Management Of Glioblastoma Research Articles

P01.08.A HYOXIA-INDUCED EXPRESSION OF ARHGAP FAMILY MEMBERS PROMOTES GLIOBLASTOMA DISSEMINATION

Abstract BACKGROUND The Rho GTPase activating proteins (ARHGAPs) perform vital roles in the regulation of the Rho GTPases with direct effect on cellular plasticity and cell migration/invasion. We recently reported on the role of five ARHGAPs, identified by a microarray screen, in morphological plasticity in established and patient-derived Glioblastoma (GBM) cell lines and associated clinical relevance in terms of tumour recurrence after treatment. We established that the ARHGAPs either promoted or targeted cell migration/invasion by allowing cells to undergo morphological changes in preparation for dissemination. We also showed that co-expression of two ARHGAPs, 12 and 29, is associated with reduced time to recurrence after initial treatment in patients. ARHGAP activity has been also reported in metastatic cancers including breast and colorectal cancer highlighting the biological relevance of these, as yet understudied, proteins. MATERIAL AND METHODS Here, we explored the GBM microenvironment and the effect of hypoxia on ARHGAP expression and localisation in glioma cell lines. RESULTS Using immunocytological and in vitro migration and invasion assays we were able to ascertain that ARHGAP4, 12, 22, 25 and 29 acquired subcellular distributions different to those recorded under normoxia and expression also decreased or increased under hypoxia. We also found that the effect of the migrastatic inhibitor 6-bromo-indirubin-3′-oxime (BIO) targeting GSK-3 signalling was potentiated when cells were challenged with the drug under hypoxic conditions. CONCLUSION Our results confirm our initial findings of biological relevance of the ARHGAPs in cellular activities and highlight important roles for the ARHGAPs for promoting migratory/invasive activity and behaviour in GBM cells. We also conclude that migrastatic inhibitors will exert enhanced activity on GBM cells under hypoxic conditions making them excellent candidates for complement treatment with cytotoxic drugs or radiotherapy for an improved management of GBM.

Unlocking the Potential of Circulating miRNAs as Biomarkers in Glioblastoma

Using microRNAs (miRNAs) as potential circulating biomarkers in diagnosing and treating glioblastoma (GBM) has garnered a lot of scientific and clinical impetus in the past decade. As an aggressive primary brain tumor, GBM poses challenges in early detection and effective treatment with significant current diagnostic constraints and limited therapeutic strategies. MiRNA dysregulation is present in GBM. The intricate involvement of miRNAs in altering cell proliferation, invasion, and immune escape makes them prospective candidates for identifying and monitoring GBM diagnosis and response to treatment. These miRNAs could play a dual role, acting as both potential diagnostic markers and targets for therapy. By modulating the activity of various oncogenic and tumor-suppressive proteins, miRNAs create opportunities for precision medicine and targeted therapies in GBM. This review centers on the critical role and function of circulating miRNA biomarkers in GBM diagnosis and treatment. It highlights their significance in providing insights into disease progression, aiding in early diagnosis, and potential use as targets for novel therapeutic interventions. Ultimately, the study of miRNA would contribute to improving patient outcomes in the challenging landscape of GBM management.

Efficacy and Cognitive Outcomes of Gamma Knife Radiosurgery in Glioblastoma Management for Elderly Patients.

Gamma Knife Radiosurgery (GKRS), a specific type of Stereotactic Radiosurgery (SRS), has developed as a significant modality in the treatment of glioblastoma, particularly in conjunction with standard chemotherapy. The goal of this study is to evaluate the efficacy of combining GKRS with surgical resection and chemotherapy in enhancing therapeutic effects for glioblastoma patients aged 55 years and older. This prospective clinical study, conducted in accordance with the STROBE guidelines, involved 49 glioblastoma patients aged 55 years and older, treated between January 2013 and January 2023. Data were collected prospectively, and strict adherence to the STUPP protocol was maintained. Only patients who conformed to the STUPP protocol were included in the analysis. Due to concerns regarding the cognitive impairment associated with conventional radiotherapy, and at the patients' request, a radiosurgery plan was offered. Radiosurgery was administered for 4-8 weeks following surgical resection. Any patients who had not received previous radiotherapy received open surgical tumor removal, followed by GKRS along with adjuvant chemotherapy. In this prospective clinical study of 49 glioblastoma patients aged 55 years and older, the average lifespan post-histopathological diagnosis was established at 22.3 months (95% CI: 12.0-28.0 months). The median time before disease progression was 14.3 months (95% CI: 13.0-29.7 months). The median duration until the first recurrence after treatment was 15.2 months, with documented cases varying between 4 and 33 months. The Gamma Knife Radiosurgery (GKRS) treatment involved a median marginal recommended dose of 12.5 Gy, targeting an average volume of 5.7 cm3 (range: 1.6-39 cm3). Local recurrence occurred in 21 patients, while distant recurrence was identified in 8 patients. Within the cohort, 34 patients were subjected to further therapeutic approaches, including reoperation, a second GKRS session, the administration of bevacizumab and irinotecan, and PCV chemotherapy. A cognitive function assessment revealed that the patients treated with GKRS experienced significantly less cognitive decline compared to the historical controls, who were treated with conventional radiotherapy. The median MMSE scores declined by 1.9 points over 12 months, and the median MoCA scores declined by 2.9 points. This study demonstrates that Gamma Knife Radiosurgery (GKRS), when integrated with surgical resection and adjuvant chemotherapy, offers a substantial benefit for glioblastoma patients aged 55 years and older. The data reveal that GKRS not only prolongs overall survival and progression-free survival but also significantly reduces cognitive decline compared to conventional radiotherapy. These findings underscore the efficacy and safety of GKRS, advocating for its incorporation into standard treatment protocols for older glioblastoma patients. The potential of GKRS to improve patient outcomes while preserving cognitive function is compelling and warrants further research to optimize and confirm its role in glioblastoma management.

Recent Advances in Marine-Derived Nanoformulation for the Management of Glioblastoma.

Glioma is the most common and aggressive type of central nervous system tumor as categorized by the World Health Organization. Glioblastoma (GBA), in general, exhibits a grim prognosis and short life expectancy, rarely exceeding 14months. The dismal prognosis is primarily attributed to the development of chemoresistance to temozolomide, the primary therapeutic agent for GBA treatment. Hence, it becomes imperative to develop novel drugs with antitumor efficacy rooted in distinct mechanisms compared to temozolomide. The vast marine environment contains a wealth of naturally occurring compounds from the sea (known as marine-derived natural products), which hold promise for future research in the quest for new anticancer drugs. Ongoing advancements in anticancer pharmaceuticals have led to an upswing in the isolation and validation of numerous pioneering breakthroughs and improvements in anticancer therapeutics. Nonetheless, the availability of FDA-approved marine-derived anticancer drugs remains limited, owing to various challenges and constraints. Among these challenges, drug delivery is a prominent hurdle. This review delves into an alternative approach for delivering marine-derived drugs using nanotechnological formulations and their mechanism of action for treating GBA.

Radiotherapeutic advances in the management of glioblastoma.

Glioblastoma remains a fatal diagnosis despite continuous efforts to improve upon the current standard backbone management paradigm of surgery, radiation therapy, systemic therapy and Tumor Treating Fields. Radiation therapy (RT) plays a pivotal role, with progress recently achieved in multiple key areas of research. The evolving landscape of dose and fractionation schedules and dose escalation options for different patient populations is explored, offering opportunities to better tailor treatment to a patient's overall status and preferences; novel efforts to modify treatment volumes are presented, such as utilizing state-of-the-art MRI-based linear accelerators to deliver adaptive therapy, hoping to reduce normal tissue exposure and treatment-related toxicity; specialized MR techniques and functional imaging using novel PET agents are described, providing improved treatment accuracy and the opportunity to target areas at risk of disease relapse; finally, the role of particle therapy and new altered dose-rate photon and proton therapy techniques in the treatment paradigm of glioblastoma is detailed, aiming to improve tumor control and patient outcome by exploiting novel radiobiological pathways. Improvements in each of these aforementioned areas are needed to make the critical necessary progress and allow for new approaches combining different advanced treatment modalities. This plethora of multiple new treatment options currently under investigation provides hope for a new outlook for patients with glioblastoma in the near future.

A cancer-associated fibroblasts related risk score (CAFscore) helps to guide prognosis and personal treatment for Glioblastoma

BackgroundRecent studies have identified the presence of cancer-associated fibroblasts (CAFs) within glioblastoma (GBM), yet their biological roles and underlying mechanisms remain poorly understood. This study aimed to construct a CAF-related prognostic model to guide patient prognosis and treatment strategies.MethodWe employed various bioinformatics methods, including enrichment analysis, Weighted Gene Co-expression Network Analysis (WGCNA), Lasso regression analysis, and machine learning techniques such as XGBoost and Random Forest, to develop a novel risk index termed CAFscore. Patients were stratified into high and low CAFscore groups for subsequent survival analysis. The area under the curve (AUC) and concordance index (C-index) for CAFscore were calculated and compared against other clinical characteristics and existing prognostic models. Drug sensitivity assessments were conducted using the Oncopredict package. Functional validation of key genes was performed through scratch and invasion assays in GBM cells.ResultsOur analyses revealed four core CAF-related genes, leading to the establishment of CAFscore. Notably, patients in the high CAFscore group exhibited significantly reduced survival and exhibited enrichment in epithelial-mesenchymal transition (EMT) and inflammation response pathways. Furthermore, CAFscore showed a significant negative correlation with the sensitivity to irinotecan and its analogs, while demonstrating a positive correlation with sensitivity to 505,124 (a TGFβRI inhibitor). LRP10 emerged as a central gene within the CAFscore, displaying markedly elevated expression in GBM and a strong association with CAF infiltration. Silencing LRP10 significantly inhibited the invasive capabilities of GBM cells.ConclusionThis study presented the first CAF related prognostic model (CAFscore) in GBM, and demonstrated that the model could effectively guide patient prognosis and potentially inform personalized treatment strategies. The core gene of CAFscore, LRP10, was significantly overexpressed in GBM and might play a pivotal role in regulating CAF infiltration as well as tumor invasion and metastasis, highlighting LRP10 as a promising therapeutic target for GBM management.

In vivo pharmacokinetic study of carmustine in rats after giving single-dose of carmustine API solution, flexible liposomes, in situ nasal gel, optimized flexible liposomes embedded in situ nasal gel, and marketed formulation

Carmustine is used in the treatment of glioblastoma (GBM). GBM is a well-known life-threatening type of cancerous tumor. GBM covers 60.00% among all primary brain tumors, with an occurrence of 74,000 cases across the globe. Management for GBM is still very difficult because most of the medicines are unable to cross the blood-brain barrier (BBB). The present work observed that flexible liposomes embedded in situ nasal gel of carmustine is the best brain-targeted medicine delivery system for the management of GBM through the nasal route. To evaluate in vivo pharmacokinetic parameters of carmustine formulations administered through nasal routes in Wistar rats. In this work, different pharmacokinetic parameters were determined for carmustine formulations viz. carmustine API (Active Pharmaceutical Ingredient) solution, flexible liposomes, in situ thermoreversible intranasal gel, optimized flexible liposomes embedded in situ thermoreversible intranasal gel via intranasal administration in rats, and compared with marketed intravenous injection of carmustine administered through intravenous route. Carmustine was estimated with the help of a validated high-performance liquid chromatography (HPLC) approach. Three to four-months-old normal Wistar rats of either sex, having a weight of 200-250 grams were used in this study. Intranasal administration of optimized flexible liposomes embedded in situ nasal gel showed greater Cmax (∼two-fold), AUC0→t (∼three-fold), AUC0→∞ (∼six-fold), and decreased Tmax (1h) data in the brain, than commercial intravenous injection of carmustine. The plasma concentration of carmustine administered through nasal route was found to be comparatively lower than intravenous administration, indicating lower systemic exposure to carmustine via the nasal route. In vivo pharmacokinetics results revealed that the optimized flexible liposomes embedded in situ nasal gel of carmustine can effectively deliver carmustine to brain by nasal drug delivery system in Wistar rats.

Risk Factors of Distant Recurrence and Dissemination of IDH Wild-Type Glioblastoma: A Single-Center Study and Meta-Analysis.

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) is a highly aggressive brain tumor with a high recurrence rate despite adjuvant treatment. This study aimed to evaluate the risk factors for non-local recurrence of GBM. In the present study, we analyzed 104 GBMs with a single lesion (non-multifocal or multicentric). Univariate analysis revealed that subventricular zone (SVZ) involvement was significantly associated with non-local recurrence (hazard ratio [HR]: 2.09 [1.08-4.05]). Tumors in contact with the trigone of the lateral ventricle tended to develop subependymal dissemination (p = 0.008). Ventricular opening via surgery did not increase the risk of non-local recurrence in patients with SVZ involvement (p = 0.190). A systematic review was performed to investigate the risk of non-local recurrence, and 21 studies were identified. A meta-analysis of previous studies confirmed SVZ involvement (odds ratio [OR]: 1.30 [1.01-1.67]) and O-6-methylguanine DNA methyltransferase promoter methylation (OR: 1.55 [1.09-2.20]) as significant risk factors for local recurrence. A time-dependent meta-analysis revealed a significant association between SVZ involvement and dissemination (HR: 1.69 [1.09-2.63]), while no significant association was found for distant recurrence (HR: 1.29 [0.74-2.27]). Understanding SVZ involvement and specific tumor locations associated with non-local recurrence provides critical insights for the management of GBM.

Local therapy in glioma: An evolving paradigm from history to horizons (Review).

Despite the implementation of multimodal treatments after surgery, glioblastoma (GBM) remains an incurable disease, posing a significant challenge in neuro-oncology. In this clinical setting, local therapy (LT), a developing paradigm, has received significant interest over time due to its potential to overcome the drawbacks of conventional therapy options for GBM. The present review aimed to trace the historical development, highlight contemporary advances and provide insights into the future horizons of LT in GBM management. In compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols criteria, a systematic review of the literature on the role of LT in GBM management was conducted. A total of 2,467 potentially relevant articles were found and, after removal of duplicates, 2,007 studies were screened by title and abstract (Cohen's κ coefficient=0.92). Overall, it emerged that 15, 10 and 6 clinical studies explored the clinical efficiency of intraoperative local treatment modalities, local radiotherapy and local immunotherapy, respectively. GBM recurrences occur within 2 cm of the radiation field in 80% of cases, emphasizing the significant influence of local factors on recurrence. This highlights the urgent requirement for LT strategies. In total, three primary reasons have thus led to the development of numerous LT solutions in recent decades: i) Intratumoral implants allow the blood-brain barrier to be bypassed, resulting in limited systemic toxicity; ii) LT facilitates bridging therapy between surgery and standard treatments; and iii) given the complexity of GBM, targeting multiple components of the tumor microenvironment through ligands specific to various elements could have a synergistic effect in treatments. Considering the spatial and temporal heterogeneity of GBM, the disease prognosis could be significantly improved by a combination of therapeutic strategies in the era of precision medicine.

Identification of new targets for glioblastoma therapy based on a DNA expression microarray

This study provides a comprehensive perspective on the deregulated pathways and impaired biological functions prevalent in human glioblastoma (GBM). In order to characterize differences in gene expression between individuals diagnosed with GBM and healthy brain tissue, we have designed and manufactured a specific, custom DNA microarray. The results obtained from differential gene expression analysis were validated by RT-qPCR. The datasets obtained from the analysis of common differential expressed genes in our cohort of patients were used to generate protein-protein interaction networks of functionally enriched genes and their biological functions. This network analysis, let us to identify 16 genes that exhibited either up-regulation (CDK4, MYC, FOXM1, FN1, E2F7, HDAC1, TNC, LAMC1, EIF4EBP1 and ITGB3) or down-regulation (PRKACB, MEF2C, CAMK2B, MAPK3, MAP2K1 and PENK) in all GBM patients. Further investigation of these genes and enriched pathways uncovered in this investigation promises to serve as a foundational step in advancing our comprehension of the molecular mechanisms underpinning GBM pathogenesis. Consequently, the present work emphasizes the critical role that the unveiled molecular pathways likely play in shaping innovative therapeutic approaches for GBM management. We finally proposed in this study a list of compounds that target hub of GBM-related genes, some of which are already in clinical use, underscoring the potential of those genes as targets for GBM treatment.

Erratum: Optimizing the management of glioblastoma per neurosurgical approach and therapeutic interventions on patient outcomes: A systematic review and meta-analysis

Erratum: Optimizing the management of glioblastoma per neurosurgical approach and therapeutic interventions on patient outcomes: A systematic review and meta-analysis

Second surgery for relapsed glioblastoma: an observational study on criteria for patient selection in real life.

Aim: There is little consensus on salvage management of glioblastoma after recurrence, for lack of evidence.Materials &methods: A retrospective study of treatments in patients with recurrent glioblastoma.Results: Surgery at recurrence was related to better overall survival (OS) and progression-free survival (PFS). Surgery at recurrence, Karnofsky index, MGMT methylation status, younger age at diagnosisand number of chemotherapy cycles were positive factors for OS and PFS. The benefit of OS was relevant for a second surgery performed at least 9months after the first one. Systemic treatments after the second surgery were linked to an improved PFS.Conclusion: Younger age, Karnofsky index, MGMT methylation statusand a median time between surgeries ≥9months may be criteria for eligibility for surgery at recurrence.

Targeted Alpha Therapy for Glioblastoma: Review on In Vitro, In Vivo and Clinical Trials.

Glioblastoma (GB), a prevalent and highly malignant primary brain tumour with a very high mortality rate due to its resistance to conventional therapies and invasive nature, resulting in 5-year survival rates of only 4-17%. Despite recent advancements in cancer management, the survival rates for GB patients have not significantly improved over the last 10-20 years. Consequently, there exists a critical unmet need for innovative therapies. One promising approach for GB is Targeted Alpha Therapy (TAT), which aims to selectively deliver potentially therapeutic radiation doses to malignant cells and the tumour microenvironment while minimising radiation exposure to surrounding normal tissue with or without conventional external beam radiation. This approach has shown promise in both pre-clinical and clinical settings. A review was conducted following PRISMA 2020 guidelines across Medline, SCOPUS, and Embase, identifying 34 relevant studies out of 526 initially found. In pre-clinical studies, TAT demonstrated high binding specificity to targeted GB cells, with affinity rates between 60.0% and 84.2%, and minimal binding to non-targeted cells (4.0-5.6%). This specificity significantly enhanced cytotoxic effects and improved biodistribution when delivered intratumorally. Mice treated with TAT showed markedly higher median survival rates compared to control groups. In clinical trials, TAT applied to recurrent GB (rGB) displayed varying success rates in extending overall survival (OS) and progression-free survival. Particularly effective when integrated into treatment regimens for both newly diagnosed and recurrent cases, TAT increased the median OS by 16.1% in newly diagnosed GB and by 36.4% in rGB, compared to current standard therapies. Furthermore, it was generally well tolerated with minimal adverse effects. These findings underscore the potential of TAT as a viable therapeutic option in the management of GB.

Targeting inflammation in glioblastoma: An updated review from pathophysiology to novel therapeutic approaches.

Glioblastoma (GBM) is a highly aggressive primary malignant brain tumor with a dismal prognosis despite current treatment strategies. Inflammation plays an essential role in GBM pathophysiology, contributing to tumor growth, invasion, immunosuppression, and angiogenesis. As a result, pharmacological intervention with anti-inflammatory drugs has been used as a potential approach for the management of GBM. To provide an overview of the current understanding of GBM pathophysiology, potential therapeutic applications of anti-inflammatory drugs in GBM, conventional treatments of glioblastoma and emerging therapeutic approaches currently under investigation. A narrative review was carried out, scanning publications from 2000 to 2023 on PubMed and Google Scholar. The search was not guided by a set research question or a specific search method but rather focused on the area of interest. Conventional treatments such as surgery, radiotherapy, and chemotherapy have shown some benefits, but their effectiveness is limited by various factors such as tumor heterogeneity and resistance.

Sequential Evaluation of Hematology Markers as a Prognostic Factor in Glioblastoma Patients.

In our study, we investigated the prognostic significance of hematological markers-NLR (Neutrophil-to-Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio), and RDW-CV (Red Blood Cell Distribution Width-Coefficient of Variation)-in 117 glioblastoma patients. The data collected from January 2016 to December 2018 included demographics, clinical scores, and treatment regimens. Unlike previous research, which often examined these markers solely before surgery, our unique approach analyzed them at multiple stages: preoperative, postoperative, and before adjuvant therapies. We correlated these markers with the overall survival (OS) and progression-free survival (PFS) using statistical tools, including ANOVA, Cox regression, and Kaplan-Meier survival analyses, employing SPSS version 29.0. Our findings revealed notable variations in the NLR, PLR, and RDW-CV across different treatment stages. The NLR and PLR decreased after surgery, with some stabilization post-STUPP phase (NLR: p = 0.007, η2p = 0.06; PLR: p = 0.001, η2p = 0.23), while the RDW-CV increased post-surgery and during subsequent treatments (RDW-CV: p < 0.001, η2p = 0.67). Importantly, we observed significant differences between the preoperative phase and other treatment phases. Additionally, a higher NLR and RDW-CV at the second-line treatment and disease progression were associated with an increased risk of death (NLR at 2nd line: HR = 1.03, p = 0.029; RDW-CV at progression: HR = 1.14, p = 0.004). We proposed specific marker cut-offs that demonstrated significant associations with survival outcomes when applied to Kaplan-Meier survival curves (NLR at 2nd line < 5: p < 0.017; RDW-CV at progression < 15: p = 0.007). An elevated NLR and RDW-CV at later treatment stages correlated with poorer OS and PFS. No significant preoperative differences were detected. These biomarkers may serve as non-invasive tools for glioblastoma management.

Beyond the margins: evaluating the necessity and timing of supramarginal resection in glioblastoma management

Glioblastoma, classified as a grade IV astrocytoma by the World Health Organization, continues to be a very aggressive cancer that requires a comprehensive strategy comprising surgery, radiation, and chemotherapy. Traditionally, gross total resection has primarily targeted the contrast-enhanced regions shown on T1-weighted magnetic resonance images. However, current studies suggest a more aggressive approach that focuses on removing the areas around the tumor, called supramarginal resection. This innovative strategy seeks to go beyond traditional bounda-ries, offering possible advantages for survival. However, it also raises worries over the removal of brain tissue that is crucial for important functions. The extremely poor prognosis of glioblastoma, characterized by a median survival of 10 months, highlights the pressing need for novel approaches to treatment. The aim of the study is to evaluate the influence of resection with a margin that extends much beyond the contrast enhancement on the survival of certain glioblastoma patients. The potential advantages documented in previous collections of cases are consistent with the notion of personalized surgical decision-making, which questions the prevailing approach of achieving the greatest possible removal of the tumor that is enhanced by contrast. Nevertheless, the potential neurological risks should be thoroughly evaluated. The objective of this study is to provide significant insights into improving the management of glioblastoma by examining the careful trade-off between aggressive tumor removal and preserving neurological function in specific groups of patients.

Supramaximal resection: retrospective study on IDH-wildtype Glioblastomas based on the new RANO-Resect classification.

The prognostic value of the extent of resection in the management of Glioblastoma is a long-debated topic, recently widened by the 2022 RANO-Resect Classification, which advocates for the resection of the non-enhancing disease surrounding the main core of tumors (supramaximal resection, SUPR) to achieve additional survival benefits. We conducted a retrospective analysis to corroborate the role of SUPR by the RANO-Resect Classification in a single center, homogenous cohort of patients. Records of patients operated for WHO-2021 Glioblastomas at our institution between 2007 and 2018 were retrospectively reviewed; volumetric data of resected lesions were computed and classified by RANO-Resect criteria. Survival and correlation analyses were conducted excluding patients below near-total resection. 117 patients met the inclusion criteria, encompassing 45 near-total resections (NTR), 31 complete resections (CR), and 41 SUPR. Median progression-free and overall survival were 11 and 15months for NTR, 13 and 17months or CR, 20 and 24months for SUPR, respectively (p < 0.001), with inverse correlation observed between survival and FLAIR residual volume (r -0.28). SUPR was not significantly associated with larger preoperative volumes or higher rates of postoperative deficits, although it was less associated with preoperative neurological deficits (OR 3.37, p = 0.003). The impact of SUPR on OS varied between MGMT unmethylated (HR 0.606, p = 0.044) and methylated (HR 0.273, p = 0.002) patient groups. Results of the present study support the validity of supramaximal resection by the new RANO-Resect classification, also highlighting a possible surgical difference between tumors with methylated and unmethylated MGMT promoter.

Principles in the Management of Glioblastoma.

Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in understanding the pathophysiology of these tumours have not translated into significant achievements in therapies or survival outcomes for patients. Progress in molecular profiling has yielded new omics data for a more refined classification of glioblastoma. Several typical genetic and epigenetic alterations in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signalling, as well as mutation of isocitrate dehydrogenase (IDH), methylation of O6-methylguanine-DNA methyltransferase (MGMT), amplification of epidermal growth factor receptor vIII, and codeletion of 1p/19q. Certain microRNAs, such as miR-10b and miR-21, have also been identified as prognostic biomarkers. Effective treatment options for glioblastoma are limited. Surgery, radiotherapy, and alkylating agent chemotherapy remain the primary pillars of treatment. Only promoter methylation of the gene MGMT predicts the benefit from alkylating chemotherapy with temozolomide and it guides the choice of first-line treatment in elderly patients. Several targeted strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles are under investigation in clinical trials. This review explores the potential genetic and epigenetic biomarkers that could be deployed as analytical tools in the diagnosis and prognostication of glioblastoma. Recent clinical advancements in treating glioblastoma are also discussed, along with the potential of liquid biopsies to advance personalized medicine in the field of glioblastoma, highlighting the challenges and promises for the future.

Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

Unraveling the Landscape of Pediatric Glioblastoma Biomarkers: A Comprehensive Review of Enhancing Diagnostics and Therapeutic Insights.

Glioblastoma, the most common and aggressive form of primary brain tumor, poses significant challenges to patients, caregivers, and clinicians alike. Pediatric glioblastoma is a rare and aggressive brain tumor that presents unique challenges in treatment. It differs from its adult counterpart in terms of genetic and molecular characteristics. Its incidence is relatively low, but the prognosis remains grim due to its aggressive behavior. Diagnosis relies on imaging techniques and histopathological analysis. The rarity of the disease underscores the need for effective treatment strategies. In recent years, the quest to understand and manage pediatric glioblastoma has seen a significant shift towards unraveling the intricate landscape of biomarkers. Surgery remains a cornerstone of glioblastoma management, aiming to resect as much of the tumor as possible. Glioblastoma's infiltrative nature presents challenges in achieving a complete surgical resection. This comprehensive review delves into the realm of pediatric glioblastoma biomarkers, shedding light on their potential to not only revolutionize diagnostics but also shape therapeutic strategies. From personalized treatment selection to the development of targeted therapies, the potential impact of these biomarkers on clinical outcomes is undeniable. Moreover, this review underscores the substantial implications of biomarker-driven approaches for therapeutic interventions. All advancements in targeted therapies and immunotherapy hold promise for the treatment of pediatric glioblastoma. The genetic profiling of tumors allows for personalized approaches, potentially improving treatment efficacy. The ethical dilemmas surrounding pediatric cancer treatment, particularly balancing potential benefits with risks, are complex. Ongoing clinical trials and preclinical research suggest exciting avenues for future interventions.