Search Results (51)

Background/Objectives: Astrocytoma, IDH-mutant, CNS WHO grade 3, is a diffuse glioma with poor prognosis, molecularly defined by IDH mutations and frequently co-occurring TP53 and ATRX alterations. This study aimed to delineate the genomic landscape and identify clinically relevant molecular features of astrocytoma, IDH-mutant, CNS WHO grade 3 using this resource. Methods: Patients in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) database were selected based on histological diagnosis of “anaplastic astrocytoma”, confirmed IDH1/2 mutation, and exclusion of CDKN2A/B homozygous deletions. We analyzed frequencies of somatic mutations, copy number alterations (CNAs), structural variants (SVs), assessed co-occurrence/exclusivity patterns, and explored associations with available demographic and limited survival data. Results: The most common somatic mutations were in IDH1 (98.0%), TP53 (94.8%), and ATRX (55.2%). The observed ATRX mutation frequency was lower than some historical reports (e.g., ~86%). Other recurrent alterations included phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (6.9%), Notch receptor 1 (NOTCH1) (6.9%), and platelet-derived growth factor receptor alpha (PDGFRA) (mutations 4.3%; CNAs also observed). Conclusions: This study provides a comprehensive genomic characterization of astrocytoma, IDH-mutant, CNS WHO grade 3 using the AACR GENIE database, confirming core mutational signatures while also highlighting potential variations in alteration frequencies, such as for ATRX. The findings establish a valuable real-world genomic benchmark for this tumor type, while promoting the need for continued data integration with robust clinical outcomes to identify actionable prognostic and therapeutic targets. Full article

Glioblastoma multiforme is a highly aggressive intrinsic brain tumor with a very poor survival rate. The main treatment for cancer is surgery combined with postoperative radiotherapy and temozolomide chemotherapy. Since the outcomes of treatment are unsatisfactory, the search for more effective drugs is crucial. Our previous study indicated that mephedrone, a synthetic cathinone, reduced neuron and astrocyte viability and oligodendrocyte proliferation. The aim of the present study was to investigate the effect of mephedrone on selected human glioblastoma (LN-18, LN-229, T98G) and human anaplastic astrocytoma (MOGGCCM) cell lines. The effects of mephedrone on cell viability and proliferation, DNA synthesis, cell cycle progression and the type of cell death were studied. Our results showed that mephedrone possesses potential anticancer activity. The viability and proliferation of all four human glioblastoma and human anaplastic astrocytoma cell lines used were decreased in a concentration-dependent manner. Studies conducted on LN-18 and T98G cells confirmed the significant antiproliferative properties of mephedrone, which reduced DNA synthesis and affected cell cycle progression. Microscopic evaluation supported the antiproliferative effect of the tested compounds. Moreover, substantial cytoplasmic vacuolization in the LN-18 cell line was revealed. This finding may indicate the potential of mephedrone in anticancer therapy. Full article

Background: Polycystin 1 (PC1) and polycystin 2 (PC2) proteins are members of the transient receptor potential (TRP) channels family and are encoded from PKD1 and PKD2 genes, respectively. Until recently, the role of PKD1 and PKD2 has been associated with the pathogenesis of the kidney since mutations in these genes cause autosomal dominant polycystic kidney disease (ADPKD). Recent data implicates polycystins in the pathogenesis of solid tumors. In this aspect, the expression of PKD1 and PKD2 in human astrocytomas is largely unknown. The aim of the present research study was to investigate the expression of PKD1 and PKD2 in astrocytic tumors and correlate it with clinicopathological characteristics such as the grade of malignancy, age, and gender of the patients. Methods: A total of 70 cases—corresponding to 8 grade II (diffuse fibrillary astrocytomas), 12 grade III (anaplastic astrocytomas), and 50 grade IV (glioblastomas multiforme)—were examined. The mRNA expression levels of PKD1 and PKD2 were determined through molecular qRT-PCR analysis using the relative quantification ΔΔCt method and the expression of PC1 and PC2 was detected through immunohistochemistry using the semi-quantitative H-score system. Results: Increased levels of PKD1 and PKD2 in astrocytomas were found compared with that of a normal brain (p < 0.05). Glioblastomas demonstrated the greatest increase in PKD1 and PKD2 expression compared to other grades of malignancy (p < 0.05). The same pattern of expression showed PC1 and PC2 proteins. A significant correlation between PKD1 and PKD2 as well as PC1 and PC2 expressions was found (p < 0.05). Although no association was detected between PC1 or PC2 and Ki67 expression (p > 0.05), a significant correlation between PC1 and p53 immunoexpressions, in grade III and between PC2 and p53 immunoexpressions, in grade II astrocytomas (p < 0.01) has emerged. PC1 expression was correlated with age of the patients (p < 0.05). PKD1 and PKD2 expression were negatively correlated with the prognosis of glioma patients. Conclusions: The results of this study indicate the potential involvement of polycystins in the pathogenesis of astrocytomas. However, further research is required to fully understand the mechanisms that these molecules are implicated. Full article

Background: 5-Aminolevulinic acid-guided surgery for adult gliomas has been approved by the European Medicines Agency and the US Food and Drug Administration, becoming a reliable tool for improving gross total resection rates and patient outcomes. This has led several medical centers to explore the off-label use of 5-ALA in the resection of pediatric brain tumors, assessing its efficacy and safety across various tumor types. However, given the differences between children and adults, the appropriateness of 5-ALA use in pediatric populations has not yet been fully established. Methods: We collected eligible publications from Embase, Scopus, PubMed, and Proquest, ultimately selecting 27 studies. Data extraction and retrospective analysis of 249 surgical cases were conducted to determine the current efficacy and safety of 5-ALA in pediatric brain tumors. The fluorescence rate and utility stratified by several clinical features, including WHO grade, tumor classification, and tumor location, were analyzed. Results: Most studies suggest that 5-ALA can enhance tumor identification in high-grade tumors, including glioblastomas and anaplastic astrocytomas. Changes in survival or recurrence rates associated with 5-ALA-guided resection have not been reported. None of the cases reported significant postoperative complications related to the use of 5-ALA. Conclusions: 5-ALA can aid in the resection of high-grade gliomas in pediatric patients. The efficacy of 5-ALA in low-grade gliomas and other tumors may require enhancement with additional tools or modified administration protocols. The safety of 5-ALA has reached a preliminary consensus, although further randomized controlled trials and data on survival and molecular characteristics are needed. Full article

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

The use of diversified raw materials and various extractant types is justified because the varied chemical composition of extracts obtained via extraction determines their biological activity. Therefore, the objective of this study was (i) to characterize the chemical profile of two types of bearberry extracts (70% ethanolic and water) and (ii) to investigate the biological activity of the analyzed extracts through an assessment of their possible proapoptotic effects on glioma cell lines. The HPLC-UV analysis of individual compounds was performed for the determination of the phytochemical profile of the bearberry extracts, and their total phenolic content (TPC) and total flavonoid content (TFC) were determined spectrophotometrically. The induction of apoptosis, autophagy, and necrosis in anaplastic astrocytoma MOGGCCM and human glioblastoma LN229 cell lines were investigated. The results indicated that the ethanolic (Et) and aqueous (Aq) extracts had different chemical profiles. The TPC in the Et was ca. 60% higher than in the Aq. Similarly, the TFC and methylarbutin (mARB) concentrations were significantly higher in the Et. On the other hand, the concentration of hydroquinone (HQ) was ca. 70% and that of corilagin (COR) was ca. 100% higher in the Aq. In turn, the presence of ursolic acid (UA) and oleanolic acid (OA) was confirmed solely in the Et. In contrast to Aq, Et demonstrated high proapoptotic activity. At the concentration of 2 µL/mL, the level of apoptosis varied between 14.7% and 26% in the case of the MOGGCCM cells and between 12.3% and 33.3% in the case of the LN229 cell line. The knowledge and information obtained in this study indicate a need for further research on the anticancer effect of the studied bearberry phytochemicals on the MOGGCCM and LN229 cell lines and for the elucidation of their molecular anticancer mechanisms. Full article

Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the key hub genes mainly associated with different grades of glioma, which were represented by pilocytic astrocytoma (PA), oligodendroglioma (OG), anaplastic astrocytoma (AA), and glioblastoma multiforme (GBM), were identified through weighted gene co-expression network analysis (WGCNA) of microarray datasets retrieved from the Gene Expression Omnibus (GEO) database. Through this, four highly correlated modules were observed to be present across the PA (GSE50161), OG (GSE4290), AA (GSE43378), and GBM (GSE36245) datasets. The functional annotation and pathway enrichment analysis done through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that the modules and hub genes identified were mainly involved in signal transduction, transcription regulation, and protein binding, which collectively deregulate several signaling pathways, mainly PI3K/Akt and metabolic pathways. The involvement of several hub genes primarily linked to other signaling pathways, including the cAMP, MAPK/ERK, Wnt/β-catenin, and calcium signaling pathways, indicates potential interconnectivity and influence on the PI3K/Akt pathway and, subsequently, glioma severity. The Drug Repurposing Encyclopedia (DRE) was used to screen for potential drugs based on the up- and downregulated hub genes, wherein the synthetic progestin hormones norgestimate and ethisterone were the top drug candidates. This shows the potential neuroprotective effect of progesterone against glioma due to its influence on EGFR expression and other signaling pathways. Aside from these, several experimental and approved drug candidates were also identified, which include an adrenergic receptor antagonist, a PPAR-γ receptor agonist, a CDK inhibitor, a sodium channel blocker, a bradykinin receptor antagonist, and a dopamine receptor agonist, which further highlights the gene network as a potential therapeutic avenue for glioma. Full article

Furanocoumarins are naturally occurring compounds in the plant world, characterized by low molecular weight, simple chemical structure, and high solubility in most organic solvents. Additionally, they have a broad spectrum of activity, and their properties depend on the location and type of attached substituents. Therefore, the aim of our study was to investigate the anticancer activity of furanocoumarins (imperatorin, isoimperatorin, bergapten, and xanthotoxin) in relation to human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cell lines. The tested compounds were used for the first time in combination with LY294002 (PI3K inhibitor) and sorafenib (Raf inhibitor). Apoptosis, autophagy, and necrosis were identified microscopically after straining with Hoechst 33342, acridine orange, and propidium iodide, respectively. The levels of caspase 3 and Beclin 1 were estimated by immunoblotting and for the blocking of Raf and PI3K kinases, the transfection with specific siRNA was used. The scratch test was used to assess the migration potential of glioma cells. Our studies showed that the anticancer activity of furanocoumarins strictly depended on the presence, type, and location of substituents. The obtained results suggest that achieving higher pro-apoptotic activity is determined by the presence of an isoprenyl moiety at the C8 position of the coumarin skeleton. In both anaplastic astrocytoma and glioblastoma, imperatorin was the most effective in induction apoptosis. Furthermore, the usage of imperatorin, alone and in combination with sorafenib or LY294002, decreased the migratory potential of MOGGCCM and T98G cells. Full article

Background: Gliomas are the most malignant tumors of the central nervous system. One of the factors in their high drug resistance is avoiding programmed death (PCD) induction. This is related to the overexpression of intracellular survival pathways: PI3K-Akt/PKB-mTOR and Ras-Raf-MEK-ERK. Apoptosis and autophagy are co-existing processes due to the interactions between Bcl-2 and beclin-1 proteins. Their complex may be a molecular “toggle-switch” between PCD types. The aim of this research was to investigate the role of Bcl-2:beclin-1 complex in glioma cell elimination through the combined action of LY294002 and sorafenib. Methods: Drug cytotoxicity was estimated with an MTT test. The type of cell death was evaluated using variant microscopy techniques (fluorochrome staining, immunocytochemistry, and transmission electron microscopy), as well as the Bcl-2:beclin-1 complex formation and protein localization. Molecular analysis of PCD indicators was conducted through immunoblotting, immunoprecipitation, and ELISA testing. SiRNA was used to block Bcl-2 and beclin-1 expression. Results: The results showed the inhibitors used in simultaneous application resulted in Bcl-2:beclin-1 complex formation and apoptosis becoming dominant. This was accompanied by changes in the location of the tested proteins. Conclusions: “Switching” between apoptosis and autophagy using PI3K and Raf inhibitors with Bcl-2:beclin-1 complex formation opens new therapeutic perspectives against gliomas. Full article

Background: Intraoperative Flow Cytometry (iFC) is a novel technique for the assessment of the grade of malignancy and the diagnosis of tumor type and resection margins during solid tumor surgery. Herein, we set out to analyze the role of iFC in the grading of gliomas and the evaluation of resection margins. Material and Methods: iFC uses a fast cell cycle analysis protocol (Ioannina Protocol) that permits the analysis of tissue samples within 5–6 min. Cell cycle analysis evaluated the G0/G1 phase, S-phase, mitosis, and tumor index (S + mitosis phase fraction) and ploidy status. In the current study, we evaluated tumor samples and samples from the peripheral borders from patients with gliomas who underwent surgery over an 8-year period. Results: Eighty-one patients were included in the study. There were sixty-eight glioblastoma cases, five anaplastic astrocytomas, two anaplastic oligodendrogliomas, one pilocytic astrocytoma, three oligodendrogliomas and two diffuse astrocytomas. High-grade gliomas had a significantly higher tumor index than low grade gliomas (median value 22 vs. 7.5, respectively, p = 0.002). Using ROC curve analysis, a cut-off value of 17% in the tumor index could differentiate low- from high-grade gliomas with a 61.4% sensitivity and 100% specificity. All low-grade gliomas were diploid. From the high-grade gliomas, 22 tumors were aneuploid. In glioblastomas, aneuploid tumors had a significantly higher tumor index (p = 0.0018). Twenty-three samples from glioma margins were evaluated. iFC verified the presence of malignant tissue in every case, using histology as the gold standard. Conclusion: iFC constitutes a promising intraoperative technique for glioma grading and resection margin assessment. Comparative studies with additional intraoperative adjuncts are necessary. Full article

Background: Stereotactic biopsy is a standard procedure for brain biopsy. However, with advances in technology, navigation-guided brain biopsy has become a well-established alternative. Previous studies have shown that frameless stereotactic brain biopsy is as effective and safe as frame-based stereotactic brain biopsy is. In this study, the authors evaluate the diagnostic yield and complication rate of frameless intracranial biopsy. Materials and Methods: We reviewed data from biopsy performed patients between March 2014 and April 2022. We retrospectively reviewed medical records, including imaging studies. Various intracerebral lesions were biopsied. Diagnostic yield and post-operative complications were compared with those of frame-based stereotactic biopsy. Results: Forty-two frameless navigation-guided biopsy were performed, and the most common pathology was primary central nervous system lymphoma (35.7%), followed by glioblastoma (33.3%), and anaplastic astrocytomas (16.7%), respectively. The diagnostic yield was 100%. Post-operative intracerebral hematoma occurred in 2.4% of cases, but it was not symptomatic. Thirty patients underwent frame-based stereotactic biopsy, and the diagnostic yield was 96.7%. There was no difference in diagnostic rates between two methods (Fisher’s exact test, p = 0.916). Conclusions: Frameless navigation-guided biopsy is as effective as frame-based stereotactic biopsy is, without causing further complications. We consider that frame-based stereotactic biopsy is no longer needed if frameless navigation-guided biopsy is used. A further study will be needed to generalize our results. Full article

Purpose: Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm²). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs. Methods: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). Results: Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01). Conclusion: These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA. Full article

Flavonoids exert many beneficial properties, such as anticancer activity. They were found to have chemopreventive effects hindering carcinogenesis, and also being able to affect processes important for cancer cell pathophysiology inhibiting its growth or promoting cell death. There are also reports on the chemosensitizing properties of flavonoids, which indicate that they could be used as a support of anticancer therapy. It gives promise for a novel therapeutic approach in tumors characterized by ineffective treatment, such as high-grade gliomas. The research was conducted on the in vitro culture of human SW1783 anaplastic astrocytoma cells incubated with neobavaisoflavone (NEO), doxorubicin, etoposide, and their combinations with NEO. The analyses involved the WST-1 cell viability assay and image cytometry techniques including cell count assay, Annexin V assay, the evaluation of mitochondrial membrane potential, and the cell-cycle phase distribution. We found that NEO affects the activity of doxorubicin and etoposide by reducing the viability of SW1783 cells. The combination of NEO and etoposide caused an increase in the apoptotic and low mitochondrial membrane potential subpopulations of SW1783 cells. Changes in the cell cycle were observed in all combined treatments. These findings indicate a potential chemosensitizing effect exerted by NEO. Full article

Temozolomide is an oral alkylating agent that is used as the first line treatment for glioblastoma multiform, and in recurrent anaplastic astrocytoma, as well as having demonstrable activity in patients with metastatic melanoma. However, as the case with other chemotherapeutic agents, the development of resistance often limits the therapeutic benefit of temozolomide, particularly in the case of glioblastoma. A number of resistance mechanisms have been proposed including the development of cytoprotective autophagy. Cytoprotective autophagy is a survival mechanism that confers upon tumor cells the ability to survive in a nutrient deficient environment as well as under external stresses, such as cancer chemotherapeutic drugs and radiation, in part through the suppression of apoptotic cell death. In this review/commentary, we explore the available literature and provide an overview of the evidence for the promotion of protective autophagy in response to temozolomide, highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of temozolomide and to overcome the development of resistance. Full article

Purpose. For recurrent high-grade gliomas (HGG), no standard therapeutic approach has been reported; thus, surgery, chemotherapy, and re-irradiation (re-RT) may all be proposed. The aim of the study was to evaluate safety and efficacy of re-RT by radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) in association to chemotherapy in patients with recurrent HGG. Material/Methods: All patients with histological diagnosis of HGG that suffered by recurrent disease diagnosed by magnetic resonance imaging (MRI), according to Response Assessment in Neuro-Oncology (RANO) criteria, after primary/adjuvant chemo-radiotherapy treatment and underwent to re-RT by SRS/FSRT were included in the analysis. Second-line chemotherapy was administered. Outcomes were evaluated by neurological examination and brain MRI performed 1 month after re-RT and then every 2–3 months. Results: From November 2019 to September 2021, 30 patients presenting recurrent HGG underwent re-RT. Median dose was 24 Gy (range 15–36 Gy), and median fractions was 5 (range 1–6). Twenty-one patients (70%) had RPA class ≤ IV. One patient had a histological diagnosis of anaplastic oligodendroglioma, 24 patients (80%) were affected by glioblastoma (GBM) including 3 cases of multifocal form, and 5 patients (17%) by anaplastic astrocytoma. Median time between primary/adjuvant RT and disease recurrence was 8 months. In six cases (20%) re-operation was performed, and in most cases (87%), a second line of systemic therapy was administrated. At a median follow-up time from recurrence of 13 months (range 6–56 months), 10 patients (33%) were alive: 2 patients with partial response disease, 7 patients with stable disease, and 1 patient with out-field progression disease. Of the 20 patients who died (67%), 15 (75%) died for progression disease and 5 (25%) for other causes (3 due to septic event, 1 due to thrombo-embolic event, and 1 due to car accident). Median OS and PFS after recurrence were 12.1 and 11.2 months. Six-month and one-year OS were, respectively, 81% and 51%. No acute or late neurological side effects grade ≥ 2 and no case of radio-necrosis were reported. One patient experienced, after reintervention and during Regorafenib treatment (administered 40 days after surgery), dehiscence of the surgical wound. In three cases, grade 2 distal paresthesia was reported. Grade 3–4 hematologic toxicity occurred in seven cases. Three case of grade 5 toxicities during chemotherapy were reported: three septic events and one thrombo-embolic event. Conclusion. Re-RT with SRT/FSRT in association with second-line systemic therapy is a safe and feasible treatment for patients with HGG recurrence. Validation of these results by prospective studies is needed. Full article