Malignant Brain Tumors Research Articles

Efficacy and safety of bevacizumab combined with temozolomide in the treatment of glioma a systematic review and meta-analysis of clinical trials.

Glioma is the most common malignant brain tumor in neurosurgery. Bevacizumab (BEV) is a monoclonal antibody that inhibits tumors by inhibiting vascular endothelial growth factor and reducing tumor angiogenesis. To evaluate the efficacy and safety of BEV combined with temozolomide (TMZ) in glioma, we performed a meta-analysis. PubMed, Embase, The Cochrane Library, and Web of Science databases were searched for randomized controlled trials comparing survival outcomes between TMZ combined with BEV and TMZ alone as well as cohort studies were included in our study. The primary outcome measures analyzed were overall survival (OS) and progression-free survival (PFS). A total of six randomized controlled trials and four cohort studies with a total of 2515 patients were included in our meta-analysis. The results of meta-analysis suggested that there were no significant improvements in overall survival, but the combination of TMZ and BEV prolonged progression-free survival, improved overall response rate (ORR), and increased the incidence of some adverse reactions, compared with TMZ alone. Subgroup analysis suggested sex, recursive partitioning analysis (RPA) grade, MGMT gene status and radiotherapy combination did not affect the improvement of OS with the combination of the two drugs, and RPA grade did not affect the improvement of PFS with the combination of the two drugs. The combination of TMZ and BEV can improve PFS as well as ORR in patients and has no benefit on OS. At the same time, the adverse reactions during the combination of the two drugs were acceptable.

Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.

The Three Pillars of Glioblastoma: A Systematic Review and Novel Analysis of Multi-Omics and Clinical Data.

Glioblastoma is the most fatal and common malignant brain tumor, excluding metastasis and with a median survival of approximately one year. While solid tumors benefit from newly approved drugs, immunotherapy, and prevention, none of these scenarios are opening for glioblastoma. The key to unlocking the peculiar features of glioblastoma is observing its molecular and anatomical features tightly entangled with the host's central nervous system (CNS). In June 2024, we searched the PUBMED electronic database. Data collection and analysis were conducted independently by two reviewers. Results: A total of 215 articles were identified, and 192 were excluded based on inclusion and exclusion criteria. The remaining 23 were used for collecting divergent molecular pathways and anatomical features of glioblastoma. The analysis of the selected papers revealed a multifaced tumor with extreme variability and cellular reprogramming that are observable within the same patient. All the variability of glioblastoma could be clustered into three pillars to dissect the physiology of the tumor: 1. necrotic core; 2. vascular proliferation; 3. CNS infiltration. These three pillars support glioblastoma survival, with a pivotal role of the neurovascular unit, as supported by the most recent paper published by experts in the field.

The Level of Circulating M-MDSCs as an Indicator for the Therapeutic Outcome of BNCT in End-Stage Malignant Brain Tumor Patients

PurposeBoron neutron capture therapy (BNCT) is a promising treatment modality for patients diagnosed with malignant brain tumors. It is currently used for emergency and compassionate purposes to treat end-stage malignant glioma or recurrent head and neck cancer patients in Taiwan. Understanding the factors influencing treatment response is crucial for optimizing patient care. This study aimed to investigate the association between tumor response and various parameters in end-stage malignant glioma patients following BNCT. Patients and MethodsFifteen patients with end-stage malignant brain tumors underwent a single fraction of BNCT. The treatment response was evaluated using cranial magnetic resonance imaging, and the association between treatment response and BNCT parameters was analyzed. Additionally, circulating myeloid-derived suppressor cell (MDSC) levels were measured by flow cytometry and correlated with patients’ survival. ResultsBNCT exhibited significant therapeutic efficacy in reducing tumor volume of these end-stage glioma patients, with 3 patients achieving complete response and 10 patients achieving partial response within 1 month, resulting in an impressive objective response rate of 80%. The median overall survival is 9 (1.77, 12.47) months, and the progression-free survival is 1.34 (0.53, 9.53) months. Kaplan-Meier analysis showed that the patients with complete response and partial response displayed better survival than those with stable disease. Treatment response was not significantly associated with initial tumor size, blood boron concentration, tumor-to-normal tissue ratio, or tumor-to-blood ratio. The ROC curve revealed a cut-off value of 5% of circulating M-MDSCs with a sensitivity of 66.67% and specificity of 73.33%, respectively, for predicting the glioma patient’s response to BNCT. ConclusionThis clinical study demonstrates that BNCT can reduce tumor burden, improve disease control, and prolong survival in end-stage glioma patients. Circulating M-MDSCs may serve as a predictive indicator for the treatment response of these patients following BNCT.

Multi-omics analysis revealed significant metabolic changes in brain cancer cells treated with paclitaxel and/or topotecan

Glioblastoma (GBM) stands as the most common primary malignant brain tumor. Despite the best standard therapies, GBM survivors have a brief survival time, about 24 months on average. The treatment is troublesome because the cancer cells may not respond well to specific therapies as they grow within an extensive network of blood vessels. Our study aims to evaluate the impact of paclitaxel 5.3 μg/mL and topotecan 0.26 μM solely and in pairwise combination on the resultant metabolic and proteomic signatures of the U87 cell line while using the precise ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF) analytical technology. The U87 cells wear treated with DMSO, paclitaxel 5.3 μM, topotecan 0.26 μM, and their combinations. Using One-way ANOVA, we observed 14 significantly altered metabolites compared to those cells treated with DMSO. For combination treatment (paclitaxel and topotecan), 11 metabolites were significantly dysregulated. Sparse partial least squares-discriminant analysis (sPLS-DA) revealed minimal overlap, highlighting distinctions among the four groups. While for proteomics, a total of 79 proteins were significantly dysregulated among the groups. These findings can aid in identifying new biomarkers associated with the utilized drugs and creating a map for targeted therapy. EIF3F, GNB2L1, HINT2, and RPA3 were shown to be significantly upregulated in the combination group relative to the control. Moreover, ribosome, apoptosis, HIF-1 signaling, arginine and proline, glutathione, purine metabolism, apelin signaling pathway, and glycolysis were significantly altered in the combination group. Overall, this study underscores the effectiveness of multi-omics approaches in revealing the molecular mechanisms driving chemotherapy responses in cancer cells. Additionally, this work generates a comprehensive list of molecular alterations that can serve as a foundation for further investigations and inform personalized healthcare strategies to enhance patient outcomes.

Effects of Raupya Suvarna Sutashekhara, a herbo-mineral-metallic formulation as adjunct Oral Ayurvedic Medicine on long-term survival in patients of malignant brain tumor

BackgroundThe incidence of brain tumors poses a significant threat, particularly with high-grade tumors that exhibit rapid growth and can significantly impair the patient's quality of life, despite treatment modalities. Ayurveda, a natural system of medicines helps to enhance health benefits when used as a complementary therapy in combination with conventional treatment through various herbal, herbo-mineral or herbo-mineral-metallic formulations. One of such formulations, Raupya Suvarna Sutshekhara (RSS), has Raupya bhasma and Suvarna bhasma (incinerated Silver and Gold respectively) ingredients and they are described as Rasayana (immunomodulatory) and possess Medhya (enhances the brain functions and intelligence) activity. ObjectiveThe study documents effects of Raupya Suvarna Sutshekhara in alleviating symptoms of malignant brain tumors. Materials and methodsThis retrospective cohort study was done for malignant brain tumor patients (n = 110) registered at our centre who were treated with Raupya Suvarna Sutshekhara 125 mg–250 mg (a herbo-mineral metallic formulation) as a treatment of choice of neural tonic along with supporting Ayurvedic medicines. Treatment response evaluation period ranged from 3 months to 5 years (median period 29 weeks). Clinical symptoms, weight, Karnofsky Performance Score (KPS), Quality of Life (QoL) score, and survival data with respect to treatment with RSS were analyzed. ResultsRSS showed a very significant (p < 0.001) effect on symptoms related to memory loss, headache, imbalance, loss of appetite, and generalized weakness while significant (p < 0.05) decrease in urinary incontinence, seizures, difficulty in thinking/articulating, and weakness in one part/side of the body. However, a not-quite significant change was seen in symptom confusion/disorientation. No significant improvement was seen in vision changes, facial numbness or tingling, swallowing difficulties, and tingling in extremities. Body weight and KPS also showed improvement. Patients with treatment between 2 and 5 years showed median survival up to 62 months. ConclusionsIt was observed that adjunct Ayurvedic treatment with RSS helped to reduce the severity of symptoms due to the tumor itself or side-effects of conventional treatments, maintain the quality of life of malignant brain tumor patients and has shown to increase survival with respect to the duration of the treatment.

RISKS AND OUTCOMES OF STROKE IN PATIENTS WITH PRIMARY BRAIN AND MENINGEAL TUMOURS

Abstract AIMS People with primary CNS tumours are at increased risk of stroke. However, there is little guidance on stroke management. We investigated the types and timing of stroke in primary brain and meningeal tumours to inform their treatment. METHOD Patient data on stroke aetiology, timing, management and outcomes was collected from electronic medical records at King’s College Hospital between April 2012 to April 2022. A primary brain tumour was defined using the 2021 World Health Organisation Classification of Tumours of the Central Nervous System. RESULTS We identified 244 patients with a brain tumour and a stroke with a total of 317 strokes in the 10-year period (male:female = 48:52; median age, 62 years [IQR 51 – 74]). The most common brain tumours were meningiomas (43%) and glioblastomas (21%). 56% of strokes were ischaemic. Ischaemic strokes were most frequent within 30 days of brain tumour surgery (38%). Haemorrhages were more common in malignant tumours (p=4.7 x10 35% of haemorrhages were intratumoural. Strokes in malignant tumours: occurred closer to diagnosis (p=0.032); caused greater functional loss (mean Modified Rankin Scale change 2.00 vs 1.17, p 0.001); and had a higher mortality rate (HR 5.87, CI 3.41 - 10.11, p=1.8x10 Recurrent strokes occurred in 64 (26%) patients and were associated with tumour malignancy (p=0.016), radiotherapy (p=0.023) and chemotherapy (p=0.009). CONCLUSION Strokes in malignant brain tumours are more lethal, disabling and often recurrent in patients undergoing chemo and radiotherapy. Clinical trials are needed to improve outcomes of stroke in neuro-oncology patients.

MULTI-OMIC INTEGRATION REVEAL INTRA-TUMOUR HETEROGENEITY AND IDENTIFY DISULfiRAM AND COPPER AS A SYNERGISTIC THERAPY IN PAEDIATRIC EPENDYMOMA

Abstract AIMS Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a significant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it difficult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN. METHOD Surgical sampling of spatially-distinct regions was performed on eight PF-A patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method. RESULTS Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulfiram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ significantly sensitized cells to Disulfiram, particularly under hypoxic conditions. This synergistic combination significantly impaired invasion in both normoxia and hypoxia. CONCLUSION This is the first instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.

Role of Contrast Perfusion Weighted Magnetic Resonance Imaging in Grading of Brain Tumors with Histopathological Correlation

Background: Traditional MRI sequences provide precise anatomical information about brain tumors. But these sequences can’t quantitatively evaluate vascular physiology, or capture tumor biology at the molecular level; which is important for tumor grading, therapeutic assessment, and prognostication. Furthermore, non-enhancing parts of the tumor affected brain, which generally indicates peri-tumoral brain edema with infiltrative tumor cells, is not visible on conventional MRI sequences. Perfusion weighted Magnetic Resonance Imaging (PW-MRI) techniques such as Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) and Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC-MRI) have shown promise as imaging biomarkers for glioma therapy, since these new sequences can also provide information about vascular hemodynamics. Our study was first prospective study from Himalayan belt of India, wherein we tried to assess the role of PW-MRI in the grading of brain tumors, with histopathological correlation. Aim and Objective: To compare tumor perfusion and histopathological tumor grading, in evaluation of brain tumor especially gliomas. Material and Method: 40 patients who were referred to Department of Radiodiagnosis for evaluation of brain tumor, and who gave informed consent, were included in this prospective study, done over a period of 18 months. All patients underwent MRI, followed by surgical resection. Observation and Result: In our study, diagnostic accuracy was 90% for mean rCBV (lesion) (cut off: 7 by ROC), mean rCBF (lesion) (cut off: 13.9 by ROC), and rCBF ratio (cut off: 2.9 by ROC); for differentiating benign versus malignant brain tumor. rCBF ratio was found to be best diagnostic parameter with sensitivity of 96%, specificity of 80%, positive predictive value of 89%, negative predictive value of 92%, diagnostic accuracy of 90%, area under ROC curve=0.909, and p value&lt;0.001. Conclusion: We come to conclusion that high grade brain tumor display higher CBF, than do low grade brain tumor. Three parameters showed good diagnostic accuracy, which includes rCBF ratio, mean rCBF (lesion), and mean rCBV (lesion). These parameters can be used to predict the grade of the brain tumor, with good diagnostic accuracy.

NOVEL HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS WITH ANTICANCER ACTIVITY IN MEDULLOBLASTOMA

Abstract AIMS Medulloblastoma is the most common malignant brain tumor of childhood. Protein kinases are often overexpressed and constitute targets for the development of novel molecularly-targeted therapies in brain tumors. Here, we report the synthesis of new derivatives with kinase inhibitory activity and their anticancer activity in an early screening in medulloblastoma cells. METHOD The synthesis route was performed through six steps using a proper amino acid as starting material. The inhibitory activity of the final derivatives on the protein kinase was measured by fluorescence. Cultured DAOY medulloblastoma cells were used to examine anticancer activity. RESULTS The compounds display potent inhibitory activity on viability of DAOY medulloblastoma cells. The more promising derivative shows IC50 in the μM range in inhibiting the targeted protein kinase. CONCLUSION Further optimization of compounds in this series is currently being carried out. The encouraging preliminary results have revealed potential novel strategies for inhibiting kinase activity for the treatment of medulloblastoma.

DYSREGULATION OF M6A RNA METHYLATION, R-LOOPS AND THE DNA DAMAGE RESPONSE IN PAEDIATRIC HIGH-GRADE GLIOMAS

Abstract AIMS Paediatric high-grade gliomas (pHGG) are virtually incurable malignant brain tumours. The regulation of R- loops is necessary for ensuring genomic stability. The formation of R-loops at DNA damage sites promotes DNA repair via m6A methylation of the RNA strand. We aimed to investigate whether m6A methylation, R-loop homeostasis and the DNA damage response is dysregulated in pHGG and whether inhibitors, such as ATM inhibitors, could be potential therapeutics for pHGG. METHOD To assess the global levels of m6A, R-loops, yH2AX, total ATM and phosphorylated ATM in paediatric HGG cell lines compared to control human astrocytes, immunocytochemistry was initially performed. Immunocyto- chemistry was also performed to assess localisation between m6A and R-loops, R-loops and yH2AX, R-loops and total/phosphorylated ATM, m6A and total/phosphorylated ATM, and total/phosphorylated ATM and yH2AX in pHGG cell lines and human astrocytes. We are also exploring two ATM inhibitors, AZD1390 and AZD0156, and are currently investigating their effects on m6A methylation, R-loops and the DNA damage response in pHGG. As a molecular mechanism involving the tumour suppressor ARID1A was recently discovered that is crucial for maintaining genomic stability, we are also exploring the role of this protein in pHGG. We are also investigating the potential involvement of m6A readers in the pathogenesis of pHGG. RESULTS Immunocytochemistry revealed that dysregulation of global m6A, R-loop, yH2AX and ATM occurs in pHGG cell lines as higher levels of expression was generally observed compared to human astrocytes. Moreover, m6A, R-loops, yH2AX and ATM appear to colocalise as high Pearson’s correlation coefficient values were obtained. Experiments exploring ATM inhibitors, ARID1A and m6A readers in pHGG are currently in progress, however the results will be presented. CONCLUSION It appears that dysregulation of m6A methylation, R-loop homeostasis and the DNA damage response occurs in pHGG and that molecular mechanisms involving m6A methylation and R-loops could be impaired.

Astaxanthin Is a Novel Candidate for Glioblastoma Treatment? A Review.

Glioblastoma (GBM) is a malignant primary brain tumor with a poor prognosis and high recurrence rates. At present, the current treatments available for GBM patients can only prolong their overall survival and cannot provide a complete cure. Discovering an effective therapy against the disease is a challenge due to its recurrence and resistance to common available treatments for GBM. Several natural products have been documented to possess the potential to function as anticancer agents through diverse mechanisms. Astaxanthin (AXT) is an orange-red pigment that is a natural lipophilic and xanthophyll carotenoid derived mostly from microalgae. Numerous studies have examined that AXT impacts GBM cells in laboratory settings and animal models. This review aims to provide the latest information about the potential of astaxanthin as a novel therapeutic option for GBM. AXT has been targeted more on reactive oxygen species (ROS), and suppressed tumor growth in vitro and in vivo conditions. The available data suggests that AXT might serve as a key component in the development of innovative cancer therapies, especially for glioblastoma.

Analysis of geographical distribution of high-grade glioma diagnoses in the Alessandria province: pilot study preliminary results

Background: one under-researched line of investigation is gliomas, which are a group of malignant brain tumours with highly poor prognoses. Despite efforts to identify environmental risk factors for gliomas, their etiology still remains unclear. It turns out that several future developments are needed in order to understand other potential risk factors. To this end, the primary objective of the present pilot study is to conduct an assessment of the spatial distribution of high-grade brain tumor cases in the province of Alessandria, where possible risk factors such as the presence of chemical industries and asbestiform fibers are found. Materials and Methods: the study sample consisted of all patients diagnosed with high-grade glioma between January 2018 and April 2023, residents in the province of Alessandria at the time of diagnosis and referred to the health facilities of the "Azienda Sanitaria Locale di Alessandria" and the "Azienda Universitario-Ospedaliera di Alessandria". Biographical and pathological history variables were collected, and finally, data were processed in aggregate and anonymized form. A total of 103 deceased patients were enrolled, stratified by age and type of diagnosis. Results: it was seen that the city with the most cases was Alessandria, with 27 diagnoses found during the period under review (26.2%), followed by cities of Acqui Terme, Casale Monferrato, and Novi Ligure with seven diagnoses (6.8%). Preliminary results presented in this paper were compared with data already published. Conclusions: analyses performed to arrive at an initial geographical distribution of high-grade glioma diagnoses are consistent relative to the population density of each municipality considered.

Pediatric Cranial Stereotactic Radiosurgery: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines.

There are limited data on the use of stereotactic radiosurgery (SRS) for pediatric patients. The aim of this systematic review was to summarize indications and outcomes specific to pediatric cranial SRS to inform consensus guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). A systematic review, using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), analyzed English-language articles on SRS, published between 1989 and 2021, that included outcomes for at least 5 pediatric patients. MEDLINE database terms included tumor types and locations, and radiosurgical and age-specific terms. We excluded nonclinical reports, expert opinions, commentaries, and review articles. Meta-regressions for associations with local control were performed for medulloblastoma, craniopharyngioma, ependymoma, glioma, and arteriovenous malformation (AVM). Of the 113 articles identified for review, 68 met the inclusion criteria. These articles described approximately 400 pediatric patients with benign and malignant brain tumors and 5119 with AVMs who underwent cranial SRS. The rates of local control for benign tumors, malignant tumors, and AVMs were 89% (95% CI, 82%-95%), 71% (95% CI, 59%-82%), and 65% (95% CI, 60%-69%), respectively. No significant associations were identified for local control with patient-, tumor-, or treatment-related variables. This review is the first to summarize outcomes specific to SRS for pediatric brain tumors and AVMs. Although data reporting is limited for pediatric patients, SRS appears to provide acceptable rates of local control. We present ISRS consensus guidelines to inform the judicious use of cranial SRS for pediatric patients.

The peritumoral brain zone in glioblastoma: a review of the pretreatment approach.

Glioblastomas are the most common and aggressive form of malignant primary brain tumors in adults. The standard treatment is surgical resection followed by radiotherapy and chemotherapy. Despite optimal treatment methods, the prognosis for patients remains poor. Preoperative determination of glioblastoma margins remains beneficial for the complete removal of the tumor mass. Radiotherapy is essential for post-surgery treatment, but radioresistance is a significant challenge contributing to high mortality rates. Advanced imaging technologies are used to analyze the changes in the peritumoral brain zone (PTZ). Consequently, they may lead to the development of novel therapeutic options, especially targeting the marginal parts of a tumor, which could improve the prognosis of glioblastoma patients. The clinical presentation of glioblastoma is heterogeneous and mostly depends on the location and size of a tumor. Glioblastomas are characterized by both intratumoral cellular heterogeneity and an extensive, diffuse infiltration into the normal tissue bordering a tumor called the PTZ. Neuroimaging techniques, such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), proton magnetic resonance spectroscopy (1H MRS), and chemical exchange saturation transfer (CEST) are useful methods in the evaluation of the tumor infiltration and thus the resection margin.

Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres.

Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs). The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model. The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model. The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.

Relationship between radiofrequency-electromagnetic radiation from cellular phones and brain tumor: meta-analyses using various proxies for RF-EMR exposure-outcome assessment

IntroductionThe authors conducted meta-analyses regarding the association between cellular and mobile phone use and brain tumor development by applying various radiofrequency-electromagnetic radiation (RF-EMR) exposure subcategories. With changing patterns of mobile phone use and rapidly developing Wireless Personal Area Network (WPAN) technology (such as Bluetooth), this study will provide insight into the importance of more precise exposure subcategories for RF-EMR.MethodsThe medical librarian searched MEDLINE (PubMed), EMBASE, and the Cochrane Library until 16 December 2020.ResultsIn these meta-analyses, 19 case-control studies and five cohort studies were included. Ipsilateral users reported a pooled odds ratio (OR) of 1.40 (95% CI 1.21–1.62) compared to non-regular users. Users with years of use over 10 years reported a pooled OR of 1.27 (95% CI 1.08–1.48). When stratified by each type of brain tumor, only meningioma (OR 1.20 (95% CI 1.04–1.39)), glioma (OR 1.45 (95% CI 1.16–1.82)), and malignant brain tumors (OR 1.93 (95% CI 1.55–2.39)) showed an increased OR with statistical significance for ipsilateral users. For users with years of use over 10 years, only glioma (OR 1.32 (95% CI 1.01–1.71)) showed an increased OR with statistical significance. When 11 studies with an OR with cumulative hours of use over 896 h were synthesized, the pooled OR was 1.59 (95% CI 1.25–2.02). When stratified by each type of brain tumor, glioma, meningioma, and acoustic neuroma reported the pooled OR of 1.66 (95% CI 1.13–2.44), 1.29 (95% CI 1.08–1.54), and 1.84 (95% CI 0.78–4.37), respectively. For each individual study that considered cumulative hours of use, the highest OR for glioma, meningioma, and acoustic neuroma was 2.89 (1.41–5.93) (both side use, > 896 h), 2.57 (1.02–6.44) (both side use, > 896 h), and 3.53 (1.59–7.82) (ipsilateral use, > 1640 h), respectively. For five cohort studies, the pooled risk ratios (RRs) for all CNS tumors, glioma, meningioma, and acoustic neuroma, were statistically equivocal, respectively. However, the point estimates for acoustic neuroma showed a rather increased pooled RR for ever-use (1.26) and over 10 years of use (1.61) compared to never-use, respectively.DiscussionIn this meta-analysis, as the exposure subcategory used became more concrete, the pooled ORs demonstrated higher values with statistical significance. Although the meta-analysis of cohort studies yielded statistically inconclusive pooled effect estimates, (i) as the number of studies included grows and (ii) as the applied exposure subcategories become more concrete, the pooled RRs could show a different aspect in future research. Additionally, future studies should thoroughly account for changing patterns in mobile phone use and the growing use of earphones or headphones with WPAN technology.

Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing.

Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development. However, they may not be suitable for large-scale studies. The aim of this study was to investigate if a zebrafish-based xenograft model can recapitulate MB growth and enable rapid drug testing. Nine different MB cell lines or patient-derived cells were transplanted into blastula-stage zebrafish embryos. Tumor development and migration were then monitored using live imaging. RNA sequencing was performed to investigate transcriptome changes after conditioning cells in neural stem cell-like medium. Furthermore, drug treatments were tested in a 96-well format. We demonstrate here that transplantation of MB cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing. Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy.

Challenges and advances in glioblastoma targeted therapy: the promise of drug repurposing and biomarker exploration.

Glioblastoma remains the most prevalent and aggressive primary malignant brain tumor in adults, characterized by limited treatment options and a poor prognosis. Previous drug repurposing efforts have yielded only marginal survival benefits, particularly those involving inhibitors targeting receptor tyrosine kinase and cyclin-dependent kinase-retinoblastoma pathways. This limited efficacy is likely due to several critical challenges, including the tumor's molecular heterogeneity, the dynamic evolution of its genetic profile, and the restrictive nature of the blood-brain barrier that impedes effective drug delivery. Emerging diagnostic tools, such as circulating tumor DNA and extracellular vesicles, offer promising non-invasive methods for real-time tumor monitoring, potentially enabling the application of targeted therapies to more selected patient populations. Moreover, innovative drug delivery strategies, including focused ultrasound, implantable drug-delivery systems, and engineered nanoparticles, hold potential for enhancing the bioavailability and therapeutic efficacy of treatments.

Tackling Anticancer Drug Resistance and Endosomal Escape in Aggressive Brain Tumors Using Bioelectronics.

Resistance mechanisms in brain tumors, such as medulloblastoma and glioblastoma, frequently involve the entrapment of chemotherapeutic agents within endosomes and the extracellular expulsion of drugs. These barriers to effective treatment are exacerbated in nanotechnology-based drug delivery systems, where therapeutic nanoparticles often remain confined within endosomes, thus diminishing their therapeutic efficacy. Addressing this challenge necessitates the development of novel strategies to enhance the efficiency of cancer therapies. This study tests the hypothesis that external electrical stimuli can modulate intracellular trafficking of chemotherapeutic drugs in common malignant brain tumors in children (medulloblastoma) and adults (glioblastoma) by using gold nanoparticles (GNPs). In our experiments, alternating current (AC) stimulation ranging from 1 kHz to 5 MHz and at a strength of 1 V/cm significantly reduced cell viability in drug-resistant medulloblastoma and enhanced delivery of GNPs in glioblastoma. Low-frequency AC resulted in a 50% increase in apoptosis compared to controls and an 8-fold increase in cell death in cisplatin-resistant medulloblastoma cells, accompanied by a substantial reduction in EC50 from 2.5 to 0.3 μM. Similarly, vincristine-resistant cells demonstrated a 4-fold enhancement in drug sensitivity. Furthermore, high-frequency AC facilitated a significant increase from 20 to 75% in the endosomal escape of GNPs in glioblastoma cells. These findings underscore the potential of AC to selectively disrupt cancer cell resistance mechanisms and bolster the efficacy of nanoparticle-based therapies. The results indicate the effectiveness of AC stimulation in circumventing the limitations inherent in current nanotechnology-based drug delivery systems but also illustrates its transformative potential for treating aggressive, drug-resistant brain tumors.