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Annals of Clinical and Translational... Jun 2024The molecular era of glioma diagnosis and treatment has arrived, and a single rapid histopathology is no longer sufficient for surgery. This study sought to present an...
OBJECTIVE
The molecular era of glioma diagnosis and treatment has arrived, and a single rapid histopathology is no longer sufficient for surgery. This study sought to present an automatic integrated gene detection system (AIGS), which enables rapid intraoperative detection of IDH/TERTp mutations.
METHODS
A total of 78 patients with gliomas were included in this study. IDH/TERTp mutations were detected intraoperatively using AIGS in 41 of these patients, and they were guided to surgical resection (AIGS detection group). The remaining 37 underwent histopathology-guided conventional surgical resection (non-AIGS detection group). The clinical utility of this technique was evaluated by comparing the accuracy of glioma subtype diagnosis before and after TERTp mutation results were obtained by pathologists and the extent of resection (EOR) and patient prognosis for molecular pathology-guided glioma surgery.
RESULTS
With NGS/Sanger sequencing and chromosome detection as the gold standard, the accuracy of AIGS results was 100%. And the timing was well matched to the intraoperative rapid pathology report. After obtaining the TERTp mutation detection results, the accuracy of the glioma subtype diagnosis made by the pathologists increased by 19.51%. Molecular pathology-guided surgical resection of gliomas significantly increased EOR (99.06% vs. 93.73%, p < 0.0001) and also improved median OS (26.77 vs. 13.47 months, p = 0.0289) and median PFS (15.90 vs. 10.57 months, p = 0.0181) in patients with glioblastoma.
INTERPRETATION
Using AIGS intraoperatively to detect IDH/TERTp mutations to accurately diagnose glioma subtypes can help achieve maximum safe resection of gliomas, which in turn improves the survival prognosis of patients.
PubMed: 38924338
DOI: 10.1002/acn3.52138 -
CNS Neuroscience & Therapeutics Jun 2024Despite the extensive neurological symptoms induced by COVID-19 and the identification of SARS-CoV-2 in post-mortem brain samples from COVID-19 patients months after...
INTRODUCTION
Despite the extensive neurological symptoms induced by COVID-19 and the identification of SARS-CoV-2 in post-mortem brain samples from COVID-19 patients months after death, the precise mechanisms of SARS-CoV-2 invasion into the central nervous system remain unclear due to the lack of research models.
METHODS
We collected glioma tissue samples from glioma patients who had a recent history of COVID-19 and examined the presence of the SARS-CoV-2 spike protein. Subsequently, spatial transcriptomic analyses were conducted on normal brain tissues, glioma tissues, and glioma tissues from glioma patients with recent COVID-19 history. Additionally, single-cell sequencing data from both glioma tissues and glioma organoids were collected and analyzed. Glioma organoids were utilized to evaluate the efficacy of potential COVID-19 blocking agents.
RESULTS
Glioma tissues from glioma patients with recent COVID-19 history exhibited the presence of the SARS-CoV-2 spike protein. Differences between glioma tissues from glioma patients who had a recent history of COVID-19 and healthy brain tissues primarily manifested in neuronal cells. Notably, neuronal cells within glioma tissues of COVID-19 history demonstrated heightened susceptibility to Alzheimer's disease, depression, and synaptic dysfunction, indicative of neuronal aberrations. Expressions of SARS-CoV-2 entry factors were confirmed in both glioma tissues and glioma organoids. Moreover, glioma organoids were susceptible to pseudo-SARS-CoV-2 infection and the infections could be partly blocked by the potential COVID-19 drugs.
CONCLUSIONS
Gliomas had inherent traits that render them susceptible to SARS-CoV-2 infection, leading to their representability of COVID-19 neurological symptoms. This established a biological foundation for the rationality and feasibility of utilization of glioma organoids as research and blocking drug testing model in SARS-CoV-2 infection within the central nervous system.
Topics: Humans; Glioma; COVID-19; Organoids; Brain Neoplasms; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Male; Female; Middle Aged; Brain
PubMed: 38923860
DOI: 10.1111/cns.14822 -
International Journal of Developmental... Jun 2024Glioma, a formidable form of brain cancer, poses significant challenges in terms of treatment and prognosis. Circular RNA nucleoporin 98 (circNUP98) has emerged as a...
Glioma, a formidable form of brain cancer, poses significant challenges in terms of treatment and prognosis. Circular RNA nucleoporin 98 (circNUP98) has emerged as a potential regulator in various cancers, yet its role in glioma remains unclear. Here, we elucidate the functional role of circNUP98 in glioma cell proliferation, invasion, and migration, shedding light on its therapeutic implications. Glioma cells were subjected to si-NUP98 transfection, followed by assessments of cell viability, proliferation, invasion, and migration. Subcellular localization of circNUP98 was determined, and its downstream targets were identified. We delineated the binding relationships between circNUP98 and microRNA (miR)-520f-3p, as well as between miR-520f-3p and ETS transcription factor ELK4 (ELK4). The expression levels of circNUP98/miR-520f-3p/ELK4 were quantified. Our findings demonstrated that circNUP98 was upregulated in glioma cells, and its inhibition significantly attenuated glioma cell proliferation, invasion, and migration. Mechanistically, circNUP98 functioned as a sponge for miR-520f-3p, thereby relieving the inhibitory effect of miR-520f-3p on ELK4. Moreover, inhibition of miR-520f-3p or overexpression of ELK4 partially rescued the suppressive effect of circNUP98 knockdown on glioma cell behaviors. In summary, our study unveils that circNUP98 promotes glioma cell progression via the miR-520f-3p/ELK4 axis, offering novel insights into the therapeutic targeting of circNUP98 in glioma treatment.
PubMed: 38923578
DOI: 10.1002/jdn.10355 -
ChemMedChem Jun 2024Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact...
Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact mechanisms leading to cancer cell death. The indole-based WIN 55,212-2 and SDB-001 are both known as potent agonists at both CB1 and CB2 receptors, yet we demonstrate herein that only the former can exert in vitro antitumour effects when tested against a paediatric brain cancer cell line KNS42. In this report, we describe the synthesis of novel 3,4-fused tricyclic indoles and evaluate their functional potencies at both cannabinoid receptors, as well as their abilities to inhibit the growth or proliferation of KNS42 cells. Compared to our previously reported indole-2-carboxamides, these 3,4-fused tricyclic indoles had either completely lost activities, or, showed moderate-to-weak antagonism at both CB1 and CB2 receptors. Compound 23 displayed the most potent antitumour properties among the series. Our results further support the involvement of non-CB pathways for the observed antitumour activities of amidoalkylindole-based cannabinoids, in line with our previous findings. Transcriptomic analysis comparing cells treated or non-treated with compound 23 suggested the observed antitumour effects of 23 are likely to result mainly from disruption of the FOXM1-regulated cell cycle pathways.
PubMed: 38923350
DOI: 10.1002/cmdc.202400098 -
Cancer Medicine Jun 2024Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current...
INTRODUCTION
Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies.
PATIENTS AND METHODS
Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age.
RESULTS
The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres.
CONCLUSIONS
The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.
Topics: Humans; Child; Glioma; Female; Male; Neurosurgical Procedures; Germany; Brain Neoplasms; Adolescent; Child, Preschool; Infant; Neoplasm Grading
PubMed: 38923198
DOI: 10.1002/cam4.7417 -
EJNMMI Research Jun 2024O-(2-[F]fluoroethyl)-L-tyrosine positron emission tomography ([F]FET PET) scanning is used in routine clinical management and evaluation of gliomas with a recommended 4...
BACKGROUND
O-(2-[F]fluoroethyl)-L-tyrosine positron emission tomography ([F]FET PET) scanning is used in routine clinical management and evaluation of gliomas with a recommended 4 h prior fasting. Knowledge of test-retest variation of [F]FET PET imaging uptake metrics and the impact of accidental protein intake can be critical for interpretation. The aim of this study was to investigate the repeatability of [F]FET-PET metrics and to assess the impact of protein-intake prior to [F]FET PET scanning of gliomas.
RESULTS
Test-retest variability in the non-protein group was good with absolute (and relative) upper and lower limits of agreement of + 0.15 and - 0.13 (+ 9.7% and - 9.0%) for mean tumour-to-background ratio (TBR), + 0.43 and - 0.28 (+ 19.6% and - 11.8%) for maximal tumour-to-background ratio (TBR), and + 2.14 cm and - 1.53 ml (+ 219.8% and - 57.3%) for biological tumour volume (BTV). Variation was lower for uptake ratios than for BTV. Protein intake was associated with a 27% increase in the total sum of plasma concentration of the L-type amino acid transporter 1 (LAT1) relevant amino acids and with decreased standardized uptake value (SUV) in both healthy appearing background brain tissue (mean SUV - 25%) and in tumour (maximal SUV - 14%). Oral intake of 24 g of protein 1 h prior to injection of tracer tended to increase variability, but the effects on derived tumour metrics TBR and TBR were only borderline significant, and changes generally within the variability observed in the group with no protein intake.
CONCLUSION
The test-retest repeatability was found to be good, and better for TBR and TBR than BTV, with the methodological limitation that tumour growth may have influenced results. Oral intake of 24 g of protein one hour before a [F]FET PET scan decreases uptake of [F]FET in both tumour and in healthy appearing brain, with no clinically significant difference on the most commonly used tumour metrics.
PubMed: 38922458
DOI: 10.1186/s13550-024-01119-0 -
Neurosurgical Review Jun 2024
Topics: Humans; Glioma; Brain Neoplasms; Meningeal Neoplasms; Neurosurgical Procedures
PubMed: 38922370
DOI: 10.1007/s10143-024-02540-8 -
Metabolites Jun 2024Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic...
Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic alterations. While multiparametric imaging enhances the characterization of ITH by capturing both spatial and functional variations, it falls short in directly assessing the metabolic activities that underpin these phenotypic differences. This gap stems from the challenge of integrating easily accessible, colocated pathology and detailed genomic data with metabolic insights. This study presents a multifaceted approach combining stereotactic biopsy with standard clinical open-craniotomy for sample collection, voxel-wise analysis of MR images, regression-based GAM, and whole-exome sequencing. This work aims to demonstrate the potential of machine learning algorithms to predict variations in cellular and molecular tumor characteristics. This retrospective study enrolled ten treatment-naïve patients with radiologically confirmed glioma. Each patient underwent a multiparametric MR scan (T1, T1, T2, T2-FLAIR, DWI) prior to surgery. During standard craniotomy, at least 1 stereotactic biopsy was collected from each patient, with screenshots of the sample locations saved for spatial registration to pre-surgical MR data. Whole-exome sequencing was performed on flash-frozen tumor samples, prioritizing the signatures of five glioma-related genes: IDH1, TP53, EGFR, PIK3CA, and NF1. Regression was implemented with a GAM using a univariate shape function for each predictor. Standard receiver operating characteristic (ROC) analyses were used to evaluate detection, with AUC (area under curve) calculated for each gene target and MR contrast combination. Mean AUC for five gene targets and 31 MR contrast combinations was 0.75 ± 0.11; individual AUCs were as high as 0.96 for both IDH1 and TP53 with T2-FLAIR and ADC, and 0.99 for EGFR with T2 and ADC. These results suggest the possibility of predicting exome-wide mutation events from noninvasive, in vivo imaging by combining stereotactic localization of glioma samples and a semi-parametric deep learning method. The genomic alterations identified, particularly in IDH1, TP53, EGFR, PIK3CA, and NF1, are known to play pivotal roles in metabolic pathways driving glioma heterogeneity. Our methodology, therefore, indirectly sheds light on the metabolic landscape of glioma through the lens of these critical genomic markers, suggesting a complex interplay between tumor genomics and metabolism. This approach holds potential for refining targeted therapy by better addressing the genomic heterogeneity of glioma tumors.
PubMed: 38921472
DOI: 10.3390/metabo14060337 -
Current Oncology (Toronto, Ont.) May 2024Canada's decentralized healthcare system may lead to regional disparities in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified...
Canada's decentralized healthcare system may lead to regional disparities in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified 50,670 patients diagnosed with a first-ever primary CNS tumour between 2008 and 2017 with follow-up until 31 December 2017. We selected the four highest incidence histologies and used proportional hazard regression to estimate hazard ratios (HRs) for five regions (British Columbia, Prairie Provinces, Ontario, Atlantic Provinces and the Territories), adjusting for sex, tumour behaviour and patient age. Ontario had the best survival profile for all histologies investigated. The Atlantic Provinces had the highest HR for glioblastoma (HR = 1.26, 95% CI: 1.18-1.35) and malignant glioma not otherwise specified (NOS) (Overall: HR = 1.87, 95% CI:1.43-2.43; Pediatric population: HR = 2.86, 95% CI: 1.28-6.39). For meningioma, the Territories had the highest HR (HR = 2.44, 95% CI: 1.09-5.45) followed by the Prairie Provinces (HR = 1.52, 95% CI: 1.38-1.67). For malignant unclassified tumours, the highest HRs were in British Columbia (HR = 1.45, 95% CI: 1.22-1.71) and the Atlantic Provinces (HR = 1.40, 95% CI: 1.13-1.74). There are regional differences in the survival of CNS patients at the population level for all four specific histological types of CNS tumours investigated. Factors contributing to these observed regional survival differences are unknown and warrant further investigation.
Topics: Humans; Central Nervous System Neoplasms; Canada; Female; Male; Middle Aged; Adult; Aged; Young Adult; Adolescent; Child; Child, Preschool; Infant
PubMed: 38920718
DOI: 10.3390/curroncol31060234 -
Cells Jun 2024The world of cancer treatment is evolving rapidly and has improved the prospects of many cancer patients. Yet, there are still many cancers where treatment prospects... (Review)
Review
The world of cancer treatment is evolving rapidly and has improved the prospects of many cancer patients. Yet, there are still many cancers where treatment prospects have not (or hardly) improved. Glioblastoma is the most common malignant primary brain tumor, and even though it is sensitive to many chemotherapeutics when tested under laboratory conditions, its clinical prospects are still very poor. The blood-brain barrier (BBB) is considered at least partly responsible for the high failure rate of many promising treatment strategies. We describe the workings of the BBB during healthy conditions and within the glioblastoma environment. How the BBB acts as a barrier for therapeutic options is described as well as various approaches developed and tested for passing or opening the BBB, with the ultimate aim to allow access to brain tumors and improve patient perspectives.
Topics: Glioblastoma; Humans; Blood-Brain Barrier; Drug Delivery Systems; Brain Neoplasms; Antineoplastic Agents; Animals
PubMed: 38920629
DOI: 10.3390/cells13120998