Search Results (3,669)

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2⁺/CX3CR1⁺ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2⁺/CX3CR1⁺ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma. Full article

The Brain Tumor Segmentation (BraTS) Challenge has been a main driver of the development of deep learning (DL) algorithms and provides by far the largest publicly available expert-annotated brain tumour dataset but contains solely preoperative examinations. The aim of our study was to facilitate the use of the BraTS dataset for training DL brain tumour segmentation algorithms for a postoperative setting. To this end, we introduced an automatic conversion of the three-label BraTS annotation protocol to a two-label annotation protocol suitable for postoperative brain tumour segmentation. To assess the viability of the label conversion, we trained a DL algorithm using both the three-label and the two-label annotation protocols. We assessed the models pre- and postoperatively and compared the performance with a state-of-the-art DL method. The DL algorithm trained using the BraTS three-label annotation misclassified parts of 10 out of 41 fluid-filled resection cavities in 72 postoperative glioblastoma MRIs, whereas the two-label model showed no such inaccuracies. The tumour segmentation performance of the two-label model both pre- and postoperatively was comparable to that of a state-of-the-art algorithm for tumour volumes larger than 1 cm³. Our study enables using the BraTS dataset as a basis for the training of DL algorithms for postoperative tumour segmentation. Full article

Recent scientific research has shown that the ketogenic diet may have potential benefits in a variety of medical fields, which has led to the diet receiving a substantial amount of attention. Clinical and experimental research on brain tumors has shown that the ketogenic diet has a satisfactory safety profile. This safety profile has been established in a variety of applications, including the management of obesity and the treatment of drug-resistant epileptic cases. However, in human studies, the impact of ketogenic therapy on the growth of tumors and the life expectancy of patients has not provided results that are well characterized. Consequently, our purpose is to improve the comprehension of these features by succinctly presenting the developments and conclusions that have been gained from the most recent study that pertains to this non-pharmacological technique. According to the findings of our study, patients with brain tumors who stick to a ketogenic diet are more likely to experience improved survival rates. However, it is required to conduct additional research on humans in order to more accurately define the anti-tumor efficiency of this diet as well as the underlying processes that support the therapeutic effects of this dieting regimen. Full article

Glioblastoma multiforme (GBM) is the most severe form of brain cancer in adults, characterized by its complex vascular network that contributes to resistance to conventional therapies. Thermal therapies, such as magnetic hyperthermia (MHT), emerge as promising alternatives, using heat to selectively target tumor cells while minimizing damage to healthy tissues. The organ-on-a-chip can replicate this complex vascular network of GBM, allowing for detailed investigations of heat dissipation in MHT, while computational simulations refine treatment parameters. In this in silico study, tumor-on-a-chip models were used to optimize MHT therapy by comparing heat dissipation in normal and abnormal vascular networks, considering geometries, flow rates, and concentrations of magnetic nanoparticles (MNPs). In the high vascular complexity model, the maximum velocity was 19 times lower than in the normal vasculature model and 4 times lower than in the low-complexity tumor model, highlighting the influence of vascular complexity on velocity and temperature distribution. The MHT simulation showed greater heat intensity in the central region, with a flow rate of 1 µL/min and 0.5 mg/mL of MNPs being the best conditions to achieve the therapeutic temperature. The complex vasculature model had the lowest heat dissipation, reaching 44.15 °C, compared to 42.01 °C in the low-complexity model and 37.80 °C in the normal model. These results show that greater vascular complexity improves heat retention, making it essential to consider this heterogeneity to optimize MHT treatment. Therefore, for an efficient MHT process, it is necessary to simulate ideal blood flow and MNP conditions to ensure heat retention at the tumor site, considering its irregular vascularization and heat dissipation for effective destruction. Full article

As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients’ life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m⁵CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects. Full article

Glioblastoma (GBM) is the most prevalent central nervous system tumour (CNS). Patients with GBM have a dismal prognosis of 15 months, despite an intensive treatment schedule consisting of surgery, chemoradiation and concurrent chemotherapy. In the last decades, many trials have been performed investigating small molecule inhibitors, which target specific genes involved in tumorigenesis. So far, these trials have been unsuccessful, and standard of care for GBM patients has remained the same since 2005. This review gives an overview of trials investigating small molecule inhibitors on their own, combined with chemotherapy or other small molecule inhibitors. We discuss possible resistance mechanisms in GBM, focussing on intra- and intertumoral heterogeneity, bypass mechanisms and the influence of the tumour microenvironment. Moreover, we emphasise how combining inhibitors can help overcome these resistance mechanisms. We also address strategies for improving trial outcomes through modifications to their design. In summary, this review aims to elucidate different resistance mechanisms against small molecule inhibitors, highlighting their significance in the search for novel therapeutic combinations to improve the overall survival of GBM patients. Full article

Amide Proton Transfer-weighted (APTw) imaging is a molecular MRI technique used to quantify protein concentrations in gliomas, which have heterogeneous components with varying cellularity and metabolic activity. This study aimed to assess the correlation between the component-specific APT signal of the neoplasm and WHO grade, molecular profile and survival status. Sixty-one patients with adult-type diffuse gliomas were retrospectively analyzed. APT values were semi-automatically extracted from tumor solid and, whenever present, necrotic components. APT values were compared between groups stratified by WHO grade, IDH-mutation, MGMT promoter methylation and 1- and 2-year survival status using Wilcoxon rank-sum test, adjusting for multiple comparisons. Overall survival (OS) was analyzed in the subgroup of 48 patients with grade 4 tumors using Cox proportional-hazards models. Random-effects models were used to assess inter-subject heterogeneity of the mean APT values in each tumor component. APT values of the solid component significantly differed between patients with grades 2–3 and 4 tumors (mean 1.58 ± 0.50 vs. 2.04 ± 0.56, p = 0.028) and correlated with OS after 1 year (1.81 ± 0.58 in survivors vs. 2.17 ± 0.51 in deceased patients, p = 0.030). APT values did not differ by IDH-mutation, MGMT methylation, and 2-year survival status. Within grade 4 glioma patients, higher APT kurtosis of the solid component was a negative prognostic factor (hazard ratio = 1.60, p = 0.040). Mean APT values of the necrosis showed high inter-subject variability, although most necrotic tumors were grade 4 and IDH wildtype. In conclusion, APTw imaging in the solid component provided metrics associated with glioma grade and survival status but showed weak correlation with IDH-mutation and MGMT promoter methylation status, in contrast to previous works. Further research is needed to understand APT signal variability within the necrotic component of high-grade gliomas. Full article

Glioblastoma represents the predominant and a highly aggressive primary neoplasm of the central nervous system that has an abnormal metabolism. Our previous study showed that chrysomycin A (Chr-A) curbed glioblastoma progression in vitro and in vivo. However, whether Chr-A could inhibit orthotopic glioblastoma and how it reshapes metabolism are still unclear. In this study, Chr-A markedly suppressed the development of intracranial U87 gliomas. The results from airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) indicated that Chr-A improved the abnormal metabolism of mice with glioblastoma. Key enzymes including glutaminase (GLS), glutamate dehydrogenases 1 (GDH1), hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD) were regulated by Chr-A. Chr-A further altered the level of nicotinamide adenine dinucleotide phosphate (NADPH), thus causing oxidative stress with the downregulation of Nrf-2 to inhibit glioblastoma. Our study offers a novel perspective for comprehending the anti-glioma mechanism of Chr-A, highlighting its potential as a promising chemotherapeutic agent for glioblastoma. Full article

Glioblastomas are impossible to completely resect and almost always recur at the borders of the resection margin. There is no established chemotherapy regimen available to patients who recur, while systemic treatment is hampered by the blood–brain barrier. Here, we report on the first evaluation in humans of the intraparenchymal injection of irinotecan into the resection cavity after surgical resection of recurrent glioblastoma patients. The cytotoxicity of irinotecan was compared to SN-38 in primary cells from recurrent glioblastoma patients. Irinotecan was injected at multiple (~30) sites of the resection cavity wall at a depth of 3 to 5 mm. SN-38 was more cytotoxic than irinotecan at concentrations below 1 µM due to enzyme kinetics. The intraparenchymal administration of irinotecan was safe, with good wound healing and an absence of swelling, inflammation, or pseudo-abscess formation. The median survival post irinotecan administration was 32.6 weeks. The median overall survival was 30.5 months, with a two-year survival rate of 56%. This study demonstrates that local delivery of irinotecan into the brain parenchyma offers a safe route of administration over systemic delivery in the treatment of recurrent glioblastoma. Full article

Overcoming temozolomide (TMZ)-resistance is a major challenge in glioblastoma therapy. Therefore, identifying the key molecular player in chemo-resistance becomes urgent. We previously reported the downregulation of PDCD10 in primary glioblastoma patients and its tumor suppressor-like function in glioblastoma cells. Here, we demonstrate that the loss of PDCD10 causes a significant TMZ-resistance during treatment and promotes a rapid regrowth of tumor cells after treatment. PDCD10 knockdown upregulated MGMT, a key enzyme mediating chemo-resistance in glioblastoma, accompanied by increased expression of DNA mismatch repair genes, and enabled tumor cells to evade TMZ-induced cell-cycle arrest. These findings were confirmed in independent models of PDCD10 overexpressing cells. Furthermore, PDCD10 downregulation led to the dedifferentiation of glioblastoma cells, as evidenced by increased clonogenic growth, the upregulation of glioblastoma stem cell (GSC) markers, and enhanced neurosphere formation capacity. GSCs derived from PDCD10 knockdown cells displayed stronger TMZ-resistance and regrowth potency, compared to their parental counterparts, indicating that PDCD10-induced stemness may independently contribute to tumor malignancy. These data provide evidence for a dual role of PDCD10 in tumor suppression by controlling both chemo-resistance and dedifferentiation, and highlight PDCD10 as a potential prognostic marker and target for combination therapy with TMZ in glioblastoma. Full article

Background: This investigation evaluated the predictive and prognostic efficacy of the newly developed global immune-nutrition-inflammation index (GINI) in patients with grade 4 adult-type diffuse gliomas, comparing it with other established indices such as the systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune-inflammation value (PIV). Method: A retrospective cohort included 198 patients diagnosed with isocitrate dehydrogenase (IDH)-mutant gr4 (grade 4) astrocytoma and IDH-wt (wilde-type) glioblastoma (GBM) gr4 treated with surgical resection, radiotherapy, and temozolomide. Patients were stratified into two groups based on their GINI values: low GINI (<5815) and high GINI (≥5815). The primary endpoint was overall survival (OS). Results: High GINI was significantly associated with older age, poor performance status, multifocal tumors, and higher SII, SIRI, and PIV values (p < 0.005). The GINI demonstrated strong correlations with SII (r = 0.694), SIRI (r = 0.516), and PIV (r = 0.657) (p < 0.001). Patients with high GINI exhibited poorer OS (5.0 vs. 17.0 months) and PFS (5.0 vs. 13.0 months) in comparison to those with low GINI. Kaplan–Meier survival analysis revealed significantly prolonged OS and PFS among patients with low GINI (p < 0.001). Multivariate analysis identified high GINI as an independent negative risk factor for both PFS and OS. Conclusions: GINI is a robust predictor of clinical outcomes in IDH-mutant gr4 astrocytoma and IDH-wt GBM gr4, highlighting the crucial impact of nutrition and cancer cachexia. It shows superior prognostic value relative to the SII, SIRI, and PIV. Full article

We have synthesized 22 symmetric and asymmetric 4-aryl-1,4-dihydropyridines (1,4-DHPs) by a “green” microwave-assisted one-pot multicomponent Hantzsch reaction and evaluated their cytotoxicity to three human cancer cell lines regarding U-251MG (human glioblastoma), HeLa 229 (human cervical adenocarcinoma), and MCF-7 (human breast carcinoma). None of the 1,4-DHPs were cytotoxic to U-251MG cells. Most of the 1,4-DHPs did not affect HeLa 229 or MCF-7 cell viability. On the other hand, symmetric 1,4-DHPs 18 (diethyl 4-(4-benzyloxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), 19 (diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), and 20 (diethyl 4-(3-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) reduced the HeLa (IC₅₀ = 3.6, 2.3, and 4.1 µM, respectively) and MCF-7 (IC₅₀ = 5.2, 5.7, and 11.9 µM, respectively) cell viability. These 1,4-DHPs were more cytotoxic to the HeLa and MCF-7 cells than to the GM07492 (normal human fibroblast) cells, as evidenced by their selectivity indexes. Therefore,1,4-DHPs 18, 19, and 20 may serve as novel lead compounds to discover other 1,4-DHP derivatives with improved anticancer potency and selectivity. Full article

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies. Full article

Some cancers have a poor prognosis and often lead to local recurrence because they are resistant to available treatments, e.g., glioblastoma. Attempts have been made to increase the sensitivity of resistant tumors by targeting pathways involved in the resistance and combining it, for example, with radiotherapy (RT). We have previously reported that treating glioblastoma stem cells with an Nrf2 inhibitor increases their radiosensitivity. Unfortunately, the application of drugs can also affect normal cells. In the present study, we aim to investigate the role of the Nrf2 pathway in the survival and differentiation of normal human adipose-derived stem cells (ADSCs) exposed to radiation. We treated ADSCs with an Nrf2 inhibitor and then exposed them to X-rays, protons or carbon ions. All three radiation qualities are used to treat cancer. The survival and differentiation abilities of the surviving ADSCs were studied. We found that the enhancing effect of Nrf2 inhibition on cell survival levels was radiation-quality-dependent (X-rays > proton > carbon ions). Furthermore, our results indicate that Nrf2 inhibition reduces stem cell differentiation by 35% and 28% for adipogenesis and osteogenesis, respectively, using all applied radiation qualities. Interestingly, the results show that the cells that survive proton and carbon ion irradiations have an increased ability, compared with X-rays, to differentiate into osteogenesis and adipogenesis lineages. Therefore, we can conclude that the use of carbon ions or protons can affect the stemness of irradiated ADSCs at lower levels than X-rays and is thus more beneficial for long-time cancer survivors, such as pediatric patients. Full article

Recently, ribavirin has demonstrated effectiveness in treating glioblastoma through intranasal administration utilizing the nose-to-brain delivery route. Enhancing ribavirin’s bioavailability can be achieved by utilizing intranasal stimuli-responsive systems that create a gel on the nasal mucosa. The research examined thermosensitive, pH-sensitive, and ion-selective polymers in various combinations and concentrations, chosen in line with the current Quality by Design (QbD) approach in pharmaceutical development. Following a thorough assessment of key parameters, the optimal composition of gellan gum at 0.5%, Poloxamer 124 at 2%, and purified water with ribavirin concentration at 100 mg/mL was formulated and subjected to in vivo testing. Through experiments on male rats, the nose-to-brain penetration mechanism of the active pharmaceutical ingredient (API) was elucidated, showcasing drug accumulation in the olfactory bulbs and brain. Full article