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The race to find an effective treatment for glioblastoma (GBM) remains a critical topic, because of its high aggressivity and impact on survival and the quality of life. Currently, due to GBM’s high heterogeneity, the conventional treatment success rate and response to therapy are relatively low, with a median survival rate of less than 20 months. A new point of view can be provided by the comprehension of the tumor microenvironment (TME) in pursuance of the development of new therapeutic strategies to aim for a longer survival rate with an improved quality of life and longer disease-free interval (DFI). The main components of the GBM TME are represented by the extracellular matrix (ECM), glioma cells and glioma stem cells (GSCs), immune cells (microglia, macrophages, neutrophils, lymphocytes), neuronal cells, all of them having dynamic interactions and being able to influence the tumoral growth, progression, and drug resistance thus being a potential therapeutic target. This paper will review the latest research on the GBM TME and the potential therapeutic targets to form an up-to-date strategy.

Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.

Temporal and parahippocampal glial tumors at early morphological stages of their development may mimic the clinical and neuroimaging picture of limbic encephalitis. Delayed diagnosis of glioblastoma can have a negative impact on the prognosis of the disease, which is why there is a need to find approaches for its earlier detection. The aim of this paper is to analyze possible difficulties and errors in the differential diagnosis of autoimmune encephalitis (AE) and glioblastoma based on literature data and our own clinical observations. Features such as onset of the disease at a young age, subacute development of symptoms, response to immunosuppressive therapy and the MRI imaging of bilateral T2 hyperintense changes in the limbic areas are typical for AE, but do not exclude the diagnosis of a primary tumor of the central nervous system. Therefore, caution should be exercised regarding the likelihood of a primary brain tumor when patients of any age group present with symptoms characteristic of AE, especially if no specific for AE antibodies are detected. To shorten the time to diagnosis, a multidisciplinary approach, critical analysis of clinical data, a shortening of the examination interval and an increase in the frequency of imaging follow-up examinations are required.

Glioblastomas synthesize, bear receptors for, and respond to bradykinin, triggering migration and proliferation. Since centrifugal migration into uninvolved surrounding brain tissue occurs early in the course of glioblastoma, this attribute defeats local treatment attempts and is the primary reason current treatments almost always fail. Stopping bradykinin-triggered migration would be a step closer to control of this disease. The recent approval and marketing of an oral plasma kallikrein inhibitor, berotralstat (Orladeyo™), and pending FDA approval of a similar drug, sebetralstat, now offers a potential method for reducing local bradykinin production at sites of bradykinin-mediated glioblastoma migration. Both drugs are approved for treating hereditary angioedema. They are ideal for repurposing as a treatment adjunct in glioblastoma. Furthermore, it has been established that peritumoral edema, a common problem during the clinical course of glioblastoma, is generated in large part by locally produced bradykinin via kallikrein action. Both brain edema and the consequent use of corticosteroids both shorten survival in glioblastoma. Therefore, by (i) migration inhibition, (ii) growth inhibition, (iii) edema reduction, and (iv) the potential for less use of corticosteroids, berotralstat may be of service in treatment of glioblastoma, slowing disease progression. This paper recounts the details and past research on bradykinin in glioblastoma and the rationale of treating it with berotralstat.

In this paper, we discuss how the clustering analysis technique can be applied to analyze functional magnetic resonance imaging (fMRI) time-series data in the context of glioblastoma (GBM), a highly heterogeneous brain tumor. The precise characterization of GBM is challenging and requires advanced analytical approaches. We have synthesized the existing literature to provide an overview of how clustering algorithms can help identify unique patterns within the dynamics of GBM. Our review shows that the clustering of fMRI time series has great potential for improving the differentiation between various subtypes of GBM, which is pivotal for developing personalized therapeutic strategies. Moreover, this method proves to be effective in capturing temporal changes occurring in GBM, enhancing the monitoring of disease progression and response to treatment. By thoroughly examining and consolidating the current research, this paper contributes to the understanding of how clustering techniques applied to fMRI data can refine the characterization of GBM. This article emphasizes the importance of incorporating cutting-edge data analysis techniques into neuroimaging and neuro-oncology research. By providing a detailed perspective, this approach may guide future investigations and boost the development of tailored therapeutic strategies for GBM.

Abstract Background In a considerable subgroup of glioma patients treated with (chemo) radiation new lesions develop either representing tumor progression (TP) or treatment-related abnormalities (TRA). Quantitative diffusion imaging metrics such as the Apparent Diffusion Coefficient (ADC) and Fractional Anisotropy (FA) have been reported as potential metrics to noninvasively differentiate between these two phenomena. Variability in performance scores of these metrics and absence of a critical overview of the literature contribute to the lack of clinical implementation. This meta-analysis therefore critically reviewed the literature and meta-analyzed the performance scores. Methods Systematic searching was carried out in PubMed, EMBASE and The Cochrane Library. Using predefined criteria, papers were reviewed. Diagnostic accuracy values of suitable papers were meta-analyzed quantitatively. Results Of 1252 identified papers, 10 ADC papers, totaling 414 patients, and 4 FA papers, with 154 patients were eligible for meta-analysis. Mean ADC values of the patients in the TP/TRA groups were 1.13 × 10−3mm2/s (95% CI 0.912 × 10–3–1.32 × 10−3mm2/s) and 1.38 × 10−3mm2/s (95% CI 1.33 × 10–3–1.45 × 10−3mm2/s, respectively. Mean FA values of TP/TRA was 0.19 (95% CI 0.189–0.194) and 0.14 (95% CI 0.137–0.143) respectively. A significant mean difference between ADC and FA values in TP versus TRA was observed (p = 0.005). Conclusions Quantitative ADC and FA values could be useful for distinguishing TP from TRA on a meta-level. Further studies using serial imaging of individual patients are warranted to determine the role of diffusion imaging in glioma patients.

This paper contains single-center prospective information showing illustrative examples of chemokine receptor-4 (CXCR4) targeting in high-grade glial brain tumors in treatment-naïve adult patients using a novel radiolabeled PET tracer: [68Ga]Ga-CXCR4 PET/CT.High-grade glioma is one of the most resistant malignancies to treatment. Despite major breakthroughs in diagnostic and therapeutic approaches, the overall 5-year survival rate remains in the 5–10% range. CXCR4 is a chemokine with the C-X-C motif that is overexpressed in high-grade gliomas.The 24 consecutive treatment- naïve enrolled patients underwent PET/CT images using the SIEMENS scanner (Biograph6 TrueV) and received the radiotracer intravenously. After approximately 60 min, the PET/CT acquisition was performed with a dedicated scanner and in 10 min time per bed position. The images were reconstructed and analyzed with the 3D-OSEM algorithm, applying point spread function (PSF) or resolution recovery algorithm (TrueX in Syngo ® software, Siemens Medical Solution), 3 iterations, and 21 subsets using a 3 mm Gaussian post-smoothing filter.These data would be potentially beneficial for automatic tumor delineation machine learning after augmented with other data retrieved from different papers as well as for differentiation between an active viable tumor vs. post-surgery/necrosis in indeterminate cases. The theranostics potential (CXCR4-tageted labeled beta emitters) is one of the most novel areas of interest for future studies.

Glioblastoma is one of the most aggressive tumours with a poor response to treatment and a poor prognosis for patients. One of the proteins expressed in glioblastoma tissue is CHI3L1 (YKL-40), which is upregulated and known for its angiogenesis-supporting and pro-tumour immunomodulatory effects in a variety of cancers. In this paper we present the anti-angiogenic, anti-migratory and immunomodulatory effects of the compound G721–0282, an inhibitor of CHI3L1. The inhibitor-induced changes were investigated using conventional techniques as well as the novel label-free digital holographic tomography (DHT), a quantitative phase imaging technique that allows the reconstruction of the refractive index (RI), which is used as an image contrast for 3D visualisation of living cells. DHT allowed digital staining of individual cells and intercellular structures based only on their specific RI. Quantitative spatially resolved analysis of the RI data shows that the concentration of G721–0282 leads to significant changes in the density of cells and their intracellular structures (in particular the cytoplasm and nucleus), in the volume of lipid droplets and in protein concentrations. Studies in the U-87 MG glioblastoma cell line, THP-1 monocytes differentiated into macrophages, human microvascular endothelial cells (HMEC-1) and in the spheroid model of glioblastoma composed of U-87 MG, HMEC-1 and macrophages suggest that inhibition of CHI3L1 may have potential in the antitumour treatment of glioblastoma. In this paper, we also propose a spheroid model for in vitro studies that mimics this type of tumour.

In the United States, an individual’s access to resources, insurance status, and wealth are critical social determinants that affect both the risk and outcomes of many diseases. One disease for which the correlation with socioeconomic status (SES) is less well-characterized is glioblastoma (GBM), a devastating brain malignancy. The aim of this study was to review the current literature characterizing the relationship between area-level SES and both GBM incidence and prognosis in the United States. A query of multiple databases was performed to identify the existing data on SES and GBM incidence or prognosis. Papers were filtered by relevant terms and topics. A narrative review was then constructed to summarize the current body of knowledge on this topic. We obtained a total of three papers that analyze SES and GBM incidence, which all report a positive correlation between area-level SES and GBM incidence. In addition, we found 14 papers that focus on SES and GBM prognosis, either overall survival or GBM-specific survival. Those studies that analyze data from greater than 1,530 patients report a positive correlation between area-level SES and individual prognosis, while those with smaller study populations report no significant relationship. Our report underlines the strong association between SES and GBM incidence and highlights the need for large study populations to assess SES and GBM prognosis to ideally guide interventions that improve outcomes. Further studies are needed to determine underlying socio-economic stresses on GBM risk and outcomes to identify opportunities for intervention.

The Zika virus has been shown to infect glioblastoma stem cells via the membrane receptor αvβ5, which is activated by the stem-specific transcription factor SOX2. Since the expression level of SOX2 is an important predictive marker for successful virotherapy, it is important to understand the fundamental mechanisms of the role of SOX2 in the dynamics of cancer stem cells and Zika viruses. In this paper, we develop a mathematical ODE model to investigate the effects of SOX2 expression levels on Zika virotherapy against glioblastoma stem cells. Our study aimed to identify the conditions under which SOX2 expression level, viral infection, and replication can reduce or eradicate the glioblastoma stem cells. Analytic work on the existence and stability conditions of equilibrium points with respect to the basic reproduction number are provided. Numerical results were in good agreement with analytic solutions. Our results show that critical threshold levels of both SOX2 and viral replication, which change the stability of equilibrium points through population dynamics such as transcritical and Hopf bifurcations, were observed. These critical thresholds provide the optimal conditions for SOX2 expression levels and viral bursting sizes to enhance therapeutic efficacy of Zika virotherapy against glioblastoma stem cells. This study provides critical insights into optimizing Zika virus-based treatment for glioblastoma by highlighting the essential role of SOX2 in viral infection and replication.

Glioblastoma multiforme (GBM) represents one of the most critical oncological diseases in neurological practice, being considered highly aggressive with a dismal prognosis. At a worldwide level, new therapeutic methods are continuously being researched. Magnetic hyperthermia (MHT) has been investigated for more than 30 years as a solution used as a single therapy or combined with others for glioma tumor assessment in preclinical and clinical studies. It is based on magnetic nanoparticles (MNPs) that are injected into the tumor, and, under the effect of an external alternating magnetic field, they produce heat with temperatures higher than 42 °C, which determines cancer cell death. It is well known that iron oxide nanoparticles have received FDA approval for anemia treatment and to be used as contrast substances in the medical imagining domain. Today, energetic, efficient MNPs are developed that are especially dedicated to MHT treatments. In this review, the subject’s importance will be emphasized by specifying the number of patients with cancer worldwide, presenting the main features of GBM, and detailing the physical theory accompanying the MHT treatment. Then, synthesis routes for thermally efficient MNP manufacturing, strategies adopted in practice for increasing MHT heat performance, and significant in vitro and in vivo studies are presented. This review paper also includes combined cancer therapies, the main reasons for using these approaches with MHT, and important clinical studies on human subjects found in the literature. This review ends by describing the most critical challenges associated with MHT and future perspectives. It is concluded that MHT can be successfully and regularly applied as a treatment for GBM if specific improvements are made.

Background. Stroke-like syndrome is defined as a rare, delayed complication of brain oncotherapy. Cases with more favorable brain cancer diagnoses and longer life expectancy have been previously reported, but here we present, for the first time, three long-term survivors of glioblastoma with stroke-like syndromes. Methods and Results. Three young or middle-aged patients underwent tumor resection and chemoradiotherapy. They received regular clinical and imaging follow-up with stable neurological status and no signs of tumor recurrence. They exhibited varied signs and symptoms (motor and sensory deficits, aphasia, memory and cognitive disorders, seizures, and headache) accompanied by imaging abnormalities. Stroke-like syndromes developed within 2-5 days and resolved in 2-6 weeks. Diffusion-weighted MRI and T2 brain perfusion abnormalities were demonstrated in all patients. In addition, there was focal T1 MRI contrast enhancement due to blood-brain barrier disruption. In addition to tumor recurrence, classic stroke, encephalitis, metabolic and mitochondrial disorders, and post-seizure swelling should be excluded. The imaging indicated intensive MRI scanning and symptomatic medication (steroids supplemented by antiepileptics, vasoactive agents, etc.) for judicious management. With respect to the course, an invasive procedure was still considered an option. Conclusion. All stroke-like syndromes are diagnoses of exclusion. To avoid misinterpretation of imaging findings as glioblastoma recurrence and avert recall oncotherapy or redundant interventions, better understanding of delayed complications of brain tumor therapy is crucial.

Chimeric antigen receptor T (CAR-T) cell therapy has been proven to be successful against different leukaemias and lymphomas. Its success has led, in recent years, to its use being tested for different solid tumours, including glioblastoma, a type of primary brain tumour, characterised by aggressiveness and recurrence. This paper presents an analytical study of a mathematical model describing the competition of CAR-T and glioblastoma tumour cells, taking into account their immunosuppressive capacity. The model is formulated in a general way, and its basic properties are investigated. However, most of the analysis considers the model with exponential tumour growth, assuming this growth type for simplicity. The existence and stability of steady states are studied, and the subsequent focus is on two different types of treatment: constant and periodic. Finally, protocols for CAR-T cell therapy of glioblastoma are numerically derived; these are aimed at preventing the tumour from reaching a critical size and at prolonging the patients’ survival time as much as possible. The analytical and numerical results provide theoretical support for the treatment of glioblastoma using CAR-T cells.

ObjectiveTo provide a comprehensive review of intra-arterial cerebral infusions of chemotherapeutics in glioblastoma multiforme treatment and discuss potential research aims. We describe technical aspects of the intra-arterial delivery, methods of blood-brain barrier disruption, the role of intraoperative imaging and clinical trials involving intra-arterial cerebral infusions of chemotherapeutics in the treatment of glioblastoma multiforme.Method159 articles in English were reviewed and used as the foundation for this paper. The Medline/Pubmed, Cochrane databases, Google Scholar, Scielo and PEDro databases have been used to select the most relevant and influential papers on the intra-arterial cerebral infusions of chemotherapeutics in the treatment of glioblastoma multiforme. Additionally, we have included some relevant clinical trials involving intra-arterial delivery of chemotherapeutics to other than GBM brain tumours.ConclusionConsidering that conventional treatments for glioblastoma multiforme fall short of providing a significant therapeutic benefit, with a majority of patients relapsing, the neuro-oncological community has considered intra-arterial administration of chemotherapeutics as an alternative to oral or intravenous administration. Numerous studies have proven the safety of IA delivery of chemotherapy and its ability to ensure higher drug concentrations in targeted areas, simultaneously limiting systemic toxicity. Nonetheless, the scarcity of phase III trials prevents any declaration of a therapeutic benefit. Given that the likelihood of a single therapeutic agent which will be effective for the treatment of glioblastoma multiforme is extremely low, it is paramount to establish an adequate multimodal therapy which will have a synergistic effect on the diverse pathogenesis of GBM. Precise quantitative and spatial monitoring is necessary to guarantee the accurate delivery of the therapeutic to the tumour. New and comprehensive pharmacokinetic models, a more elaborate understanding of glioblastoma biology and effective methods of diminishing treatment-related neurotoxicity are paramount for intra-arterial cerebral infusion of chemotherapeutics to become a mainstay treatment for glioblastoma multiforme. Additional use of other imaging methods like MRI guidance during the procedure could have an edge over X-ray alone and aid in selecting proper arteries as well as infusion parameters of chemotherapeutics making the procedure safer and more effective.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient’s body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with “glioblastoma”, “CAR-T”, “T cell therapy”, “overall survival”, and “progression free survival” were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard treatments including surgical resection, radiotherapy, and chemotherapy, have failed to significantly improve the prognosis of glioblastoma patients. Currently, immunotherapeutic approaches based on vaccines, chimeric antigen-receptor T-cells, checkpoint inhibitors, and oncolytic virotherapy are showing promising results in clinical trials. The combination of different immunotherapeutic approaches is proving satisfactory and promising. In view of the challenges of immunotherapy and the resistance of glioblastomas, the treatment of these tumors requires further efforts. In this review, we explore the obstacles that potentially influence the efficacy of the response to immunotherapy and that should be taken into account in clinical trials. This article provides a comprehensive review of vaccine therapy for glioblastoma. In addition, we identify the main biomarkers, including isocitrate dehydrogenase, epidermal growth factor receptor, and telomerase reverse transcriptase, known as potential immunotherapeutic targets in glioblastoma, as well as the current status of clinical trials. This paper also lists proposed solutions to overcome the obstacles facing immunotherapy in glioblastomas.

Introduction: Due to its highly aggressiveness and malignancy, glioblastoma (GBM) urgently requires a safe and effective treatment strategy. Zeylenone, a natural polyoxygenated cyclohexenes compound isolated from Uvaria grandiflora, has exhibited potential biological activities in various human diseases, including tumors.Methods: We designed and synthesized a series of (+)-Zeylenone analogues and evaluated their anti-GBM roles through structural-activity analysis. Cell Counting Kit-8, TUNEL, transwell and flow cytometry were employed for investigating the anticancer effects of CA on GBM cells. Western blotting, molecular docking, qRT-PCR and ChIP assays were performed to reveal the underlying mechanisms by which CA regulates the GBM cell cycle. The nude mouse xenograft model, HE staining, immunohistochemistry and was used to evaluate the anticancer effect of CA in vivo.Results: We identified CA ((1R, 2R, 3S)-3-p-fluorobenzoyl-zeylenone) as having the lowest IC50 value in GBM cells. CA treatment significantly inhibited the malignant behaviors of GBM cells and induced G0/G1 phase arrest in vitro. Furthermore, we validated the molecular mechanism by which CA interferes with EZH2, attenuating the down-regulation of cyclin-dependent kinase inhibitors p27 and p16 by the PRC2 complex. By establishing orthotopic nude mice models, we further validated the inhibitory role of CA on tumorigenesis of GBM cells in vivo and its potential values to synergistically potentiate the anti-tumor effects of EZH2 inhibitors.Conclusion: Overall, this paper elucidated the anti-GBM effects and potential mechanisms of CA, and may provide a therapeutic drug candidate for GBM treatment.

GFAPδ, the delta isoform of the glial fibrillary acidic protein, is mainly expressed in the subventricular zone of the brain, together with other neural stem cell markers like nestin. The authors of this paper were among the first that described in detail the expression of GFAPδ and its correlation with malignancy and invasiveness in cerebral astrocytoma. Later, several papers confirmed these findings, showing that the alternative splice variant GFAPδ is overexpressed in glioblastoma (CNS WHO grade 4) compared with lower grade gliomas. Other studies suggested that a high GFAPδ/α ratio is associated with a more malignant and invasive behavior of glioma cells. Moreover, the changing of GFAPδ/α ratio affects the expression of high-malignant genes. It is now suggested that discriminating between predominant GFAP isoforms, GFAPδ or GFAPα, is useful for assessing the malignancy state of astrocytoma, and may even contribute to the classification of gliomas. Therefore, the purpose of this paper is to review the literature with emphasize on the role of GFAPδ as a potential biomarker, and as a possible therapeutic target in glioblastoma.

Glioblastoma (GBM) is a common and highly malignant primary tumor of the central nervous system in adults. Ever more recent papers are focusing on understanding the role of the tumor microenvironment (TME) in affecting tumorigenesis and the subsequent prognosis. We assessed the impact of macrophages in the TME on the prognosis in patients with recurrent GBM. A PubMed, MEDLINE and Scopus review was conducted to identify all studies dealing with macrophages in the GBM microenvironment from January 2016 to December 2022. Glioma-associated macrophages (GAMs) act critically in enhancing tumor progression and can alter drug resistance, promoting resistance to radiotherapy and establishing an immunosuppressive environment. M1 macrophages are characterized by increased secretion of proinflammatory cytokines, such as IL-1ß, tumor necrosis factor (TNF), IL-27, matrix metalloproteinase (MMPs), CCL2, and VEGF (vascular endothelial growth factor), IGF1, that can lead to the destruction of the tissue. In contrast, M2 is supposed to participate in immunosuppression and tumor progression, which is formed after being exposed to the macrophage M-CSF, IL-10, IL-35 and the transforming growth factor-ß (TGF-β). Because there is currently no standard of care in recurrent GBM, novel identified targeted therapies based on the complex signaling and interactions between the glioma stem cells (GSCs) and the TME, especially resident microglia and bone-marrow-derived macrophages, may be helpful in improving the overall survival of these patients in the near future.

Abstract Background Over the last decade, since clinical trials examining targeted therapeutics for gliomas have failed to demonstrate a meaningful increase in survival, the emphasis has recently been switched toward innovative techniques for modulating the immune response against tumors and their microenvironments (TME). Cancerous cells have eleven hallmarks which make it distinct from normal ones, among which is immune evasion. Immune evasion in glioblastoma helps it evade various treatment modalities. Summary Glioblastoma’s TME is composed of various array of cellular actors, ranging from peripherally derived immune cells to a variety of organ-resident specialized cell types. For example, the blood–brain barrier (BBB) serves as a selective barrier between the systemic circulation and the brain, which effectively separates it from other tissues. It is capable of blocking around 98% of molecules that transport different medications to the target tumor. Objectives The purpose of this paper is to offer a concise overview of fundamental immunology and how ‘clever’ gliomas avoid the immune system despite the discovery of immunotherapy for glioma. Conclusions Herein, we highlight the complex interplay of the tumor, the TME, and the nearby normal structures makes it difficult to grasp how to approach the tumor itself. Numerous researchers have found that the brain TME is a critical regulator of glioma growth and treatment efficacy.

Mathematical modeling for cancerous disease has attracted increasing attention from the researchers around the world. Being an effective tool, it helps to describe the processes that happen to the tumour as the diverse treatment scenarios. In this paper, a density-dependent reaction-diffusion equation is applied to the most aggressive type of brain cancer, Glioblastoma multiforme. The model contains the terms responsible for the growth, migration and proliferation of the malignant tumour. The traveling wave solution used is justified by stability analysis. Numerical simulation of the model is provided and the results are compared with the experimental data obtained from the reference papers.

Background and Aim. Oncologists play a vital role in the interpretation of radiographic results in glioblastoma patients. Molecular pathology and information on radiation treatment protocols among others are all important for accurate interpretation of radiology images. One important issue that may arise in interpreting such images is the phenomenon of tumor "pseudoprogression"; oncologists need to be able to distinguish this effect from true disease progression.Exact knowledge about the location of high-dose radiotherapy region is needed for valid determination of pseudoprogression according to RANO (Response Assessment in Neuro-Oncology) criteria in neurooncology. The aim of the present study was to evaluate the radiologists' understanding of a radiotherapy high-dose region in routine clinical practice since radiation oncologists do not always report 3-dimensional isodoses when ordering follow up imaging. Methods: Eight glioblastoma patients who underwent postresection radiotherapy were included in this study. Four radiologists worked with their pre-radiotherapy planning MR, however, they were blinded to RT target volumes which were defined by radiation oncologists according to current guidelines. The aim was to draw target volume for high dose RT fields (that is the region, where they would consider that there may be a pseudoprogression in future MRI scans). Many different indices describing structure differences were analyzed in comparison with original per-protocol RT target volumes. Results: The median volume for RT high dose field was 277 ccm (range 218 to 401 ccm) as defined per protocol by radiation oncologist and 87 ccm (range 32-338) as defined by radiologists (median difference of paired difference 31%, range 15-112%). The Median Dice index of similarity was 0.46 (range 0.14 - 0.78), the median Hausdorff distance 25 mm. Conclusion: Continuing effort to improve education on specific procedures in RT and in radiology as well as automatic tools for exporting RT targets is needed in order to increase specificity and sensitivity in response evaluation.

Abstract This ‘Neurooncology: 2022 update’ presents topics that were selected by the authors as top ten discoveries published in 2021 in the broader field of neurooncological pathology. This time, the spectrum of topics includes: papers with a direct impact on daily diagnostic practice of CNS tumors in general and with information on how to improve grading of meningiomas; studies shedding new light on the oncogenesis of gliomas (in particular ‘optic gliomas’ and H3-mutant gliomas); several ‘multi-omic’ investigations unraveling the intra-tumoral heterogeneity of especially glioblastomas further; a study indicating the potential of ‘repurposing’ Prozac®; for the treatment of glioblastomas; liquid biopsy using CSF for assessment of residual medulloblastoma. In the last part of this review some other papers are mentioned that didn’t make it to this (quite subjective) top ten list.

Human glioblastoma is probably the most malignant and aggressive among cerebral tumors, of which it represents approximately 80% of the reported cases, with an overall survival rate that is quite low. Current therapies include surgery, chemotherapy, and radiotherapy, with associated consistent side effects and low efficacy. The hardness in reaching the site of action, and overcoming the blood–brain barrier, is a major limitation of pharmacological treatments. In this paper, we report the synthesis and characterization of ZIF-90 (ZIF, Zeolitic Imidazolate Framework) nanoparticles as putative carriers of anticancer drugs to the brain. In particular, we successfully evaluated the biocompatibility of these nanoparticles, their stability in body fluids, and their ability to uptake in U251 human glioblastoma cell lines. Furthermore, we managed to synthesize ZIF-90 particles loaded with berberine, an alkaloid reported as a possible effective adjuvant in the treatment of glioblastoma. These findings could suggest ZIF-90 as a possible new strategy for brain cancer therapy and to study the physiological processes present in the central nervous system.

Brain tumors, including glioblastoma multiforme, are currently a cause of suffering and death of tens of thousands of people worldwide. Despite advances in clinical treatment, the average patient survival time from the moment of diagnosis of glioblastoma multiforme and application of standard treatment methods such as surgical resection, radio- and chemotherapy, is less than 4 years. The continuing development of new therapeutic methods for targeting and treating brain tumors may extend life and provide greater comfort to patients. One such developing therapeutic method is photodynamic therapy. Photodynamic therapy is a progressive method of therapy used in dermatology, dentistry, ophthalmology, and has found use as an antimicrobial agent. It has also found wide application in photodiagnosis. Photodynamic therapy requires the presence of three necessary components: a clinically approved photosensitizer, oxygen and light. This paper is a review of selected literature from Pubmed and Scopus scientific databases in the field of photodynamic therapy in brain tumors with an emphasis on glioblastoma treatment.

Glioblastoma (GBL) is the most common (60–70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they have been proven to prolong overall survival. Within an optimal treatment regimen (incl. surgical resection, radiation therapy, and chemotherapy) temozolomide as the current anti-GBL first-line chemotherapeutic has increased the median overall survival to 14–15 months, and the percentage of patients alive at two years has been reported to rise from 10.4% to 26.5%. Though, the effectiveness of temozolomide chemotherapy is limited by the serious systemic, dose-related side effects. Therefore, the ponderation regarding novel treatment methods along with innovative formulations is crucial to emerging the therapeutic potential of the widely used drug simultaneously reducing the drawbacks of its use. Herein the complex temozolomide application restrictions present at different levels of therapy as well as, the currently proposed strategies aimed at reducing those limitations are demonstrated. Approaches increasing the efficacy of anti-GBL treatment are addressed. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for temozolomide delivery and their functionalization towards more effective blood-brain-barrier crossing and/or tumour targeting. Appropriate designing accounting for the physical and chemical features of formulations along with distinct routes of administration is also discussed. In addition, considering the multiple resistance mechanisms, the molecular heterogeneity and the evolution of tumour the purposely selected delivery methods, the combined therapeutic approaches and specifically focused on GBL cells therapies are reviewed.

Introduction. glioblastomas multiforme (grade Iv gliomas) are common and the most aggressive primary tumors of the brain with very unfavorable prognosis. In all previously published papers on epileptiform activity in glioblastomas, not enough information on encephalogram results is presented.Aim. To study the features of epileptiform activity in patients with glioblastomas and development of a plan for further study of these patients.Materials and methods. An analysis of articles from Elsevier, Embase, Scopus, The Cochrane Library, global Health, Russian Science Citation Index (RSCI) databases, Scholar, google, web of Science, pubmed search engines and scientific electronic library CyberLeninka was performed. materials were selected considering journal indexing system and citations, scientific novelty of the studies, statistical significance of the results. publications repeating data from previous articles or describing animal experiments were excluded from analysis.Results. During the study, data on mechanisms of epileptiform activity pathogenesis, predisposing factors (tumor location in the temporal, frontal or parietal lobes, IDH-1 and / or IDH-2 gene mutations), treatment options in patients with glioblastomas were systemized. Additionally, and original plan of data accumulation for clinical studied taking into account limitations of the previous studies was developed to increase quality of results interpretation.Conclusion. Epileptiform symptoms in glioblastomas negatively affect patients’ quality of life and lifespan. Currently, researchers actively search for an effective method of treatment of epileptic seizures in patients with glioblastomas. The most effective is combination of temozolomide with valproate and levetiracetam due to good control of seizure frequency, low toxicity, and pharmacological synergy between the drugs.

Gliomas are malignant brain tumors responsible for 50% of primary human brain cancer cases. They have a combination of rapid growth and invasiveness, and high fatality rates with a median survival time of one year. Mathematical models that describe its growth have helped to improve treatment. In this paper, a combined model formed by terms of two other models known in the literature is analyzed. The combined model is a Reactive-Advective-Diffusive partial differential equation, which is solved by combining the finite difference method, the Crank-Nicolson method and the upwind method. Logistic growth is used for cell proliferation ensuring a saturation threshold for glioma growth, which is crucial to properly estimate patient survival time. The well-known linear-quadratic radiobiological model is used to describe cell death due to radiotherapy treatment. Two initial conditions are compared in the simulations, indicating the need for further studies to have a model as close as possible to reality. Simulation results are shown for four scenarios: no radiotherapy, application of a single dose, and two dose fractionation schemes.

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis and high recurrence rate. The presence of the blood–brain barrier (BBB) prevents diagnostic and therapeutic drugs from penetrating and working in GBM. In traditional surgical treatment, it is difficult to completely distinguish the boundary between tumor and surrounding normal tissue, resulting in incomplete resection of tumor. Therefore, the diagnosis and treatment of GBM are very challenging. Several molecular probes and nanoprobes have been reported to successfully penetrate the BBB, selectively target and accumulate in GBM to achieve in situ imaging of brain tumors, thus achieving accurate diagnosis and treatment of orthotopic or non‐orthotopic GBM. This paper reviews the advances of molecular probes and nanoprobes in image‐guided diagnosis and treatment of GBM. The design principle, application, and advantages of each probe are enumerated in detail. Finally, the prospects and potential challenges of probes in the diagnosis and treatment of GBM are discussed with a view to further promote the study and application of novel imaging probes in GBM.

Objective This paper reports a case of malignant intracranial hypertension, reviews his diagnosis and treatment, and analyzes his etiology, in order to improve the clinicians' cognition of this disease. Methods and Results The patient was a 19⁃year⁃old male with subacute onset and chronic course of disease, presenting with amaurosis, headache, neck and shoulder pain, blurred vision and tinnitus disease. Imaging findings showed cerebral venous sinus stenosis (VSS) with obvious pressure difference at both ends of stenosis. However, venous sinus stenting was ineffective. After optic nerve sheath decompression, the symptoms of headache and blurred vision were not significantly improved. Finally, the patient was diagnosed as glioblastoma (WHO Ⅳ), and died 8 months after removal of the tumor foci. Conclusions Patients with the pressure difference at both ends of malignant intracranial hypertension with VSS should not take stenting. Clarifying the cause and type of stenosis is very important for correct diagnosis and guide treatment.

Glioma is the most common primary intracranial tumor, and most patients present as glioblastoma, with high morbidity and mortality. The prognosis of patients with glioblastoma remains poor after surgical resection combined with standardized treatment of radiotherapy and chemotherapy. In recent years, although the breakthrough of immunotherapy have been achieved in the treatment of a variety of solid tumors, the existing data show that immunotherapy is not effective in improving the survival of patients with glioblastoma. However, studies have shown that immunotherapy can have a synergistic effect with radiotherapy which can increase antigen presentation and promote the formation of pro-inflammatory tumor microenvironment, providing more relevant targets for immunotherapy. The purpose of this paper is to discuss the effect of radiotherapy on tumor immune microenvironment and the role of radiotherapy combined with immune checkpoint inhibitors in the treatment of glioblastoma.

Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.

Abstract Background Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM. Results Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2. Conclusion The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice. Graphical Abstract

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to “glioblastomas,” “immunotherapies,” and “treatment.” The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.

Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor, and the most prevalent primary malignant tumor affecting the brain and central nervous system. Recent research indicates that the genetic profile of GBM makes it resistant to drugs and radiation. However, the main obstacle in treating GBM is transporting drugs through the blood–brain barrier (BBB). Albumin is a versatile biomaterial for the synthesis of nanoparticles. The efficiency of albumin-based delivery systems is determined by their ability to improve tumor targeting and accumulation. In this review, we will discuss the prevalence of human glioblastoma and the currently adopted treatment, as well as the structure and some essential functions of the BBB, to transport drugs through this barrier. We will also mention some aspects related to the blood–tumor brain barrier (BTBB) that lead to poor treatment efficacy. The properties and structure of serum albumin were highlighted, such as its role in targeting brain tumors, as well as the progress made until now regarding the techniques for obtaining albumin nanoparticles and their functionalization, in order to overcome the BBB and treat cancer, especially human glioblastoma. The albumin drug delivery nanosystems mentioned in this paper have improved properties and can overcome the BBB to target brain tumors.

Despite countless papers in the field of radioresistance, researchers are still far from clearly understanding the mechanisms triggered in glioblastoma. Cancer stem cells (CSC) are important to the growth and spread of cancer, according to many studies. In addition, more recently, it has been suggested that CSCs have an impact on glioblastoma patients’ prognosis, tumor aggressiveness, and treatment outcomes. In reviewing this new area of biology, we will provide a summary of the most recent research on CSCs and their role in the response to radio-chemotherapy in GB. In this review, we will examine the radiosensitivity of stem cells. Moreover, we summarize the current knowledge of the biomarkers of stemness and evaluate their potential function in the study of radiosensitivity.

Glioblastoma multiform (GBM) tumor progression has been recognized to be correlated with extracellular matrix (ECM) stiffness. Dynamic variation of tumor ECM is primarily regulated by a family of enzymes which induce remodeling and degradation. In this paper, we investigated the effect of matrix stiffness on the invasion pattern of human glioblastoma tumoroids. A 3D-printed tumor-on-a-chip platform was utilized to culture human glioblastoma tumoroids with the capability of evaluating the effect of stiffness on tumor progression. To induce variations in the stiffness of the collagen matrix, different concentrations of collagenase were added, thereby creating an inhomogeneous collagen concentration. To better understand the mechanisms involved in GBM invasion, an in silico hybrid mathematical model was used to predict the evolution of a tumor in an inhomogeneous environment, providing the ability to study multiple dynamic interacting variables. The model consists of a continuum reaction–diffusion model for the growth of tumoroids and a discrete model to capture the migration of single cells into the surrounding tissue. Results revealed that tumoroids exhibit two distinct patterns of invasion in response to the concentration of collagenase, namely ring-type and finger-type patterns. Moreover, higher concentrations of collagenase resulted in greater invasion lengths, confirming the strong dependency of tumor behavior on the stiffness of the surrounding matrix. The agreement between the experimental results and the model’s predictions demonstrates the advantages of this approach in investigating the impact of various extracellular matrix characteristics on tumor growth and invasion.

Recently, magnetic nanoparticles (MNPs) have more and more often been used in experimental studies on cancer treatments, which have become one of the biggest challenges in medical research. The main goal of this research is to treat and to cure advanced or metastatic cancer with minimal side effects through nanotechnology. Drug delivery approaches take into account the fact that MNPs can be bonded to chemotherapeutical drugs, nucleic acids, synthetized antibodies or radionuclide substances. MNPs can be guided, and different treatment therapies can be applied, under the influence of an external magnetic field. This paper reviews the main MNPs’ synthesis methods, functionalization with different materials and highlight the applications in cancer therapy. In this review, we describe cancer cell monitorization based on different types of magnetic nanoparticles, chemotherapy, immunotherapy, magnetic hyperthermia, gene therapy and ferroptosis. Examples of applied treatments on murine models or humans are analyzed, and glioblastoma cancer therapy is detailed in the review. MNPs have an important contribution to diagnostics, investigation, and therapy in the so called theranostics domain. The main conclusion of this paper is that MNPs are very useful in different cancer therapies, with limited side effects, and they can increase the life expectancy of patients with cancer drug resistance.

Gliomas are the most common primary tumors of the central nervous system. Their aggressive form – glioblastomas is characterized by an unfavorable prognosis and a high frequency of relapses. It is believed that prior traumatic brain injury is one of the possible factors for the subsequent development of glial brain tumors. Several authors have proposed several criteria for establishing a possible causal relationship between traumatic brain injury and gliomas. However, the actual role of antecedent brain injury in the pathogenesis of this tumor type is still a matter of debate. It has been suggested that traumatic injuries cause an active and prolonged inflammatory process, while disrupting the permeability of the blood-brain barrier, which leads to exposure of the brain tissue to carcinogenic (toxic) substances, various growth factors or cells of the immune system circulating in the bloodstream, which ultimately can lead to malignant transformation of glial cells. One of the evidence for this hypothesis is supported by reports of meningiomas located adjacent to posttraumatic meninges and cerebral scars. In this paper, we will try to elucidate the potential relationship between traumatic brain injury and the formation of glial brain tumors.

Glioma-associated macrophage/microglia (GAM) represents a key player in shaping a unique glioma ecosystem to facilitate tumor progression and therapeutic resistance. Numerous studies have been published concerning GAM, but no relevant bibliometric study has been performed yet. Our bibliometric study aimed to comprehensively summarize and analyze the global scientific output, research hotspots, and trendy topics of publications on GAM over time. Data on publications on GAM were collected using the Web of Science (WoS). The search date was 16 January 2022, and the publications were collected from 2002 to 2021. Totally, 1,224 articles and reviews were incorporated and analyzed in the current study. It showed that the annual publications concerning GAM kept increasing over the past 20 years. The United States had the largest number of publications and total citations. Holland, Kettenmann, and Gutmann were the top three authors in terms of citation frequency. Neuro-oncology represented the most influential journal in GAM studies, with the highest H-index, total citations, and publication numbers. The paper published by Hambardzumyan in 2016 had the highest local citations. Additionally, the analysis of keywords implied that “prognosis,” “tumor microenvironment,” and “immunotherapy” might become research hotspots. Furthermore, trendy topics in GAM studies suggested that “immune infiltration,” “immune microenvironment,” “bioinformatics,” “prognosis,” and “immunotherapy” deserved additional attention. In conclusion, this bibliometric study comprehensively analyzed the publication trend of GAM studies for the past 20 years, in which the research hotspots and trendy topics were also uncovered. This information offered scholars critical references for conducting in-depth studies on GAM in the future.

Abstract Glioblastoma is the most common primary brain malignancy and carries with it a poor prognosis. New agents are urgently needed, however nearly all Phase III trials of GBM patients of the past 25 years have failed to demonstrate improvement in outcomes. In 2019, the National Cancer Institute Clinical Trials and Translational Research Advisory Committee (CTAC) Glioblastoma Working Group (GBM WG) identified 5 broad areas of research thought to be important in the development of new herapeutics for GBM. Among those was optimizing radioresponse for GBM in situ. One such strategy to increase radiation efficacy is the addition of a radiosensitizer to improve the therapeutic ratio by enhancing tumor sensitivity while ideally having minimal to no effect on normal tissue. Historically the majority of trials using radiosensitizers have been unsuccessful, but they provide important guidance in what is required to develop agents more efficiently. Improved target selection is essential for a drug to provide maximal benefit, and once that target is identified it must be validated through pre-clinical studies. Careful selection of appropriate in vitro and in vivo models to demonstrate increased radiosensitivity and suitable bioavailability are then necessary to prove that a drug warrants advancement to clinical investigation. Once investigational agents are validated pre-clinically, patient trials require consistency both in terms of planning study design as well as reporting efficacy and toxicity in order to assess the potential benefit of the drug. Through this paper we hope to outline strategies for developing effective radiosensitizers against GBM using as models the examples of XPO1 inhibitors and HDAC inhibitors developed from our own lab.

The presence of the blood–brain barrier (BBB) limits the delivery of therapies into the brain. There has been significant interest in overcoming the BBB for the effective delivery of therapies to the brain. Inorganic nanomaterials, especially silica nanoparticles with varying surface chemistry and surface topology, have been recently used as permeation enhancers for oral protein delivery. In this context, nanoparticles with varying sizes and surface chemistries have been employed to overcome this barrier; however, there is no report examining the effect of nanoscale roughness on BBB permeability. This paper reports the influence of nanoscale surface roughness on the integrity and permeability of the BBB in vitro, using smooth surface Stöber silica nanoparticles (60 nm) compared to rough surface virus-like silica nanoparticles (VSNP, 60 nm). Our findings reveal that VSNP (1 mg/mL) with virus-mimicking-topology spiky surface have a greater effect on transiently opening endothelial tight junctions of the BBB than the same dose of Stöber silica nanoparticles (1 mg/mL) by increasing the FITC-Dextran (70 kDa) permeability 1.9-fold and by decreasing the trans-endothelial electrical resistance (TEER) by 2.7-fold. This proof-of-concept research paves the way for future studies to develop next-generation tailored surface-modified silica nanoparticles, enabling safe and efficient macromolecule transport across the BBB.

Artificial intelligence (AI) is rapidly integrating into diagnostic methods across many branches of medicine. Significant progress has been made in tumor assessment using AI algorithms, and research is underway on how image manipulation can provide information with diagnostic, prognostic and treatment impacts. Glioblastoma (GB) remains the most common primary malignant brain tumor, with a median survival of 15 months. This paper presents literature data on GB imaging and the contribution of AI to the characterization and tracking of GB, as well as recurrence. Furthermore, from an imaging point of view, the differential diagnosis of these tumors can be problematic. How can an AI algorithm help with differential diagnosis? The integration of clinical, radiomics and molecular markers via AI holds great potential as a tool for enhancing patient outcomes by distinguishing brain tumors from mimicking lesions, classifying and grading tumors, and evaluating them before and after treatment. Additionally, AI can aid in differentiating between tumor recurrence and post-treatment alterations, which can be challenging with conventional imaging methods. Overall, the integration of AI into GB imaging has the potential to significantly improve patient outcomes by enabling more accurate diagnosis, precise treatment planning and better monitoring of treatment response.

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of β-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave β-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of β-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance (R2 = 0.82, Q2loo = 0.81). According to the QSAR study, the activity has a strong link with various atoms such as aromatic carbons and ring Sulfur, acceptor atoms, sp2-hybridized oxygen, etc. Following that, a database of 26,467 food compounds was primarily used for QSAR-based virtual screening accompanied by the application of the Lipinski rule of five; the elimination of duplicates, salts, and metal derivatives resulted in a truncated dataset of 8,453 molecules. The molecular descriptor was calculated and a well-validated 6-parametric version of the QSAR model was used to predict the bioactivity of the 8,453 food compounds. Following this, the food compounds whose predicted activity (pKi) was observed above 7.0 M were further docked into the BACE1 receptor which gave rise to the Identification of 4-(3,4-Dihydroxyphenyl)-2-hydroxy-1H-phenalen-1-one (PubChem I.D: 4468; Food I.D: FDB017657) as a hit molecule (Binding Affinity = −8.9 kcal/mol, pKi = 7.97 nM, Ki = 10.715 M). Furthermore, molecular dynamics simulation for 150 ns and molecular mechanics generalized born and surface area (MMGBSA) study aided in identifying structural motifs involved in interactions with the BACE1 enzyme. Molecular docking and QSAR yielded complementary and congruent results. The validated analyses can be used to improve a drug/lead candidate’s inhibitory efficacy against the BACE1. Thus, our approach is expected to widen the field of study of repurposing nutraceuticals into neuroprotective as well as anti-cancer and anti-viral therapeutic interventions.

Tumor treating fields (TTFields) is an anti-cancer technology increasingly used for the treatment of glioblastoma. Recently, cranial burr holes have been used experimentally to enhance the intensity (dose) of TTFields in the underlying tumor region. In the present study, we used computational finite element methods to systematically characterize the impact of the burr hole position and the TTFields transducer array layout on the TTFields distribution calculated in a realistic human head model. We investigated a multitude of burr hole positions and layouts to illustrate the basic principles of optimal treatment planning. The goal of the paper was to provide simple rules of thumb for physicians to use when planning the TTFields in combination with skull remodeling surgery. Our study suggests a number of key findings, namely that (1) burr holes should be placed directly above the region of interest, (2) field enhancement occurs mainly underneath the holes, (3) the ipsilateral array should directly overlap the holes and the contralateral array should be placed directly opposite, (4) arrays in a pair should be placed at far distance and not close to each other to avoid current shunting, and finally (5) rotation arrays around their central normal axis can be done without diminishing the enhancing effect of the burr holes. Minor deviations and adjustments (

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a “combination therapy”, produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time.

BackgroundSeveral studies have confirmed the impact of 5-aminolevulinic acid (5-ALA) on the extent of resection in newly diagnosed glioblastoma (GBM). However, there are controversies on the 5-ALA fluorescence status in recurrent GBM surgery, with specific reference to pseudoprogression or radionecrosis; therefore, the safety and accuracy of surgical planning in 5-ALA-assisted procedures in the recurrent context are still unclear.Materials and MethodsThis is a systematic review and meta-analysis of comparative studies on the use of 5-ALA in newly diagnosed and recurrent GBM, consistently conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data on fluorescence status and correlation between fluorescence and histological findings were collected. We performed a meta-analysis of proportions to estimate the pooled rates of each outcome.ResultsThree online medical databases (PubMed, Scopus, Cochrane Library) were screened, 448 articles were evaluated, and 3 papers were finally included for data analysis. Fluorescence rate was not different between newly diagnosed and recurrent GBM [p = 0.45; odds ratio (OR): 1.23; 95% CI: 0.72–2.09; I2 = 0%], while the rate of 5-ALA fluorescence-positive areas not associated with histological findings of GBM cells was higher in recurrent GBM (p = 0.04; OR: 0.24; 95% CI: 0.06–0.91; I2 = 19%). Furthermore, there were no cases of radionecrosis in false-positive samples, while inflammation and signs of pseudoprogression were found in 81.4% of the cases.Discussion and ConclusionsTherefore, a robust awareness of 5-ALA potentialities and pitfalls in recurrent GBM surgery should be considered for a cognizant surgical strategy. Further clinical trials could confirm the results of the present meta-analysis.

The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.

Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients’ quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM.

Glioblastoma (GBM) is a common and deadly brain tumor with late diagnoses and poor prognoses. Machine learning (ML) is an emerging tool that can create highly accurate diagnostic and prognostic prediction models. This paper aimed to systematically search the literature on ML for GBM metabolism and assess recent advancements. A literature search was performed using predetermined search terms. Articles describing the use of an ML algorithm for GBM metabolism were included. Ten studies met the inclusion criteria for analysis: diagnostic (n = 3, 30%), prognostic (n = 6, 60%), or both (n = 1, 10%). Most studies analyzed data from multiple databases, while 50% (n = 5) included additional original samples. At least 2536 data samples were run through an ML algorithm. Twenty-seven ML algorithms were recorded with a mean of 2.8 algorithms per study. Algorithms were supervised (n = 24, 89%), unsupervised (n = 3, 11%), continuous (n = 19, 70%), or categorical (n = 8, 30%). The mean reported accuracy and AUC of ROC were 95.63% and 0.779, respectively. One hundred six metabolic markers were identified, but only EMP3 was reported in multiple studies. Many studies have identified potential biomarkers for GBM diagnosis and prognostication. These algorithms show promise; however, a consensus on even a handful of biomarkers has not yet been made.