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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 socioeconomic stresses on GBM risk and outcomes to identify opportunities for intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper discusses the challenges in treating high-grade gliomas, particularly glioblastomas, which are aggressive brain tumors with high recurrence rates. It highlights the limitations of current diagnostic imaging modalities, such as gadolinium-based MRI, in accurately detecting tumor recurrence versus treatment-related changes. The paper explores the emerging role of positron emission tomography (PET) in glioma imaging, especially with the use of radiotracers like PSMA, which can help differentiate between tumor recurrence and treatment effects. Furthermore, the paper reviews the concept of theranostics, which integrates diagnostics and therapy, offering a targeted approach to glioma treatment. It discusses various radioligands, including PSMA, 213Bi-DOTA-substance P, 90Y-DOTATOC, 18F-FDOPA, p-[131I]-iodo-L-phenylalanine, and 18F-GE-180, which have shown promise in diagnosing and treating recurrent gliomas. The potential of theranostics to minimize systemic toxicity and improve treatment outcomes is emphasized. Moreover, the paper highlights the importance of considering quality-of-life (QOL) outcomes in glioma patients, as conventional treatments often have significant impacts on patients' well-being. While theranostics offers a personalized approach to treatment, its potential promise for functional outcomes and QOL needs further investigation. The paper suggests that future research should focus on understanding the broader implications of theranostics on patient well-being, incorporating factors such as demographics, tumor characteristics, and treatment-related effects into QOL assessments. Overall, the paper underscores the potential of theranostics to revolutionize glioma management and improve patient outcomes in the future. Gliomas represent the most commonly occurring tumors in the central nervous system and account for approximately 80% of all malignant primary brain tumors. With a high malignancy and recurrence risk, the prognosis of high-grade gliomas is poor, with a mean survival time of 12–18 months. While contrast-enhanced MRI serves as the standard diagnostic imaging modality for gliomas, it faces limitations in the evaluation of recurrent gliomas, failing to distinguish between treatment-related changes and tumor progression, and offers no direct therapeutic options. Recent advances in imaging modalities have attempted to address some of these limitations, including positron emission tomography (PET), which has demonstrated success in delineating tumor margins and guiding the treatment of recurrent gliomas. Additionally, with the advent of theranostics in nuclear medicine, PET tracers, when combined with therapeutic agents, have also evolved beyond a purely diagnostic modality, serving both diagnostic and therapeutic roles. This review will discuss the growing involvement of theranostics in diagnosing and treating recurrent gliomas and address the associated impact on quality of life and functional recovery. [ABSTRACT FROM AUTHOR]

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 antiinflammatory 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. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the emerging area of the therapeutic use of chimeric antigen receptor (CAR)-T cells in nervous tissue tumors. Through a detailed analysis of the existing literature, this paper highlights the most recent applications of CAR-T cells to the therapy of pediatric and adult nervous system neoplasia. Furthermore, it discusses the potential mechanisms underlying sensitivity or resistance to CAR-T cell-based therapies. Overall, this review underscores the importance of CAR-T cell therapies to the treatment of some nervous system tumors. Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies. [ABSTRACT FROM AUTHOR]

Context: One of the most common aggressive and primary brain tumors is glioma. The majority of diagnoses are referred to high-grade malignant glioblastoma, which carries the worst prognosis. Still, treatment of brain tumors remains a big challenge for clinicians. This study was designed to investigate the efficacy of gene therapy in the treatment of brain cancer. Methods: Studies use genes as a therapeutic agent in brain cancer treatment even alone or in combination with other treatment methods. Full-text papers, which met the inclusion criteria, were independently assessed by two reviewers. Disagreements were resolved by consultation with a third reviewer. Results: Statistical analysis showed that 50% of the papers used a virus, 36% used polymers, and 14% used cells as carriers to transfect the genes as a therapeutic agent in brain tumor models. Data showed that the estimated size of the brain tumor was reduced by using co-treatment of the gene with one of the conventional therapies. Conclusions: According to the results, co-treatment of the gene with conventional therapies could be more effective than the monotherapy methods. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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Simple Summary: Currently, contrast-enhancing gliomas FLAIRectomies or supramarginal gliresections are gaining momentum. This paper presents a semiquantitative analysis of FET uptake in biopsy targets inside and outside glioma masses based on PET/MR images. An exact threshold to differentiate glioma and astrogliosis within FLAIR using dual-timepoint PET acquisition and referring to various anatomical structures is a major strength of this study. Doing so paves the way for an optimized PET protocol to enable precise and reproducible FET-PET quantification for glioma mapping in clinical trials and practice. Accurately defining glioma infiltration is crucial for optimizing radiotherapy and surgery, but glioma infiltration is heterogeneous and MRI imperfectly defines the tumor extent. Currently, it is impossible to determine the tumor infiltration gradient within a FLAIR signal. O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET often reveals high-grade glioma infiltration beyond contrast-enhancing areas on MRI. Here, we studied FET uptake dynamics in tumor and normal brain structures by dual-timepoint (10 min and 40–60 min post-injection) acquisition to optimize analysis protocols for defining glioma infiltration. Over 300 serial stereotactic biopsies from 23 patients (mean age 47, 12 female/11 male) of diffuse contrast-enhancing gliomas were taken from areas inside and outside contrast enhancement or outside the FET hotspot but inside FLAIR. The final diagnosis was G4 in 11, grade 3 in 10, and grade 2 in 2 patients. The target-to-background (TBRs) ratios and standardized uptake values (SUVs) were calculated in areas used for biopsy planning and in background structures. The optimal method and threshold values were determined to find a preferred strategy for defining glioma infiltration. Standard thresholding (1.6× uptake in the contralateral brain) in standard acquisition PET images differentiated a tumor of any grade from astrogliosis, although the uptake in astrogliosis and grade 2 glioma was similar. Analyzing an optimal strategy for infiltration volume definition astrogliosis could be accurately differentiated from tumor samples using a choroid plexus as a background. Early acquisition improved the AUC in many cases, especially within FLAIR, from 56% to 90% sensitivity and 41% to 61% specificity (standard TBR 1.6 vs. early TBR plexus). The current FET-PET evaluation protocols for contrast-enhancing gliomas are limited, especially at the tumor border where grade 2 tumor and astrogliosis have similar uptake, but using choroid plexus uptake in early acquisitions as a background, we can precisely define a tumor within FLAIR that was outside of the scope of current FET-PET protocols. [ABSTRACT FROM AUTHOR]

Gene identification for genetic diseases is critical for the development of new diagnostic approaches and personalized treatment options. Prioritization of gene translation is an important consideration in the molecular biology field, allowing researchers to focus on the most promising candidates for further investigation. In this paper, we discussed different approaches to prioritize genes for translation, including the use of computational tools and machine learning algorithms, as well as experimental techniques such as knockdown and overexpression studies. We also explored the potential biases and limitations of these approaches and proposed strategies to improve the accuracy and reliability of gene prioritization methods. Although numerous computational methods have been developed for this purpose, there is a need for computational methods that incorporate tissue-specific information to enable more accurate prioritization of candidate genes. Such methods should provide tissue-specific predictions, insights into underlying disease mechanisms, and more accurate prioritization of genes. Using advanced computational tools and machine learning algorithms to prioritize genes, we can identify potential targets for therapeutic intervention of complex diseases. This represents an up-and-coming method for drug development and personalized medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is an aggressive brain cancer. Despite progress made in cancer research, patients diagnosed with glioblastomas continue to have a poor rate of survival. Lipidomics is a field of study that seeks to comprehend the structure and function of lipids, otherwise known as fats. Glioblastomas have demonstrated imbalance in lipids, and, therefore, lipidomics shows promise as an avenue to better understand glioblastomas. This paper reviews the literature on lipidomics in glioblastomas and suggests future directions for lipidomic research into the diagnosis, prognosis, and treatment of glioblastomas. Glioblastoma is the most aggressive primary brain malignancy in adults, and has a survival duration of approximately 15 months. First line treatment involves surgical resection, chemotherapy, and radiation, but despite the multi-pronged approach and advances in cancer research, glioblastoma remains devastating with a high mortality rate. Lipidomics is an emerging discipline that studies lipid pathways and characteristics, and is a promising field to understand biochemical mechanisms. In glioblastoma, disrupted lipid homeostasis has been reported in the literature. A thorough understanding of serum lipidomics may offer ways to better understand glioblastoma biomarkers, prognosis, and treatment options. Here, we review the literature, offering future directions for lipidomics research in glioblastomas. [ABSTRACT FROM AUTHOR]

In this paper, we introduce a mathematical model given by ... where ... to enhance established mathematical methodologies for better understanding glioblastoma dynamics at the macroscopic scale. The tumor growth model exhibits an innovative structure even within the conventional framework, including a proliferation term, f (u), presented in a different form compared to existing macroscopic glioblastoma models. Moreover, it represents a further refined model by incorporating a calibration criterion based on the integration of a fractional derivative, a, which differs from the existing models for glioblastoma. Throughout this study, we initially discuss the modeling dynamics of the tumor growth model. Given the frequent recurrence observed in glioblastoma cases, we then track tumor mass formation and provide predictions for tumor visibility timing on medical imaging to elucidate the recurrence periods. Furthermore, we investigate the correlation between tumor growth speed and survival duration to uncover the relationship between these two variables through an experimental approach. To conduct these patient-specific analyses, we employ glioblastoma patient data and present the results via numerical simulations. In conclusion, the findings on tumor visibility timing align with empirical observations, and the investigations into patient survival further corroborate the well-established inter-patient variability for glioblastoma cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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, qRTPCR 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 antitumor 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. [ABSTRACT FROM AUTHOR]

Background: Glioma patients suffer from a wide range of symptoms which influence quality of life negatively. The aim of this review is to give an overview of symptoms most prevalent in glioma patients throughout the total disease trajectory, to be used as a basis for the development of a specific glioma Patient Reported Outcome Measure (PROM) for early assessment and monitoring of symptoms in glioma patients.Methods: A systematic review focused on symptom prevalence in glioma patients in different phases of disease and treatment was performed in MEDLINE, CINAHL and EMBASE according to PRISMA recommendations. We calculated weighted means for prevalence rates per symptom.Results: The search identified 2.074 unique papers, of which 32 were included in this review. In total 25 symptoms were identified. The ten most prevalent symptoms were: seizures (37%), cognitive deficits (36%), drowsiness (35%), dysphagia (30%), headache (27%), confusion (27%), aphasia (24%), motor deficits (21%), fatigue (20%) and dyspnea (20%).Conclusions: Eight out of ten of the most prevalent symptoms in glioma patients are related to the central nervous system and therefore specific for glioma. Our findings emphasize the importance of tailored symptom care for glioma patients and may aid in the development of specific PROMs for glioma patients in different phases of the disease. [ABSTRACT FROM AUTHOR]

Keywords: ASIC; fear conditioning; desensitization; amiloride; pain; immune activation; glioblastoma; cell signaling EN ASIC fear conditioning desensitization amiloride pain immune activation glioblastoma cell signaling 1 3 3 02/02/22 20220131 NES 220131 The receptor for protons was first reported by Krishtal and Pidoplichko in the early 1980s (Krishtal and Pidoplichko, [3], [4]). We expect this collection of papers will further contribute to potentiate the ASIC research progress and understanding of the specific role of ASICs in physiology, pathology, and pharmaceutical potential. ASIC, fear conditioning, desensitization, pain, immune activation, amiloride, cell signaling, glioblastoma. [Extracted from the article]

Simple Summary: The new trends in the research on glioblastomas (GBMs) are focusing on understanding the crosstalk between proper neoplastic tissue and its microenvironment. Against this background, the extracellular matrix (ECM) has been classically linked to a purely structural role. However, it has recently become clear that it actively shapes the functional responses of cells to their environment as well. While many components of the ECM have been isolated and characterized, its modifications in the specific setting of GBMs have only been recently explored in the literature. The aim of this paper is to provide a systematic review on the topic and to assess the ECM's role in shaping tumoral development. Background and aim: While many components of the ECM have been isolated and characterized, its modifications in the specific setting of GBMs have only been recently explored in the literature. The aim of this paper is to provide a systematic review on the topic and to assess the ECM's role in shaping tumoral development. Methods: An online literature search was launched on PubMed/Medline and Scopus using the research string "((Extracellular matrix OR ECM OR matrix receptor OR matrix proteome) AND (glioblastoma OR GBM) AND (tumor invasion OR tumor infiltration))", and a systematic review was conducted in accordance with the PRISMA-P guidelines. Results: The search of the literature yielded a total of 693 results. The duplicate records were then removed (n = 13), and the records were excluded via a title and abstract screening; 137 studies were found to be relevant to our research question and were assessed for eligibility. Upon a full-text review, 59 articles were finally included and were summarized as follows based on their focus: (1) proteoglycans; (2) fibrillary proteins, which were further subdivided into the three subcategories of collagen, fibronectin, and laminins; (3) glycoproteins; (4) degradative enzymes; (5) physical forces; (6) and glioma cell and microglia migratory and infiltrative patterns. Conclusions: Our systematic review demonstrates that the ECM should not be regarded anymore as a passive scaffold statically contributing to mechanical support in normal and pathological brain tissue but as an active player in tumor-related activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) generally recurs locally with a dismal median survival of <18 months. Combining thermal therapy with radiation therapy enhances radiation response and improves clinical outcomes. This study evaluates a thermobrachytherapy balloon implant intended for the simultaneous heat and radiation treatment of tumor resection cavities. The data demonstrate that our prototype implant produces spherically symmetric heat and radiation dose distributions around the balloon, while the in vivo experiments confirm our ability to heat ≥40 °C at a 5 mm distance from the balloon surface in highly perfused pig brain tissue. The device is now ready for the finalization of regulatory approvals in anticipation of early-stage clinical investigation. Previous work has reported the design of a novel thermobrachytherapy (TBT) balloon implant to deliver magnetic nanoparticle (MNP) hyperthermia and high-dose-rate (HDR) brachytherapy simultaneously after brain tumor resection, thereby maximizing their synergistic effect. This paper presents an evaluation of the robustness of the balloon device, compatibility of its heat and radiation delivery components, as well as thermal and radiation dosimetry of the TBT balloon. TBT balloon devices with 1 and 3 cm diameter were evaluated when placed in an external magnetic field with a maximal strength of 8.1 kA/m at 133 kHz. The MNP solution (nanofluid) in the balloon absorbs energy, thereby generating heat, while an HDR source travels to the center of the balloon via a catheter to deliver the radiation dose. A 3D-printed human skull model was filled with brain-tissue-equivalent gel for in-phantom heating and radiation measurements around four 3 cm balloons. For the in vivo experiments, a 1 cm diameter balloon was surgically implanted in the brains of three living pigs (40–50 kg). The durability and robustness of TBT balloon implants, as well as the compatibility of their heat and radiation delivery components, were demonstrated in laboratory studies. The presence of the nanofluid, magnetic field, and heating up to 77 °C did not affect the radiation dose significantly. Thermal mapping and 2D infrared images demonstrated spherically symmetric heating in phantom as well as in brain tissue. In vivo pig experiments showed the ability to heat well-perfused brain tissue to hyperthermic levels (≥40 °C) at a 5 mm distance from the 60 °C balloon surface. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GB) is characterized by a high level of resistance to radiotherapy. Recent studies focused attention on the importance of cancer stem cells (CSC) as elements that influence not only the growth of GB but also its resistance to available treatments. Therefore, stem cells' radiosensitivity has become an important area of investigation. In this context, biomarkers of stemness (namely, the ability of a cell to perpetuate its lineage, give rise to differentiated cells, and interact with its environment to maintain a balance between quiescence, proliferation, and regeneration) seem to play an important role. The aim of this review is to summarize findings both on stem cells' radiosensitivity and on biomarkers of stemness, in order to evaluate their relevance in this field. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK–STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common, aggressive and malignant type of glioma, with poor prognosis, despite advances in medical knowledge and technology. It's known that some microRNAs (miRNAs) can be dysregulated and associated with tumors. We aim to investigate miRNAs that may have a role as potential biomarkers in human glioblastoma. A search was performed using PubMed, LILACS and SCIELO databases to find papers from 2015 to 2020, related to human in vitro and ex vivo data. From 99 articles, 10 were eligible and 13 dysregulated miRNAs were found with description of regulation, target(s), pathway(s) and mechanism(s). The miRNAs of interest were found and seem to be involved in development and progression of glioblastoma and used as target therapies. Understanding the mechanisms in which those miRNAs are involved and their role in epigenetic pathways that lead to cancer, as well as their potential in clinical application, may improve GBM clinical outcome (CRD42020182706, 07/10/2020, retrospectively registered). [ABSTRACT FROM AUTHOR]

Objective: To 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 intraarterial 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. Method: 159 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. Conclusion: Considering 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. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme represent > 50% of primary gliomas and have five year survival rates of ~ 5%. Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide remains the standard treatment since published by Stupp et al. (in N Engl J Med 352:987-996, 2005), with additional benefit for patients with MGMT-methylated tumors. We review the current treatment landscape and ongoing efforts to improve these outcomes. An extensive literature search of Pubmed and Google Scholar involving the search terms "glioblastoma," "glioblastoma multiforme," or "GBM" for papers published to July 2021 was conducted and papers evaluated for relevance. As well as current data that informs clinical practice, we review ongoing clinical research in both newly diagnosed and recurrent settings that provides hope for a breakthrough. The Stupp protocol remains standard of care in 2021. Addition of tumor treating fields improved mOS modestly, with benefit seen in MGMT-methylated and unmethylated cohorts and also improved time to cognitive decline but has not been widely adopted. The addition of lomustine to temozolomide, in MGMT-methylated patients, also showed a mOS benefit but further investigation is required. Other promising therapeutic strategies including anti-angiogenic therapy, targeted therapy, and immunotherapy have yet to show a survival advantage. Improvements in the multidisciplinary management, surgical techniques and equipment, early palliative care, carrier support, and psychological support may be responsible for improving survival over time. Despite promising preclinical rationale, immunotherapy and targeted therapy are struggling to impact survival. A number of ongoing clinical trials provide hope for a breakthrough. [ABSTRACT FROM AUTHOR]

Background: Possible advantages of magnetic resonance (MR)-guided radiation therapy (MRgRT) for the treatment of brain tumors include improved definition of treatment volumes and organs at risk (OARs) that could allow margin reductions, resulting in limited dose to the OARs and/or dose escalation to target volumes. Recently, hybrid systems integrating a linear accelerator and an magnetic resonance imaging (MRI) scan (MRI-linacs, MRL) have been introduced, that could potentially lead to a fully MRI-based treatment workflow. Methods: We performed a systematic review of the published literature regarding the adoption of MRL for the treatment of primary or secondary brain tumors (last update November 3, 2022), retrieving a total of 2487 records; after a selection based on title and abstracts, the full text of 74 articles was analyzed, finally resulting in the 52 papers included in this review. Results and discussion: Several solutions have been implemented to achieve a paradigm shift from CT-based radiotherapy to MRgRT, such as the management of geometric integrity and the definition of synthetic CT models that estimate electron density. Multiple sequences have been optimized to acquire images with adequate quality with on-board MR scanner in limited times. Various sophisticated algorithms have been developed to compensate the impact of magnetic field on dose distribution and calculate daily adaptive plans in a few minutes with satisfactory dosimetric parameters for the treatment of primary brain tumors and cerebral metastases. Dosimetric studies and preliminary clinical experiences demonstrated the feasibility of treating brain lesions with MRL. Conclusions: The adoption of an MRI-only workflow is feasible and could offer several advantages for the treatment of brain tumors, including superior image quality for lesions and OARs and the possibility to adapt the treatment plan on the basis of daily MRI. The growing body of clinical data will clarify the potential benefit in terms of toxicity and response to treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper describes a new MR imaging technique known as downfield MR spectroscopic imaging (DF-MRSI) that has only recently been shown to be possible in the human brain on commonly available 3 Tesla MRI scanners. This is the first application of this methodology to human brain tumors. Purpose: To investigate the use of 3D downfield proton magnetic resonance spectroscopic imaging (DF-MRSI) for evaluation of tumor recurrence in patients with glioblastoma (GBM). Methods: Seven patients (4F, age range 44–65 and mean ± standard deviation 59.3 ± 7.5 years) with previously treated GBM were scanned using a recently developed 3D DF-MRSI sequence at 3T. Short TE 3D DF-MRSI and water reference 3D-MRSI scans were collected with a nominal spatial resolution of 0.7 cm3. DF volume data in eight slices covered 12 cm of brain in the cranio-caudal axis. Data were analyzed using the 'LCModel' program and a basis set containing nine peaks ranging in frequency between 6.83 to 8.49 ppm. The DF8.18 (assigned to amides) and DF7.90 peaks were selected for the creation of metabolic images and statistical analysis. Longitudinal MR images and clinical history were used to classify brain lesions as either recurrent tumor or treatment effect, which may include necrosis. DF-MRSI data were compared between lesion groups (recurrent tumor, treatment effect) and normal-appearing brain. Results: Of the seven brain tumor patients, two were classified as having recurrent tumor and the rest were classified as treatment effect. Amide metabolite levels from recurrent tumor regions were significantly (p < 0.05) higher compared to both normal-appearing brain and treatment effect regions. Amide levels in lesion voxels classified as treatment effect were significantly lower than normal brain. Conclusions: 3D DF-MRSI in human brain tumors at 3T is feasible and was well tolerated by all patients enrolled in this preliminary study. Amide levels measured by 3D DF-MRSI were significantly different between treatment effect and tumor regrowth. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common malignant brain tumor associated with a poor prognosis, with a median survival of 14 months. Despite initial treatment with surgery, radiotherapy, and chemotherapy, recurrence is the usual situation. Controversy remains over the best treatment strategy for recurrent disease, and there is no standard of treatment in this situation. Different forms of treatment have been addressed, including a surgical procedure or radiotherapy, systemic treatment with chemotherapy or targeted drugs, and different immunotherapy strategies. Knowledge of the data from these studies allows for improved decision-making in this clinical situation. Glioblastoma is a disease with a poor prognosis. Multiple efforts have been made to improve the long-term outcome, but the 5-year survival rate is still 5–10%. Recurrence of the disease is the usual way of progression. In this situation, there is no standard treatment. Different treatment options can be considered. Among them would be reoperation or reirradiation. There are different studies that have assessed the impact on survival and the selection of patients who may benefit most from these strategies. Chemotherapy treatments have also been considered in several studies, mainly with alkylating agents, with data mostly from phase II studies. On the other hand, multiple studies have been carried out with target-directed treatments. Bevacizumab, a monoclonal antibody with anti-angiogenic activity, has demonstrated activity in several studies, and the FDA has approved it for this indication. Several other TKI drugs have been evaluated in this setting, but no clear benefit has been demonstrated. Immunotherapy treatments have been shown to be effective in other types of tumors, and several studies have evaluated their efficacy in this disease, both immune checkpoint inhibitors, oncolytic viruses, and vaccines. This paper reviews data from different studies that have evaluated the efficacy of different forms of relapsed glioblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper, we report on the inhibition of glioblastoma (GBM) cell growth and migration by the putative S1PR1 modulator ACT-2009905, using appropriate in vitro models. This work is based on our previously published finding that S1PR1 expression is strongly up-regulated in human glioblastoma samples and the fact that there is an association between S1PR1 with patients' survival times. We now show that pharmacological modulation by the putative S1PR1 modulator ACT-209905 inhibits GBM cell growth and migration. Furthermore, we investigated the influence of co-culture of GBM cells with THP-1 cells as a model for human monocytes, showing pro-tumoral effects and arguing for a complex interplay between GBM cells, immune cells and underlying signaling pathways. We believe that this manuscript fits the interests of the readership of the journal Cancers as it addresses the impact of alternative therapeutic options using ACT-209905 for improving GBM therapy. Glioblastoma (GBM) is still a deadly tumor due to its highly infiltrative growth behavior and its resistance to therapy. Evidence is accumulating that sphingosine-1-phosphate (S1P) acts as an important tumor-promoting molecule that is involved in the activation of the S1P receptor subtype 1 (S1PR1). Therefore, we investigated the effect of ACT-209905 (a putative S1PR1 modulator) on the growth of human (primary cells, LN-18) and murine (GL261) GBM cells. The viability and migration of GBM cells were both reduced by ACT-209905. Furthermore, co-culture with monocytic THP-1 cells or conditioned medium enhanced the viability and migration of GBM cells, suggesting that THP-1 cells secrete factors which stimulate GBM cell growth. ACT-209905 inhibited the THP-1-induced enhancement of GBM cell growth and migration. Immunoblot analyses showed that ACT-209905 reduced the activation of growth-promoting kinases (p38, AKT1 and ERK1/2), whereas THP-1 cells and conditioned medium caused an activation of these kinases. In addition, ACT-209905 diminished the surface expression of pro-migratory molecules and reduced CD62P-positive GBM cells. In contrast, THP-1 cells increased the ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905. In conclusion, our study suggests the role of S1PR1 signaling in the growth of GBM cells and gives a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive and infiltrative glioma, classified as Grade IV, with the poorest survival rate among patients. Accurate and rigorously tested mechanistic in silico modeling offers great value to understand and quantify the progression of primary brain tumors. This paper presents a continuum‐based finite element framework that is built on high performance computing, open‐source libraries to simulate glioblastoma progression. We adopt the established proliferation invasion hypoxia necrosis angiogenesis model in our framework to realize scalable simulations of cancer, and has demonstrated to produce accurate and efficient solutions in both two‐ and three‐dimensional brain models. The in silico solver can successfully implement arbitrary order discretization schemes and adaptive remeshing algorithms. A model sensitivity analysis is conducted to test the impact of vascular density, cancer cell invasiveness and aggressiveness, the phenotypic transition potential, including that of necrosis, and the effect of tumor‐induced angiogenesis in the evolution of glioblastoma. Additionally, individualized simulations of brain cancer progression are carried out using pertinent magnetic resonance imaging data, where the in silico model is used to investigate the complex dynamics of the disease. We conclude by arguing how the proposed framework can deliver patient‐specific simulations of cancer prognosis and how it could bridge clinical imaging with modeling. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies. Methods: A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information's PubMed database. Results: A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization. Conclusion: In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood–brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery. [ABSTRACT FROM AUTHOR]

Simple Summary: We present eight core attributes of cancer growth that we must address for a more effective treatment than we currently have. To do this we outline why a regimen simultaneously using many different drugs will be needed. At our current state of knowledge, even adding two or three drugs will not counter all the growth attributes of a currently incurable cancer. We show in this paper, the details of how an example six drug regimen, when added alongside of current traditional treatments, might inhibit enough of the eight core growth driving elements to allow those standard treatments to be more effective. We further show how medicines from general medical practice used to treat pain, fungal infections, psychosis, leprosy and other non-cancer related illnesses can be repurposed to block cancer cells' survival pathways and growth drives. In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells' growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Several 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 Methods: This 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. Results: Three 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 Conclusions: Therefore, 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. [ABSTRACT FROM AUTHOR]

High-grade gliomas (HGGs) constitute the most common malignant primary brain tumor with a poor prognosis despite the standard multimodal therapy. In recent years, immunotherapy has changed the prognosis of many cancers, increasing the hope for HGG therapy. We conducted a comprehensive search on PubMed, Scopus, Embase, and Web of Science databases to include relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Fifty-two papers were finally included (44 phase II and eight phase III clinical trials) and further divided into four different subgroups: 14 peptide vaccine trials, 15 dendritic cell vaccination (DCV) trials, six immune checkpoint inhibitor (ICI) trials, and 17 miscellaneous group trials that included both "active" and "passive" immunotherapies. In the last decade, immunotherapy created great hope to increase the survival of patients affected by HGGs; however, it has yielded mostly dismal results in the setting of phase III clinical trials. An in-depth analysis of these clinical results provides clues about common patterns that have led to failures at the clinical level and helps shape the perspective for the next generation of immunotherapies in neuro-oncology. [ABSTRACT FROM AUTHOR]

Chlorotoxin (CTX), a peptide derived from scorpion venom, is used to detect chloride channels. CTX targets cancer cells like glioblastoma (GBM) via GBM-specific chloride channels. CTX-based uses in GBM focused on diagnostic, imaging, and therapeutic techniques. After discovering CTX, researchers began screening different scorpion venoms for peptides with CTX-like characteristics. CTX and its derivatives have been studied for their effects on GBM for over 20 years; however, there is no systematic assessment of these studies in the literature. This is the first systematic review examining the association between CTX and GBM. Through a comprehensive systematic review and analysis of existing literature, we ultimately evaluated and cross-related 22 papers published over 22 years (1999–2023). This systematic review strives to advance our understanding of the role of CTX in GBM treatment. These outcomes could shape future research directions in neuro-oncology. [ABSTRACT FROM AUTHOR]

In this paper, we proposed a lightweight two-dimensional (2D) methodology to predict the survival time of Glioblastoma Multiforme patients. Firstly, we trained the 2D ResUNet-SEG (Residual UNet for Segmentation) model to perform semantic segmentation on brain tumour subregions. Then, we used the raw and segmented MRI volumes along with clinical data to train the 2D CNN-SP (Convolutional Neural Network for Survival Prediction) model to predict the survival time in days. The experiments showed that our proposed methodology achieved an accuracy of 0.517, Mean Square Error of 136,783.42, MSE, Median Square Error (medianSE) of 106,608.6, Standard Deviation Error (stdSE) of 139,210.8, and SpearmanR correlation score of 0.299 on the Multimodal Brain Tumour Segmentation (BraTS) 2020 validation set. The obtained results are competitive compared to the state-of-the-art automated techniques for survival prognosis of GBM patients validated on the same set of patients. Results proved that Deep Learning (DL) based feature learning is better than existing Machine Learning based techniques with handcrafted radiomics based feature extraction. It eliminates the need for feature selection as well. However, the results achieved are limited due to the unavailability of vast clinical data required to train Convolutional Neural Network (CNN) based deep architectures. [ABSTRACT FROM AUTHOR]

With the increasing availability of biomedical data from multiple platforms of the same patients in clinical research, such as epigenomics, gene expression, and clinical features, there is a growing need for statistical methods that can jointly analyze data from different platforms to provide complementary information for clinical studies. In this paper, we propose a two‐stage hierarchical Bayesian model that integrates high‐dimensional biomedical data from diverse platforms to select biomarkers associated with clinical outcomes of interest. In the first stage, we use Expectation Maximization‐based approach to learn the regulating mechanism between epigenomics (e.g., gene methylation) and gene expression while considering functional gene annotations. In the second stage, we group genes based on the regulating mechanism learned in the first stage. Then, we apply a group‐wise penalty to select genes significantly associated with clinical outcomes while incorporating clinical features. Simulation studies suggest that our model‐based data integration method shows lower false positives in selecting predictive variables compared with existing method. Moreover, real data analysis based on a glioblastoma (GBM) dataset reveals our method's potential to detect genes associated with GBM survival with higher accuracy than the existing method. Moreover, most of the selected biomarkers are crucial in GBM prognosis as confirmed by existing literature. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]