"Doctor, what would you do if you were me?" - A survey of physician perspectives toward glioblastoma resection.

OBJECTIVE: How maximal safe resection (MSR) of glioblastoma is implemented in the clinical setting remains understudied. Here, we utilized a survey-based approach to understand physician perspectives on this matter. METHODS: Scenarios involving glioblastomas were presented to physicians who were asked to select from planned sub-total resection (STR), gross total resection (GTR), medical therapy only, or palliative care. Demographic, experience, and Likert scales of value assessment were collected. RESULTS: In the scenario involving a corpus callosum glioblastoma, 2.33% opted for GTR. For a right frontal glioblastoma, 91.7% opted for GTR. In contrast, only 30.8% chose GTR of a right motor strip glioblastoma (p< 0.001). When presented with a left motor strip glioblastoma, fewer respondents (12.7%,p < 0.001) opted for GTR. Physicians who placed a high value on preserving physical independence were more likely to forgo GTR for right motor glioblastomas (HR=0.068,95% CI:0.47-0.97,p=0.035), and physicians who placed a high value on their faith were more likely to opt for surgical treatments that differ from the general consensus, for instance opting for GTR of the corpus callosum glioblastoma (HR=4.18,95%CI:1.63-10.74,p=0.003). No other associations were found between the choice for GTR and other variables collected. INTERPRETATION: Our results suggest that while maximal safe resection remains a guiding principle for glioblastoma resection, physician preference in terms of the extent of resection varies significantly as a function of tumor location and personal values.

Diagnosing Progression in Glioblastoma-Tackling a Neuro-Oncology Problem Using Artificial-Intelligence-Derived Volumetric Change over Time on Magnetic Resonance Imaging to Examine Progression-Free Survival in Glioblastoma.

Glioblastoma (GBM) is the most aggressive and the most common primary brain tumor, defined by nearly uniform rapid progression despite the current standard of care involving maximal surgical resection followed by radiation therapy (RT) and temozolomide (TMZ) or concurrent chemoirradiation (CRT), with an overall survival (OS) of less than 30% at 2 years. The diagnosis of tumor progression in the clinic is based on clinical assessment and the interpretation of MRI of the brain using Response Assessment in Neuro-Oncology (RANO) criteria, which suffers from several limitations including a paucity of precise measures of progression. Given that imaging is the primary modality that generates the most quantitative data capable of capturing change over time in the standard of care for GBM, this renders it pivotal in optimizing and advancing response criteria, particularly given the lack of biomarkers in this space. In this study, we employed artificial intelligence (AI)-derived MRI volumetric parameters using the segmentation mask output of the nnU-Net to arrive at four classes (background, edema, non-contrast enhancing tumor (NET), and contrast-enhancing tumor (CET)) to determine if dynamic changes in AI volumes detected throughout therapy can be linked to PFS and clinical features. We identified associations between MR imaging AI-generated volumes and PFS independently of tumor location, MGMT methylation status, and the extent of resection while validating that CET and edema are the most linked to PFS with patient subpopulations separated by district rates of change throughout the disease. The current study provides valuable insights for risk stratification, future RT treatment planning, and treatment monitoring in neuro-oncology.

Cadherin Expression Profiles Define Glioblastoma Differentiation and Patient Prognosis.

Cadherins are cell-cell adhesion proteins which have been strongly implicated in cancer invasion, dissemination and metastasis capacity; thus, they are key players in the epithelial-to-mesenchymal transition (EMT) program. However, their role in glioblastoma (GBM), a primary central nervous system aggressive tumor, remains to be clarified. N-, E- and P-cadherin expression was analyzed on a large series of GBMs, characterized with clinical, imaging and neuropathological parameters, as well as with patients' survival data. In addition, cadherins' expression was studied in match-recurrent cases. Using TCGA data, cadherin expression profiles were also evaluated according to GBM transcription subtypes. N-cadherin expression was observed in 81.5% of GBM, followed by E-cadherin in 31% and P-cadherin in 20.8%. Upon tumor recurrence, P-cadherin was the only significantly upregulated cadherin compared with the primary tumor, being positive in 65.8% of the cases. Actually, P-cadherin gain was observed in 51.4% of matched primary-recurrent cases. Cadherins' co-expression was also explored. Interestingly, E- and N-cadherin co-expression identified a GBM subgroup with frequent epithelial differentiation and a significant survival benefit. On the other hand, subgroups with P-cadherin expression carried the worse prognosis. P- and N-cadherin co-expression correlated with the presence of a mesenchymal phenotype. Expressions of isolated P-cadherin or E- and P-cadherin co-expression were associated with imaging characteristics of aggressiveness, to highly heterogeneous tumors, an d to worse patient survival. Classical cadherins co-expression subgroups present consistent clinical, imaging, neuropathological and survival differences, which probably reflect different states of an EMT-like program in GBM.

Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression.

Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type (EGFRwt) gene amplification and/or EGFRvIII activating mutation. EGFR-driven GBM relies on the thioredoxin (Trx) and/or glutathione (GSH) antioxidant systems to withstand the excessive production of reactive oxygen species (ROS). The impact of EGFRwt or EGFRvIII overexpression on the response to a Trx/GSH co-targeting strategy is unknown. In this study, we investigated Trx/GSH co-targeting in the context of EGFR overexpression in GBM. Auranofin is a thioredoxin reductase (TrxR) inhibitor, FDA-approved for rheumatoid arthritis. L-buthionine-sulfoximine (L-BSO) inhibits GSH synthesis by targeting the glutamate-cysteine ligase catalytic (GCLC) enzyme subunit. We analyzed the mechanisms of cytotoxicity of auranofin and the interaction between auranofin and L-BSO in U87MG, U87/EGFRwt, and U87/EGFRvIII GBM isogenic GBM cell lines. ROS-dependent effects were assessed using the antioxidant N-acetylsteine. We show that auranofin decreased TrxR1 activity and increased ROS. Auranofin decreased cell vitality and colony formation and increased protein polyubiquitination through ROS-dependent mechanisms, suggesting the role of ROS in auranofin-induced cytotoxicity in the three cell lines. ROS-dependent PARP-1 cleavage was associated with EGFRvIII downregulation in U87/EGFRvIII cells. Remarkably, the auranofin and L-BSO combination induced the significant depletion of intracellular GSH and synergistic cytotoxicity regardless of EGFR overexpression. Nevertheless, molecular mechanisms associated with cytotoxicity were modulated to a different extent among the three cell lines. U87/EGFRvIII exhibited the most prominent ROS increase, P-AKT(Ser-473), and AKT decrease along with drastic EGFRvIII downregulation. U87/EGFRwt and U87/EGFRvIII displayed lower basal intracellular GSH levels and synergistic ROS-dependent DNA damage compared to U87MG cells. Our study provides evidence for ROS-dependent synergistic cytotoxicity of auranofin and L-BSO combination in GBM in vitro. Unraveling the sensitivity of EGFR-overexpressing cells to auranofin alone, and synergistic auranofin and L-BSO combination, supports the rationale to repurpose this promising pro-oxidant treatment strategy in GBM.

Liquid Biopsy in Whole Blood for Identification of Gene Expression Patterns (mRNA and miRNA) Associated with Recurrence of Glioblastoma WHO CNS Grade 4.

GBM WHO CNS Grade 4 represents a major challenge for oncology due to its aggressive behavior. Conventional imaging has restrictions in detecting tumor recurrence. This prospective study aims to identify gene-based biomarkers in whole blood instead of isolating exosomes for the early detection of tumor recurrence. Blood samples (n = 33) were collected from seven GBM patients at time points before and after surgery as well as upon tumor recurrence. Four tumor tissue samples were assessed in parallel. Next-generation sequencing (NGS), including mRNA-seq and small RNA-seq, was used to analyze gene expression profiles in blood samples and tumor tissues. A novel filtering pipeline was invented to narrow down potential candidate genes. In total, between 6-93 mRNA and 1-19 small RNA candidates could be identified among the seven patients. The overlap of genes between the patients was minimal, indicating significant inter-individual variance among GBM patients. In summary, this prospective study supports the applicability of gene expression measurements in whole blood for the detection of tumor recurrence. It might provide an alternative to the challenging workflow of liquid biopsy after laborious exosome isolation from whole blood.

A New Vista of Aldehyde Dehydrogenase 1A3 (ALDH1A3): New Specific Inhibitors and Activity-Based Probes Targeting ALDH1A3 Dependent Pathways in Glioblastoma, Mesothelioma and Other Cancers.

Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.

Deep Residual Learning-Based Classification with Identification of Incorrect Predictions and Quantification of Cellularity and Nuclear Morphological Features in Digital Pathological Images of Common Astrocytic Tumors.

Interobserver variations in the pathology of common astrocytic tumors impact diagnosis and subsequent treatment decisions. This study leveraged a residual neural network-50 (ResNet-50) in digital pathological images of diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma to recognize characteristic pathological features and perform classification at the patch and case levels with identification of incorrect predictions. In addition, cellularity and nuclear morphological features, including axis ratio, circularity, entropy, area, irregularity, and perimeter, were quantified via a hybrid task cascade (HTC) framework and compared between different characteristic pathological features with importance weighting. A total of 95 cases, including 15 cases of diffuse astrocytoma, 11 cases of anaplastic astrocytoma, and 69 cases of glioblastoma, were collected in Taiwan Hualien Tzu Chi Hospital from January 2000 to December 2021. The results revealed that an optimized ResNet-50 model could recognize characteristic pathological features at the patch level and assist in diagnosis at the case level with accuracies of 0.916 and 0.846, respectively. Incorrect predictions were mainly due to indistinguishable morphologic overlap between anaplastic astrocytoma and glioblastoma tumor cell area, zones of scant vascular lumen with compact endothelial cells in the glioblastoma microvascular proliferation area mimicking the glioblastoma tumor cell area, and certain regions in diffuse astrocytoma with too low cellularity being misrecognized as the glioblastoma necrosis area. Significant differences were observed in cellularity and each nuclear morphological feature among different characteristic pathological features. Furthermore, using the extreme gradient boosting (XGBoost) algorithm, we found that entropy was the most important feature for classification, followed by cellularity, area, circularity, axis ratio, perimeter, and irregularity. Identifying incorrect predictions provided valuable feedback to machine learning design to further enhance accuracy and reduce errors in classification. Moreover, quantifying cellularity and nuclear morphological features with importance weighting provided the basis for developing an innovative scoring system to achieve objective classification and precision diagnosis among common astrocytic tumors.

Evaluation of the Immunomodulatory Effects of Radiation for Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme.

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM.

Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma.

Objectives: CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma. Methods: We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion function in vitro (using real-time impedance, flow cytometry, imaging and bead-based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma). Results: FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells. Conclusions: Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.

Nodular Melanoma in a 53-year-old Male with Glioblastoma Multiforme: A Rare Case Report.

Although melanoma only accounts for 1% of skin cancers, it is responsible for most skin cancer deaths. Glioblastoma multiforme, a high-grade astrocytoma, is the most aggressive and devastating primary brain tumor. These two diseases remain to be the biggest therapeutic challenge in both specialties of dermatology and neuro-oncology. A 53-year-old Filipino male who presented with a 2-year history of generalized dark brown and black patches on the body developed weakness and numbness of the left extremities. Biopsy and immunohistochemical staining of the skin revealed nodular melanoma with adjacent regressing melanoma. Biopsy of the intracranial mass showed glioblastoma multiforme. One month after the partial excision of the intracranial mass, the patient expired due to brain herniation. Nodular melanoma and glioblastoma multiforme may occur concomitantly in a patient. A review of the literature suggests a shared genetic predisposition. Its existence carries a poor prognosis and requires early detection to start aggressive treatment.

Epidemiology of malignant gliomas in Iran: first report of Iranian National Population-based Cancer Registry, 2009-2017.

OBJECTIVE: Malignant gliomas constitute the most common type of primary malignant brain tumors. Most previous studies have evaluated the epidemiology of malignant gliomas in developed countries. Hence, there is a lack of evidence in this regard from developing countries. This study is the first epidemiological report on the status of malignant glioma in Iran between 2009 and 2017. METHODS: Data from the Iranian National Population-based Cancer Registry (covering 98% of the Iranian population) on CNS tumors recorded from 2009 to 2017 were used for analysis. Age-adjusted incidence rates were calculated by sex, tumor histology, tumor site, and year of diagnosis. Trend analysis of incidence rates was also performed. Survival data were recorded and the Cox proportional hazards model was used to evaluate underlying risk factors. RESULTS: A total of 8484 patients were diagnosed with malignant glioma between 2009 and 2017 in Iran. The overall age-adjusted incidence rate of malignant gliomas over the 9-year period was 1.71 per 100,000 persons. The most common histology of malignant gliomas was glioblastoma (81.4%). A significant increase in the incidence of malignant gliomas was found between 2009 and 2012. The median overall survival was 13.0 (95% CI 12.6-13.5) months over the study period. Older age groups, higher tumor grade, male sex, the first half of the study period, and receiving no treatment were significantly associated with worse prognoses. CONCLUSIONS: This study is the latest epidemiological report on the status of malignant gliomas in Iran. Although the overall incidence rate was lower than the rates in developed countries, several findings were consistent with those in prior reports.

Porphyrin-Based Organic Nanoparticles with NIR-IIa Fluorescence for Orthotopic Glioblastoma Theranostics.

The development of efficient theranostic nanoagents for the precise diagnosis and targeted therapy of glioblastoma (GBM) remains a big challenge. Herein, we designed and developed porphyrin-based organic nanoparticles (PNP NPs) with strong emission in the near-infrared IIa window (NIR-IIa) for orthotopic GBM theranostics. PNP NPs possess favorable photoacoustic and photothermal properties, high photostability, and low toxicity. After modification with the RGD peptide, the obtained PNPD NPs exhibited enhanced blood-brain barrier (BBB) penetration capability and GBM targeting ability. NIR-IIa imaging was employed to monitor the in vivo biodistribution and accumulation of the nanoparticles, revealing a significant enhancement in penetration depth and signal-to-noise ratio. Both in vitro and in vivo results demonstrated that PNPD NPs effectively inhibited the proliferation of tumor cells and induced negligible side effects in normal brain tissues. In general, the work presented a kind of brain-targeted porphyrin-based NPs with NIR-IIa fluorescence for orthotopic glioblastoma theranostics, showing promising prospects for clinical translation.

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues for GBM treatment. However, challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness hinder their effectiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.

2-Methoxyestradiol, an Endogenous 17ß-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oligodendroglial Precursor Cells and Triggers Endoreduplication via the p53 Pathway.

The abnormal growth of oligodendrocyte precursor cells (OPCs) significantly contributes to the progression of glioblastoma tumors. Hence, molecules that block OPC growth may be of therapeutic importance in treating gliomas. 2-Methoxyestradiol (2ME), an endogenous tubulin-interacting metabolite of estradiol, is effective against multiple proliferative disorders. Based on its anti-carcinogenic and anti-angiogenic actions, it is undergoing phase II clinical trials. We hypothesize that 2ME may prevent glioma growth by targeting OPC growth. Here, we tested this hypothesis by assessing the impact of 2ME on the growth of an OPC line, "Oli-neu", and dissected the underlying mechanism(s). Treatment with 2ME inhibited OPC growth in a concentration-dependent manner, accompanied by significant upregulation in the expression of p21 and p27, which are negative cell-cycle regulators. Moreover, treatment with 2ME altered OPC morphology from multi-arm processes to rounded cells. At concentrations of 1uM and greater, 2ME induced apoptosis, with increased expressions of caspase 3, PARP, and caspase-7 fragments, externalized phosphatidylserine staining/APOPercentage, and increased mitochondrial activity. Flow cytometry and microscopic analysis demonstrated that 2ME triggers endoreduplication in a concentration-dependent fashion. Importantly, 2ME induced cyclin E, JNK1/2, and p53 expression, as well as OPC fusion, which are key mechanisms driving endoreduplication and whole-genome duplication. Importantly, the inhibition of p53 with pifithrin-α rescued 2ME-induced endoreduplication. The pro-apoptotic and endoreduplication actions of 2ME were accompanied by the upregulation of survivin, cyclin A, Cyclin B, Cyclin D2, and ppRB. Similar growth inhibitory, apoptotic, and endoreduplication effects of 2ME were observed in CG4 cells. Taken together, our findings provide evidence that 2ME not only inhibits OPC growth and triggers apoptosis, but also activates OPCs into survival (fight or flight) mode, leading to endoreduplication. This inherent survival characteristic of OPCs may, in part, be responsible for drug resistance in gliomas, as observed for many tubulin-interacting drugs. Importantly, the fate of OPCs after 2ME treatment may depend on the cell-cycle status of individual cells. Combining tubulin-interfering molecules with drugs such as pifithrin-α that inhibit endoreduplication may help inhibit OPC/glioma growth and limit drug resistance.

Simplifying synthesis of the expanding glioblastoma literature: a topic modeling approach.

PURPOSE: Our study aims to discover the leading topics within glioblastoma (GB) research, and to examine if these topics have "hot" or "cold" trends. Additionally, we aim to showcase the potential of natural language processing (NLP) in facilitating research syntheses, offering an efficient strategy to dissect the landscape of academic literature in the realm of GB research. METHODS: The Scopus database was queried using "glioblastoma" as the search term, in the "TITLE" and "KEY" fields. BERTopic, an NLP-based topic modeling (TM) method, was used for probabilistic TM. We specified a minimum topic size of 300 documents and 5% probability cutoff for outlier detection. We labeled topics based on keywords and representative documents and visualized them with word clouds. Linear regression models were utilized to identify "hot" and "cold" topic trends per decade. RESULTS: Our TM analysis categorized 43,329 articles into 15 distinct topics. The most common topics were Genomics, Survival, Drug Delivery, and Imaging, while the least common topics were Surgical Resection, MGMT Methylation, and Exosomes. The hottest topics over the 2020s were Viruses and Oncolytic Therapy, Anticancer Compounds, and Exosomes, while the cold topics were Surgical Resection, Angiogenesis, and Tumor Metabolism. CONCLUSION: Our NLP methodology provided an extensive analysis of GB literature, revealing valuable insights about historical and contemporary patterns difficult to discern with traditional techniques. The outcomes offer guidance for research directions, policy, and identifying emerging trends. Our approach could be applied across research disciplines to summarize and examine scholarly literature, guiding future exploration.

Prognostic value of surgical resection over biopsy in elderly patients with glioblastoma: a meta-analysis.

PURPOSE: Maximal-safe resection has been shown to improve overall survival in elderly patients with glioblastoma in observational studies, however, the only clinical trial comparing resection versus biopsy in elderly patients with surgically-accessible glioblastoma showed no improvements in overall survival. A meta-analysis is needed to assess whether surgical resection of glioblastoma in older patients improves surgical outcomes when compared to biopsy alone. METHODS: A search was conducted until October 9th, 2023, to identify published studies reporting the clinical outcomes of glioblastoma patients > 65 years undergoing resection or biopsy (PubMed, MEDLINE, EMBASE, and COCHRANE). Primary outcomes were overall survival (OS), progression-free survival (PFS), and complications. We analyzed mean difference (MD) and hazard ratio (HR) for survival outcomes. Postoperative complications were analyzed as a dichotomic categorical variable with risk ratio (RR). RESULTS: From 784 articles, 20 cohort studies and 1 randomized controlled trial met our inclusion criteria, considering 20,523 patients for analysis. Patients undergoing surgical resection had an overall survival MD of 6.13 months (CI 95%=2.43-9.82, p = < 0.001) with a HR of 0.43 (95% CI = 0.35-0.52, p = < 0.00001). The progression-free survival MD was 2.34 months (95%CI = 0.79-3.89, p = 0.003) with a 0.50 h favoring resection (95%CI = 0.37-0.68, p = < 0.00001). The complication RR was higher in the resection group favoring biopsy (1.49, 95%CI = 1.06-2.10). CONCLUSIONS: Our meta-analysis suggests that upfront resection is associated with improved overall survival and progression-free survival in elderly patients with newly diagnosed glioblastoma over biopsy. However, postoperative complications are more common with resection. Future clinical trials are essential to provide more robust evaluation in this challenging patient population.

Glioblastoma stem cell long non-coding RNAs: therapeutic perspectives and opportunities.

Glioblastoma poses a formidable challenge among primary brain tumors: its tumorigenic stem cells, capable of self-renewal, proliferation, and differentiation, contribute substantially to tumor initiation and therapy resistance. These glioblastoma stem cells (GSCs), resembling conventional stem and progenitor cells, adopt pathways critical for tissue development and repair, promoting uninterrupted tumor expansion. Long non-coding RNAs (lncRNAs), a substantial component of the human transcriptome, have garnered considerable interest for their pivotal roles in normal physiological processes and cancer pathogenesis. They display cell- or tissue-specific expression patterns, and extensive investigations have highlighted their impact on regulating GSC properties and cellular differentiation, thus offering promising avenues for therapeutic interventions. Consequently, lncRNAs, with their ability to exert regulatory control over tumor initiation and progression, have emerged as promising targets for innovative glioblastoma therapies. This review explores notable examples of GSC-associated lncRNAs and elucidates their functional roles in driving glioblastoma progression. Additionally, we delved deeper into utilizing a 3D in vitro model for investigating GSC biology and elucidated four primary methodologies for targeting lncRNAs as potential therapeutics in managing glioblastoma.

The effects of the combination therapy of chemotherapy drugs on the fluctuations of genes involved in the TLR signaling pathway in glioblastoma multiforme therapy.

One of the most lethal and aggressive types of malignancies with a high mortality rate and poor response to treatment is glioblastoma multiforme (GBM). This means that modernizing the medications used in chemotherapy, in addition to medicines licensed for use in other illnesses and chosen using a rationale process, can be beneficial in treating this illness. Meaningly, drug combination therapy with chemical or herbal originations or implanting a drug wafer in tumors to control angiogenesis is of great importance. Importantly, the primary therapeutic hurdles in GBM are the development of angiogenesis and the blood-brain barrier (BBB), which keeps medications from getting to the tumor. This malignancy can be controlled if the drug's passage through the BBB and the VEGF (vascular endothelial growth factor), which promotes angiogenesis, are inhibited. In this way, the effect of combination therapy on the genes of different main signaling pathways like TLRs may be indicated as an impressive therapeutic strategy for treating GBM. This article aims to discuss the effects of chemotherapeutic drugs on the expression of various genes and associated translational factors involved in the TLR signaling pathway.

Inhibition of PERK mediated UPR acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma.

BACKGROUND: Glioblastoma due to recurrence is clinically challenging with 10-15months overall survival. Previously we showed therapy induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate TIS reversal mechanism for potential therapeutic intervention to prevent GBM recurrence. METHODS: Residual senescent (RS) and End of Residual Senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenario. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays and IHCs were performed for mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model. RESULTS: Transcriptome analysis showed co-expression of ER stress-UPR and senescence associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, ROS, DNA damage and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1ß, suppressed SASP and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in Endoplasmic reticulum, RS cells displayed stressed ER morphology, upregulated ER stress markers and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21 and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival. CONCLUSION: We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma.

Dissecting causal relationships between gut microbiota, blood metabolites, and glioblastoma multiforme: a two-sample Mendelian randomization study.

Background: Given the increasing interest in the role of gut microbiota in glioblastoma multiforme (GBM), our objective was to examine the potential causal relationship between gut microbiota and GBM, as well as the mediating effects of specific metabolites. Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the associations between 196 microbial taxa and GBM. A two-step MR technique was used to identify significant mediators in this relationship. Subsequently, a mediation analysis was performed to explore and quantify the mediating effects of specific metabolites on the causal relationship between gut microbiota and GBM. Results: Five taxa showed significant associations with GBM. Among them, family Victivallaceae [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.21, 3.13; p = 0.005] and genus Lactococcus (OR: 1.81; 95% CI: 1.04, 3.15; p = 0.036) were positively correlated with the risk of GBM, while phylum Cyanobacteria had a protective effect against GBM (OR: 0.45; 95% CI: 0.22, 0.89; p = 0.021). The mediation analysis revealed that the connections among family Victivallaceae, genus Lactococcus, phylum Cyanobacteria and GBM were mediated by Methyl-4-hydroxybenzoate sulfate, phosphoethanolamine and dehydroepiandrosterone sulfate. Each of these accounted for 7.27, 7.98, and 8.65%, respectively. Conclusion: Our study provides evidence supporting a potential causal association between certain gut microbiota taxa and GBM. The study highlights the central role of gut microbiota in GBM pathogenesis and their interactions with vital serum metabolites. This paves the way for potential novel therapeutic interventions in GBM management.