role in providing diagnostic and prognostic information. A study published in European Radiology evaluated the use of two imaging metrics, normalized relative cerebral blood volume (nrCBV) and percentage signal recovery (PSR), to differentiate between astrocytoma and oligodendroglioma. The results showed that PSR performed better than nrCBV, and combining the two metrics improved their performance. However, further research is needed to validate these findings and determine the optimal imaging parameters for clinical use. [Extracted from the article]

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

Oligodendrogliomas (ODGs) are rare brain tumors in adults, mostly presenting as a supratentorial solid mass, while less than 10% occur infratentorially. Infratentorial cystic ODGs are extremely rare. We reported a large partially cystic cerebellar ODG in a 31‐week pregnant patient with an unusual presentation and discussed the challenging management. [ABSTRACT FROM AUTHOR]

Background: Diffuse gliomas are the most frequent primary central nervous system (CNS) neoplasms, originating from the parenchyma itself, oligodendrogliomas accounting for approximately 10% of cerebral gliomas. For the past 20 years, the study of genetic/molecular mechanisms of glioma genesis and progression has gradually come into focus. However, the biological and clinical significance of these mutations are still to be completely characterized. The purpose of this article is to describe our clinical experience with oligodendrogliomas and to review the current literature, in order to better describe the characteristics of the molecular/genetic oligodendroglioma subgroups. Methods: We performed a single-institution retrospective study that included 66 patients with oligodendrogliomas operated in our department between January 2011 and December 2018. Results: Our study included 26 female patients (39%) and 40 male patients (59%). The mean age at presentation was 39.9year-old (range 26-59year-old). The tumours were located predominantly in the right hemisphere (53%), the majority being situated in the frontal lobe (59%). 64% of the patients had signs of mass effect on the imaging studies, 13% presented with brain herniation syndromes, and 16 % of the surgically treated patients had a relapse with regrowth and malignant transformation of the tumour. The most common complaint that the patients had at admission was a headache. Seizures were the second most common symptom that determined the patients to seek medical attention. Conclusion: The expanding knowledge regarding the genetic alterations of oligodendroglial tumours could lead to significant changes in treatment strategies. However, the utility of each particular marker in planning the treatment has yet to be established. Emerging data will, most likely, improve outcome prediction and adjuvant therapy strategies by identifying the patients most likely to benefit from a particular treatment. [ABSTRACT FROM AUTHOR]

Introduction: Isocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and IDH-mutant and 1p/19q-codeleted oligodendrogliomas. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to standard of care (SOC). Methods: AMPLIFY-NEOVAC is a randomized, 3-arm, window-of-opportunity, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with avelumab (AVE), an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1). The target population includes patients with resectable IDH1R132H-mutant recurrent astrocytoma or oligodendroglioma after SOC. Neoadjuvant and adjuvant immunotherapy will be administered to 48 evaluable patients. In arm 1, 12 patients will receive IDH1-vac; in arm 2, 12 patients will receive the combination of IDH1-vac and AVE, and in arm 3, 24 patients will receive AVE only. Until disease progression according to immunotherapy response assessment for neuro-oncology (iRANO) criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment. Perspective: IDH1R132H 20-mer peptide is a shared clonal driver mutation-derived neoepitope in diffuse gliomas. IDH1-vac safely targets IDH1R132H in newly diagnosed astrocytomas. AMPLIFY-NEOVAC aims at (1) demonstrating safety of enhanced peripheral IDH1-vac-induced T cell responses by combined therapy with AVE compared to IDH1-vac only and (2) investigating intra-glioma abundance and phenotypes of IDH1-vac induced T cells in exploratory post-treatment tissue analyses. In an exploratory analysis, both will be correlated with clinical outcome. Trial registration: NCT03893903. [ABSTRACT FROM AUTHOR]

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up. [ABSTRACT FROM AUTHOR]

Introduction: The noncoding RNAs (ncRNAs) play a role in biological processes of various cancers including gliomas. The majority of these transcripts are uniquely expressed in differentiated tissues or specific glioma types. Pediatric oligodendroglioma (POG) is a rare subtype of diffuse glioma and accounts for <1% of pediatric brain tumors. Because histologically POG resembles adult OG, the same treatment is applied as adults. However, the significance in predicting outcomes in POG patients is unclear. In this study, we aimed to investigate the prognostic significance of expression profiles of microRNA (miRNA) and long noncoding RNA (LncRNA) in POGs. Methods: We investigated the levels of 13 known miRNAs and 6 LncRNAs in tumor samples from 9 patients with primary POG by using RT-PCR and analyzed their association with outcomes. Results: The expression levels of miR-21, miR-106a, miR-10b, and LncRNA NEAT1 were higher, and the expression level of miR-143 was lower in POG tissues compared with normal brain tissues (p = 0.006, p = 0.032, p = 0.034, p = 0.002, and p = 0.001, respectively). High levels of NEAT1 and low expression of miR-143 were associated with decreased probability of short disease-free survival (p = 0.018 and p = 0.022, respectively). Discussion: NEAT1 and miR-143 levels could serve as reciprocal prognostic predictors of disease progression in patients with POG. New treatment models to regulate the expression levels of NEAT1 and miR-143 will bring a new approach to the therapy of POG. [ABSTRACT FROM AUTHOR]

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

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

Glioma is the most common primary malignant brain tumor with a poor prognosis. Immune checkpoint inhibitors have been of great interest in investigation of glioma treatments. Here, we report single-cell transcriptomic analyses of two tumor areas from an oligodendroglioma taken from a patient who had multiple tumor recurrences, following several chemotherapies and radiation treatments. The patient subsequently received nivolumab and was considered have disease progression based on conventional diagnostic imaging after two cycles of treatment. He underwent a debulking surgical resection and pathological diagnosis was recurrent disease. During the surgery, tumor tissues were also collected from the enhancing and non-enhancing areas for a scRNAseq analysis to investigate the tumor microenvironment of these radiographically divergent areas. The scRNAseq analysis reveals a plethora of immune cells, suggesting that the increased mass observed on MRI may be partially a result of immune cell infiltration. The patient continued to receive immunotherapy after a short course of palliative radiation and remained free of disease progression for at least 12 months after the last surgery, suggesting a sustained response to immunotherapy. The scRNAseq analysis indicated that the radiological progression was in large part due to immune cell infiltrate and continued immunotherapy led to a positive clinical outcome in a patient who would have otherwise been admitted to hospice care with halting of immunotherapy. Our study demonstrates the potential of scRNAseq analyses in understanding the tumor microenvironment, which may assist the clinical decision-making process for challenging glioma cases following immunotherapy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with great invasiveness and resistance to chemotherapy, which presents a treatment challenge. In this study, we investigated the antitumor effect of Cedrol, a sesquiterpene alcohol isolated from Cedrus atlantica, against GBM cells in vitro and in vivo. Cedrol was found to potently inhibit cell growth and induce intracellular ROS generation and DNA damage response. In addition, Cedrol induced significant G0/G1 cell cycle arrest and cell apoptosis via the extrinsic (Fas/FasL/Caspase-8) and intrinsic (Bax/Bcl-2/Caspase-9) pathways. In addition, Cedrol had a synergistic effect with temozolomide (TMZ) and reduced drug resistance by blockage of the AKT/mTOR pathway. Cedrol suppressed tumor growth in both orthotopic and xenograft GBM animal models with low or no short-term acute toxicity or long-term accumulative toxicity. In a molecular docking study, Cedrol targeted the androgen receptor (AR), and reduced DHT-mediated AR nuclear translocation, downstream gene KLK3/TMPRSS2 expression and cell proliferation. Our study demonstrates that Cedrol may be a potential candidate for drug development for single or combination treatment with TMZ in GBM therapy. [ABSTRACT FROM AUTHOR]

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

Glioblastoma (GBM) is the most common primary brain tumor, carrying a very poor prognosis, with median overall survival at about 12 to 15 months despite surgical resection, chemotherapy with temozolomide (TMZ), and radiation therapy. GBM recurs in the vast majority of patients, with recurrent tumors commonly displaying increase in resistance to standard of care chemotherapy, TMZ, as well as radiotherapy. One of the most commonly cited mechanisms of chemotherapeutic and radio-resistance occurs via the glucose-regulated protein 78 (GRP78), a well-studied mediator of the unfolded protein response (UPR), that has also demonstrated potential as a biomarker in GBM. Overexpression of GRP78 has been directly correlated with malignant tumor characteristics, including higher tumor grade, cellular proliferation, migration, invasion, poorer responses to TMZ and radiation therapy, and poorer patient outcomes. GRP78 expression is also higher in GBM tumor cells upon recurrence. Meanwhile, knockdown or suppression of GRP78 has been shown to sensitize cells to TMZ and radiation therapy. In light of these findings, various novel developing therapies are targeting GRP78 as monotherapies, combination therapies that enhance the effects of TMZ and radiation therapy, and as treatment delivery modalities. In this review, we delineate the mechanisms by which GRP78 has been noted to specifically modulate glioblastoma behavior and discuss current developing therapies involving GRP78 in GBM. While further research is necessary to translate these developing therapies into clinical settings, GRP78-based therapies hold promise in improving current standard-of-care GBM therapy and may ultimately lead to improved patient outcomes. [ABSTRACT FROM AUTHOR]

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

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

Granular cell astrocytoma (GCA) is an aggressive variant of astrocytoma characterized by predominantly round-to-polygonal cells with abundant eosinophilic granular cytoplasm. This tumor usually lack the morphological signatures of conventional astrocytoma and are devoid of typical features which define a malignant neoplasm, leading to potential misdiagnosis. We report GCA in a 50-year-old man presenting with severe headache along with vertiginous sensation and sensory seizures of left upper limb for past two months. Imaging showed multiple intra-axial, hyperintense space-occupying lesions in bilateral anterior temporal lobe, left parietal lobe, left thalamus and cerebellum, raising possibility of lymphoma/metastases. Histopathologic examination revealed sheets of large polygonal cells with distinct cellular outline, ample amount of eosinophilic PAS-positive granular cytoplasm, eccentrically placed irregular, round-to-ovoid nuclei with occasional prominent nucleoli. On immunohistochemistry, tumor cells were diffusely immunopositive for Olig2, S100, EMA, lysozyme and CD68, and they were immunonegative for GFAP, LCA, pan-CK, TTF-1, TFE-3, PAX-8, SOX10, MAP2, MBP, NF, H3K27M, H3K27me3, p53, IDH1 (R132H), CD1a, langerin and BRAFV600E. Numerous scattered macrophages were highlighted by CD163. MIB 1-labelling-index was approximately 5%–6%. Overall features were congruous with final diagnosis of GCA. GCAs behave in a belligerent manner irrespective of their morphologic grade as they are seen to exhibit genetic alterations similar to glioblastoma. Thereby, they warrant early diagnosis for conducive patient management. [ABSTRACT FROM AUTHOR]

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

Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O6-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl-histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence. [ABSTRACT FROM AUTHOR]

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

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

Oligodendrogliomas are a rare diffuse astrocytic tumor, usually present in young adults, which depending on the pathogenic alterations can lead to major disabilities or even death. We present a case of a male patient in the fifth decade of life, who initially presented with an oligodendroglioma, and approximately one year after the first therapeutic intervention the condition recurred in the form of an anaplastic oligodendroglioma. We made a complete histopathological and immunohistochemical panel in order to have a final diagnosis with the greatest accuracy, thus making a comparison with the literature in order to assess the diagnosis and subsequent therapeutic conduct. [ABSTRACT FROM AUTHOR]

Glioma is the most prevalent primary brain tumor in adults and has an extremely unfavorable prognosis. As a member of the lysyl oxidase (LOX) family, lysyl-oxidase-like-2 (LOXL2) is known to play different roles in different tumors. However, the role of LOXL2 in glioma has not yet been fully elucidated. In the present study, we detected that LOXL2 was considerably upregulated in glioma and that LOXL2 upregulation was evidently related to glioma WHO grade, malignant molecular subtypes, and poor prognosis in glioma patients. Additionally, we found that LOXL2 not only promoted glioma cells proliferation, migration, invasion, and induced the epithelial-to-mesenchymal transition (EMT) process, but also reduced the sensitivity of glioma cells to temozolomide (TMZ). Furthermore, we identified that LOXL2 reduced TMZ sensitivity and induced EMT in glioma via the activation of autophagy. Mechanistically, LOXL2 enhanced Atg7 expression by promoting the phosphorylation of Erk1/2, leading to the activation of autophagy and regulation of EMT process and TMZ sensitivity through autophagy. Our study describes an LOXL2-Erk1/2-Atg7 signaling axis that influences glioma EMT and chemosensitivity through autophagy; moreover, LOXL2 may serve as a promising therapeutic target in the treatment of glioma. [ABSTRACT FROM AUTHOR]

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

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

Malignant gliomas, including glioblastoma (GBM) as the most aggressive type of adult CNS tumors, are notoriously resistant to current standard of care treatments, including surgery, systemic chemotherapy, and radiation therapy (RT). This lack of effective treatment options highlights the urgent need for novel therapies, including immunotherapies. The overarching goal of immunotherapy is to stimulate and activate the patient's immune system in a targeted manner to kill tumor cells. The success of immunotherapeutic interventions in other cancer types has led to interest in and evaluation of various experimental immunotherapies in patients with malignant gliomas. However, these primary malignant brain tumors present a challenge because they exist in a vital and sensitive organ with a unique immune environment. The challenges and current status of experimental immunotherapeutic approaches, including vaccines, immune-checkpoint blockade, chimeric antigen receptor T-cell therapy, and oncolytic viruses will be discussed, as well as the potential for combinatorial therapies. [ABSTRACT FROM AUTHOR]

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

Glioblastoma is the most common and most malignant primary brain tumor. Despite aggressive multimodal treatment, its prognosis remains poor. Even with continuous developments in MRI, which has provided us with newer insights into the diagnosis and understanding of tumor biology, response assessment in the posttherapy setting remains challenging. We believe that the integration of additional information from advanced neuroimaging techniques can further improve the diagnostic accuracy of conventional MRI. In this article, we review the utility of advanced neuroimaging techniques such as diffusion-weighted imaging, diffusion tensor imaging, perfusion-weighted imaging, proton magnetic resonance spectroscopy, and chemical exchange saturation transfer in characterizing and evaluating treatment response in patients with glioblastoma. We will also discuss the existing challenges and limitations of using these techniques in clinical settings and possible solutions to avoiding pitfalls in study design, data acquisition, and analysis for future studies. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:978-997. [ABSTRACT FROM AUTHOR]

Sodium MRI is a promising method for assessing the metabolic properties of brain tumours. In a recent study, a strong relationship between semi‐quantitative abnormalities in sodium MRI and the mutational status of the isocitrate dehydrogenase enzyme (IDH) with untreated cerebral gliomas was observed. Here, sodium relaxometry in brain tumour tissue was investigated in relation to molecular markers in order to reveal quantitative sodium tissue parameters and the differences between healthy tissue and brain tumour. The previous semi‐quantitative approach is extended by use of suitable relaxometry methods accompanied by numerical simulation to achieve detailed quantitative analysis of intra‐ and extracellular sodium concentration using an enhanced SISTINA sequence at 4 T. Using optimised techniques, biexponential sodium relaxation times in tumour (T*2f, T*2s) and in healthy contralateral brain tissue (T*2f,CL, T*2s,CL) were estimated in 10 patients, along with intracellular sodium molar fractions (χ, χCL), volume fractions (η, ηCL) and concentrations (ρin, ρin,CL). The total sodium tissue concentrations (ρT, ρT,CL) were also estimated. The ratios T*2f/T*2f,CL (P =.05), η/ηCL (P =.02) and χ/χCL (P =.02) were significantly lower in IDH mutated than in IDH wildtype gliomas (n = 4 and n = 5 patients, respectively). The Wilcoxon rank‐sum test was used to compare sodium MRI parameters in patients with and without IDH mutation. Thus, quantitative analysis of relaxation rates, intra‐ and extracellular sodium concentrations, intracellular molar and volume fractions based on enhanced SISTINA confirmed a relationship between abnormalities in sodium parameters and the IDH mutational status in cerebral gliomas, hence catering for the potential to provide further insights into the status of the disease. [ABSTRACT FROM AUTHOR]

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Background: Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumor. Carmustine is used by intravenous injection or local implantation in the resection cavity for gliomas, including GBMs. However, the therapeutic potential of carmustine is not well-recognized. This analysis aimed to evaluate the survival benefits of carmustine in glioma patients, especially those with GBM. Methods: Randomized controlled trials (RCTs) and cohort studies regarding carmustine for glioma treatment were searched in PubMed, the Cochrane Library, and Embase from January 1979 to March 2020. Quality assessment was conducted with Jadad and Newcastle–Ottawa scales (NOS). Statistical analysis was conducted by the Revman 5.3 software. Results: Twenty-two eligible RCTs and cohort studies involving 5,821 glioma patients were included. Overall, glioma patients receiving carmustine as an adjuvant therapy had better progression-free survival [PFS; hazard ratio (HR) = 0.85, 95% CI = 0.77–0.94, P = 0.002] and overall survival (OS; HR = 0.85, 95% CI = 0.79–0.92, P < 0.0001) than those without carmustine treatment. Subgroup analysis showed that the OS benefit was observed in GBM (HR = 0.84, 95% CI = 0.78–0.91, P < 0.00001) but not in anaplastic glioma patients (HR = 1.20, 95% CI = 0.70–2.07, P = 0.50). Additionally, both newly diagnosed and recurrent GBM patients who received carmustine treatment showed better OS (HR = 0.86, 95% CI = 0.79–0.95, P = 0.002; HR = 0.77, 95% CI = 0.67–0.89, P = 0.0002, respectively). Both carmustine implantation in resection cavity and intravenous administration significantly prolonged OS (HR = 0.84, 95% CI = 0.78–0.92, P < 0.0001; HR = 0.86, 95% CI = 0.75–0.99, P = 0.04, respectively). Moreover, GBM patients receiving a combined carmustine and temozolomide (TMZ) therapy had longer OS than those receiving TMZ alone (HR = 0.78, 95% CI = 0.63–0.97, P = 0.03). Conclusion: Carmustine implantation in resection cavity provides survival benefit for GBM patients, and it may be a promising supplement to standard therapeutic protocol by offering a bridge between surgical resection and onset of TMZ therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a discouraging prognosis. Its aggressive and highly infiltrative nature renders the current standard treatment of maximal surgical resection, radiation, and chemotherapy relatively ineffective. Identifying the signaling pathways that regulate GBM migration/invasion and resistance is required to develop more effective therapeutic regimens to treat GBM. Expression of TROY, an orphan receptor of the TNF receptor superfamily, increases with glial tumor grade, inversely correlates with patient overall survival, stimulates GBM cell invasion in vitro and in vivo , and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in a preclinical intracranial xenograft model. Here, we have identified for the first time that TROY interacts with JAK1. Increased TROY expression increases JAK1 phosphorylation. In addition, increased TROY expression promotes STAT3 phosphorylation and STAT3 transcriptional activity that is dependent upon JAK1. TROY-mediated activation of STAT3 is independent of its ability to stimulate activity of NF-κB. Inhibition of JAK1 activity by ruxolitinib or knockdown of JAK1 expression by siRNA significantly inhibits TROY-induced STAT3 activation, GBM cell migration, and decreases resistance to temozolomide. Taken together, our data indicate that the TROY signaling complex may represent a potential therapeutic target with the distinctive capacity to exert effects on multiple pathways mediating GBM cell invasion and resistance. [ABSTRACT FROM AUTHOR]

Glioblastomas are among the most common primary brain tumors with an abysmal prognosis. The significance of glucose metabolism in glioblastoma cell metabolism and proliferation is well-known. However, a significant correlation between the systemic metabolic status of the patient and the cellular proliferation of the glioblastoma has not yet been established. Our aim was to observe and analyze for a possible correlation between glioblastoma cellular proliferation and patients' glycated hemoglobin (HbA1c) levels as a marker of chronic systemic glycemia. We analyzed the data from 25 patients and compared their Ki-67 values with their preoperative HbA1c values. We observed a statistically significant correlation (P < 0.03) between chronic glycemia (measured using HbA1c) and the cellular proliferation of glioblastoma (measured by cellular Ki-67 expression). These results imply a possible positive correlation between glioblastoma cell proliferation and chronic systemic glycemia, a correlation that, to the best of our knowledge, has not yet been reported. Further research in this area could not only lead to a better understanding of glioblastoma but also have significant clinical applications in treating this devastating disease. [ABSTRACT FROM AUTHOR]

Background: The 4977-bp common deletion (mtDNA4977) is a well-established mitochondrial genome alteration that has been described in various types of human cancers. However, to date, no studies on mtDNA4977 in brain tumors have been reported. The present study aimed to determine mtDNA4977 prevalence in common brain tumors, specifically, low- and high-grade gliomas (LGGs and HGGs), and meningiomas in Malaysian cases. Its correlation with clinicopathological parameters was also evaluated. Methods: A total of 50 patients with pathologically confirmed brain tumors (13 LGGs, 20 HGGs, and 17 meningiomas) were enrolled in this study. mtDNA4977 was detected by using polymerase chain reaction (PCR) technique and later confirmed via Sanger DNA sequencing. Results: Overall, mtDNA4977 was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients. Conclusion: The prevalence of mtDNA4977 in Malaysian glioma and meningioma cases has been described for the first time and it was, indeed, comparable with previously published studies. This study provides initial insights into mtDNA4977 in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive primary brain tumor in adults. The prognosis of patients with primary glioblastoma treated with the current standard of care, tumor resection followed by radiation therapy and auxiliary temozolomide, remains poor. Integrative genomic analyses have identified essential core signaling pathways and frequent genetic aberrations, which provide potential drug targets for glioblastoma treatment. Drugs against these therapeutic targets have been developed rapidly in recent years. Although some have shown promising effects on models in preclinical studies, many have shown only modest efficacy in clinical trials. New therapeutic strategies and potent drugs are urgently needed to improve the prognosis of patients with glioblastoma. The goal of this review is to summarize the current advances in drug development for targeted glioblastoma therapies and to reveal the major challenges encountered in clinical trials or treatment. This study will provide new perspectives for future studies of targeted therapeutic drug development and provide insights into the clinical treatment of glioblastoma. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is a common symptom of brain tumors and is often pharmacoresistent. Among new antiseizure medications (ASMs) Brivaracetam (BRV) has been approved as adjunctive treatment for focal seizures and it was tested in non-oncological patient populations. This is the first study that retrospectively explored efficacy and tolerability of BRV as add-on therapy in brain tumor-related epilepsy (BTRE) patients. Materials and Methods: We reviewed the medical records of 33 BTRE patients from six Italian epilepsy centers; charts included tumor history, diagnosis of BTRE, BRV added as first or second add-on for uncontrolled seizures and/or adverse events (AEs) of the previous ASMs, at least 1-month follow-up, seizure frequency, and AEs assessment. Results: Thirty-three patients (19 males, mean age: 57.6 years; 14 females, mean age: 42.4 years): 11 low grade gliomas, five high grade gliomas, six meningiomas, 10 glioblastomas, one primary cerebral lymphoma. Fourteen patients had focal aware seizures, nine focal unaware, seven focal to bilateral tonic-clonic seizures, three patients presented more than one seizure type: focal unaware with focal to bilateral tonic clonic seizures (two patients) and focal aware and unaware seizures (one patient). Mean seizure frequency in the month preceding BRV introduction: 7.0; at last follow-up: 2.0 (p = 0.001). Seven patients (21.2%) reported AEs (anxiety, agitation, fatigue, vertigo) and three of them (9.0%) required drug withdrawal due to psychiatric adverse events (PAEs). Three other patients withdrew BRV: one for scarce compliance (3.0%), two for uncontrolled seizures (6.0%). Conclusion: Our results showed that BRV could be a new therapeutic option effective in reducing seizures in BTRE patients, taking into account the incidence of PAEs in this particular population. Future and larger prospective studies are needed. [ABSTRACT FROM AUTHOR]

Gliomas are the most common primary brain cancers. In recent years, IDH mutation and 1p/19q codeletion have been suggested as biomarkers for the diagnosis, treatment, and prognosis of gliomas. However, these biomarkers are only effective for a part of glioma patients, and thus more biomarkers are still emergently needed. Recently, an electrochemical communication between normal neurons and glioma cells by neuro-glioma synapse has been reported. Moreover, it was discovered that breast-to-brain metastasis tumor cells have pseudo synapses with neurons, and these synapses were indicated to promote tumor progression and metastasis. Based on the above observations, we first curated a panel of 17 synapse-related genes and then proposed a metric, synapse score to quantify the "stemness" for each sample of 12 glioma gene expression datasets from TCGA, CGGA, and GEO. Strikingly, synapse score showed excellent predictive ability for the prognosis, diagnosis, and grading of gliomas. Moreover, being compared with the two established biomarkers, IDH mutation and 1p/19q codeletion, synapse score demonstrated independent and better predictive performance. In conclusion, this study proposed a quantitative method, synapse score, as an efficient biomarker for monitoring gliomas. [ABSTRACT FROM AUTHOR]

Background: Low‐grade gliomas (LGGs) are primary diffuse slow‐growing brain tumors derived from glial cells. The management of these tumors is dependent on their location, which often harbors eloquent areas. We retrospectively recorded the location of diffuse gliomas to identify whether specific differences exist between the histological types. Methods: We analyzed 102 patients with previous histological diagnosis of WHO‐II astrocytomas (62) and WHO‐II oligodendrogliomas (40) according to WHO‐2016 classification. MRI sequences (T2‐FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations within the Montreal Neurological Institute (MNI) space. The Brain‐Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was created and merged with a tractography atlas for infiltration analysis. Results: Astrocytomas frequently infiltrated association and projection white matter pathways within fronto‐temporo‐insular regions on the left side. Oligodendrogliomas infiltrated larger white matter networks (association‐commissural‐projection) of the frontal lobe bilaterally. A critical number of infiltrated BG voxels (7 for astrocytomas, 10 for oligodendrogliomas) significantly predicted shorter overall survival (OS) in both groups. Bilateral tumor extension in astrocytomas and preoperative tumor volume in oligodendrogliomas were independent prognostic factors for shorter OS. Conclusions: Astrocytomas and oligodendrogliomas differ in preferential location, and this has an impact on the type and the extent of white matter involvement. The number of BG voxels infiltrated reflected different tumor invasiveness and its impact on OS in both groups. All this new information may be valuable in neurosurgical oncology to classify and plan treatment for patients with diffuse gliomas. [ABSTRACT FROM AUTHOR]

The importance of genomic information in intrinsic brain tumors is highlighted in the World Health Organization (WHO) 2016 classification of gliomas, which now incorporates both phenotype and genotype data to assign a diagnosis. By using genetic markers to both categorize tumors and advise patients on prognosis, this classification system has minimized the risk of tissue sampling error, improved diagnostic accuracy, and reduced inter-rater variability. In the neurosurgical community, it is critical to understand the role genetics plays in tumor biology, what certain mutations mean for the patient's prognosis and adjuvant treatment, and how to interpret the results of sequencing data that are generated following tumor resection. In this review, we examine the critical role of genetics for diagnosis and prognosis and highlight the importance of tumor genetics for neurosurgeons caring for patients with diffuse lower grade gliomas. [ABSTRACT FROM AUTHOR]

AbstractTargeted therapy has gained mainstream attention with notable successes against specific genetic mutations in many cancers. One particular mutation, the BRAF V600E mutation, is present in a small subset of gliomas in adults. Although clinical experience and trial data of RAF-targeted therapy in adults with glioma are lacking at this time, the poor prognosis of adult high-grade glioma has led neuro-oncology practitioners to consider the use of targeted therapy in these patients. In this manuscript, we describe the use of RAF and MEK inhibitors in adults with recurrent glioma. We discuss the utility of these agents, describe their toxicities, and give examples of management strategies. Given the significant toxicities of RAF and MEK inhibitors, along with the long potential duration of treatment, neuro-oncology providers should counsel patients carefully before initiating therapy and monitor them closely while undergoing treatment with RAF-targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Due to technical advancements and availability of neuroimaging, detection of incidental pediatric brain tumors (IPBT) is growing rapidly. The management of these asymptomatic lesions remains unclear; radiological, pathological, and clinical risk factors for further growth and malignant transformation (MT) are not well defined. Methods: We systematically reviewed the literature on the dilemmas and management of IPBT suggestive of a low-grade brain tumor (LGBT). Keyword searches of the PubMed and Medline (NCBI) databases identified studies on IPBT describing the prevalence, neuroimaging, management, or risk of MT through July 2019. References of the identified articles were also reviewed. Results: A total of 2021 records were screened. Fifty-nine full-text articles were reviewed, and 34 published studies were included. IPBT are diagnosed in 0.2–5.7% of children undergoing brain imaging for various reasons. The accepted approach for management of lesions showing radiological characteristics suggestive of LGBT is radiological follow-up. The rate at which additional intervention is required during follow-up for these apparently low-grade lesions is 9.5%. Nevertheless, the dilemma of early surgical resection or biopsy vs. clinical and radiological follow-up of IPBT is still unresolved. The risk in these cases is missing a transformation to a higher grade tumor. However, MT of pediatric LGBT is very rare, occurring in less than 3% of the cases of proven low-grade gliomas in children. The risk of future MT in pediatric low-grade gliomas seems to be greater in the presence of specific molecular markers such as BRAF V-600E, CDKN2A, and H3F3A K27M. Conclusions: The natural history, management, and prognosis of IPBT remain ambiguous. It seems that lesions suggestive of LGBT can initially be followed, since many of these lesions remain stable over time and MT is rare. However, controversy among centers concerning the ideal approach still exists. Further observational and prospective cohort studies, focusing on potential clinical and radiological characteristics or risk factors suggestive of high-grade tumors, tumor progress, or MT of IPBT, are needed. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive and malignant brain tumor, resulting in a poor prognosis. The current therapy for GBM consists in concurrent radiation and chemotherapy following removal of the tumor. Although the therapy prolongs patient survival, recurrence often occurs. The major cause of tumor recurrence is thought to be GBM stem cells (GSCs), which aid the development of chemo-radiotherapy resistance, and can self-renew and aberrantly differentiate. Therefore, GSCs should be targeted to eradicate the tumor and prevent recurrence. Transcriptomic analysis has categorized GBM into proneural (PN), mesenchymal and classical subtypes, and the outcome of recurrence and prognosis markedly depends on subtype. To identify specific GSC markers, the present study analyzed public microarray and RNA-seq data and identified dihydropyrimidinase-related protein 5 (DRP5) as a candidate GSC marker. DRP5 is known to mediate semaphorin 3A signaling and is involved in the regulation of neurite outgrowth and axon guidance during neuronal development. In the present study, DRP5 was specifically upregulated in the PN-subtype GSCs and served crucial roles in maintaining GSC properties, including tumor sphere formation, stem cell marker expression and xenograft tumor growth. Furthermore, bioinformatics analysis revealed that DRP5 expression was positively correlated with signatures of stemness, including Notch, Hedgehog and Wnt/β-catenin expression, which are also known to be positively correlated with PN-subtype gene signatures. Conversely, DRP5 expression was negatively correlated with NF-κB and signal transducer and activator of transcription 3 stemness signatures, which are negatively correlated with PN-subtype gene signatures. Taken together, these findings suggested that DRP5 was specifically expressed in PN-subtype GSCs and may be used as a functional marker of PN-subtype GSCs. [ABSTRACT FROM AUTHOR]

In the latest World Health Organization classification of brain tumors, gliomatosis cerebri has been redefined to varying subsets of diffuse gliomas; however, the term is still used to describe gliomas with infiltrative growth into three or more cerebral lobes. These tumors are frequently misdiagnosed and difficult to treat due to their atypical presentation using structural imaging modalities including computed tomography and T1/T2-weighted magnetic resonance imaging (MRI). In this retrospective case series, we compared clinical MRI to amino acid positron emission tomography (PET) to assess the potential value of PET in the assessment of the extent of tumor involvement and in monitoring disease progression. We report the clinical course and serial multimodal imaging findings of four patients. Each patient presented at varying points in disease progression with widespread glioma brain involvement and was evaluated at least once by amino acid PET using alpha-[11C]methyl-L-tryptophan ([11C]-AMT). Increased uptake of [11C]-AMT was detected in a subset of non-enhancing brain lesions and detected tumor invasion before MRI signs of tumor in some regions. Increased uptake of [11C]-AMT was also detected in tumorous regions not detected by perfusion MRI or MR spectroscopy. Metabolic response to treatment was also observed in two patients. Overall, these data are consistent with and expand upon previous reports using other amino acid PET tracers in gliomatosis and show the potential added value of this imaging modality to clinical MRI in the detection and monitoring of these diffusely infiltrative tumors. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis, despite surgical resection combined with radio- and chemotherapy. The major clinical obstacles contributing to poor GBM prognosis are late diagnosis, diffuse infiltration, pseudo-palisading necrosis, microvascular proliferation, and resistance to conventional therapy. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and the dynamic plasticity of GBM cells. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. An immunosuppressive tumor microenvironment of GBM provides multiple pathways for tumor immune evasion. Infiltrating immune cells, mostly tumor-associated macrophages, comprise much of the non-neoplastic population in GBM. Further understanding of the immune microenvironment of GBM is essential to make advances in the development of immunotherapeutics. Recently, whole-genome sequencing, epigenomics and transcriptional profiling have significantly helped improve the prognostic and therapeutic outcomes of GBM patients. Here, we discuss recent genomic advances, the role of innate and adaptive immune mechanisms, and the presence of an established immunosuppressive GBM microenvironment that suppresses and/or prevents the anti-tumor host response. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. DEPDC1B (DEP domain-containing protein 1B) has been shown to be associated with some types of malignancies. However, the role and underlying regulatory mechanisms of DEPDC1B in GBM remain elusive. Methods: In this research, the expression level of DEPDC1B in GBM tissues was detected by IHC. The DEPDC1B knockdown cell line was constructed, identified by qRT-PCR and western blot and used to construct the xenotransplantation mice model and intracranial xenograft model. MTT assay, colony formation assay, flow cytometry, and Transwell assay were used to detected cell proliferation, apoptosis and migration. Results: The results proved that DEPDC1B was significantly upregulated in tumor tissues, and silencing DEPDC1B could inhibit proliferation, migration and promote apoptosis of GBM cell. In addition, human apoptosis antibody array detection showed that after DEPDC1B knockdown, the expression of apoptosis-related proteins was downregulated, such as IGFBP-2, Survivin, N-cadherin, Vimentin and Snail. Finally, we indicated that knockdown of DEPDC1B significantly inhibited tumor growth in vivo. Conclusions: In summary, DEPDC1B was involved in the development and progression of GBM, which may be a potential therapeutic target and bring a breakthrough in the treatment. [ABSTRACT FROM AUTHOR]

Background: Low grade gliomas (LGG) are most often noted with the unpredictable overall survival and progression to higher grades. Objective: In the present study, we analyze the clinicopathological features influencing the prognostic outcomes and compared the features with criteria developed by EORTC.Materials and Methods: We observed the 130 LGG clinical cases in single institute and maintained the follow-up for more than 5 years. In addition, the molecular details were confirmed with markers as IDH, 1p/19q codeletion, p53 and ATRX mutations.Results: The mean age of patients as 37.67 years and male population contributing to 70%. We observed biased incidence among the male population with dominating occurrence at frontal and parietal lobes in the brain. 40.8% patients had oligodendroglioma, 33.8% astrocytoma, 19.2% oligoastrocytoma and 2.3% gemistocytic astrocytoma pathology. Patients who were subjected to chemotherapy and radiotherapy were noted with average survival of 29 months. Oligodendroglial tumors were found with progression free survival (PFS) of 25 months, oligoastrocytoma cases with 32 months, diffuse astrocytoma cases with 23 months while the gemistocytic astrocytoma cases had 22 months. The PFS for LGG cases was 4.7 years while the overall survival was 4.9 years. Mean survival of patients with KPS score <70 and >70 was 1.5 & 4.9 years respectively. 64 patients were observed with the tumor size >5 cm. In total, 72.3% of the patients were underwent GTR, 23.3% STR and 3.8% underwent biopsy.Conclusion: Taken together, the clinical symptoms, expression of molecular markers and the prognosis details provided by our results can help for better management of LGG cases. We further propose to use following five factors to accurately describe the prognosis and tumor recurrence: 1) Age >50 years, 2) tumor size >5 cm, 3) MIB index >5%, 4) KPS score < 70 and 5) gemistocytic pathology. [ABSTRACT FROM AUTHOR]

The concept of thermal therapy toward the treatment of brain tumors has gained traction in recent years. Traditionally, thermal therapy has been subdivided into hyperthermia, with mild elevation of temperature in treated tissue above the physiologic baseline; and thermal ablation, where even higher temperatures are achieved. The recent surge in interest has been driven by the use of novel thermal ablation technologies, including laser interstitial thermal therapy (LITT), that are implemented in brain tumor treatment. Here, we review previous scientific literature on the biologic effects of thermal therapy on brain tumors, with an emphasis on glioblastoma (GBM), an aggressive brain malignancy. In addition, we present in vitro evidence from our laboratory that even moderate elevations in temperature achieved in the penumbra around laser-ablated coagulum may also produce GBM cell death. While much remains to be elucidated in terms of the biology of thermal therapy, we propose that it is a welcome addition to the neuro-oncology armamentarium, in particular with regard to GBM, which is generally resistant to current chemoradiotherapeutic regimens. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma. [ABSTRACT FROM AUTHOR]

Obtaining diagnostic specimens, notably to monitor disease course in cancer patients undergoing therapy, is an emerging area of research, however, with few clinical implications so far in the field of Neuro-oncology. Specifically for patients with primary brain tumors where repeat biosampling from the tumor and clinical decision making based on neuroimaging alone remain challenging, this area may assume a central role. In principle, sampling could focus on blood, cerebrospinal fluid or urine with differential sensitivities and specificities of findings that differ between specific parameters and target molecules. These include protein, mRNA, miRNA, cell-free DNA, either freely circulating or as cargo of extracellular vesicles, as well circulating tumor cells. The most solid biomarkers are those directly reflecting neoplastic disease, e.g., in the case of primary brain tumors isocitrate dehydrogenase mutation or epidermal growth factor receptor variant III. Importantly, the main goals of liquid biopsy marker development are to better understand response to therapy, natural evolution and emergence of resistant clones, rather than obviating the need for surgical interventions which remain to be a mainstay of therapy for the vast majority of primary brain tumors. [ABSTRACT FROM AUTHOR]

Based on a literature review and our database, we report on the smallest 14q deletion identified in a brain tumor characterized by 1p/19q codeletion low-grade oligodendroglioma. In 2013, array-comparative genomic hybridization of the brain tumor revealed 1p/19q codeletion as a sole abnormality. In 2019, the patient relapsed showing additional abnormalities including a 14q deletion of 16.5 Mb at 14q24.2q31.3. This region overlaps with 2 previously identified minimal regions, 14q21.2q24.3 and 14q31.3q32.1, based on 142 cases of glioma. The authors reported no correlation between these 2 regions and survival. By extracting these 2 regions from our patient's deletion and comparing it to 12 other cases of 1p/19q codeletion oligodendrogliomas reported in the literature, we narrowed down the 14q loss possible critical region to 5.6 Mb mapping at 14q31.1q31.2. This region contains 2 potential relapse-related genes: SEL1L and STON2. [ABSTRACT FROM AUTHOR]