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Acta Neuropathologica Oct 2023Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene...
Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients. Thereby, we uncovered that PAs segregated into two molecularly distinct groups, namely, Group 1 and Group 2, which were validated in three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and showed worse progression-free survival compared to patients with group 2 tumors. Ingenuity pathways analysis (IPA) and gene set enrichment analysis (GSEA) revealed that Group 1 tumors were enriched for immune response pathways, such as interferon signaling, while Group 2 tumors showed enrichment for action potential and neurotransmitter signaling pathways. Analysis of immune cell-related gene signatures showed an enrichment of infiltrating T Cells in Group 1 versus Group 2 tumors. Taken together, integrative multi-omics of PA identified biologically distinct and prognostically relevant tumor groups that may improve risk stratification of this single pathway driven tumor type.
Topics: Child; Humans; Multiomics; Proteomics; Astrocytoma; Brain Neoplasms; Action Potentials
PubMed: 37656187
DOI: 10.1007/s00401-023-02626-5 -
Orphanet Journal of Rare Diseases Dec 2023The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms... (Clinical Trial)
Clinical Trial
BACKGROUND
The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC.
RESULTS
The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment.
CONCLUSIONS
Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Middle Aged; Young Adult; Angiomyolipoma; Antineoplastic Agents; Astrocytoma; Epilepsy; Everolimus; Kidney Neoplasms; Seizures; Tuberous Sclerosis
PubMed: 38042867
DOI: 10.1186/s13023-023-02982-1 -
Nature Communications Jul 2023Current technologies to subtype glioblastoma (GBM), the most lethal brain tumor, require highly invasive brain biopsies. Here, we develop a dedicated analytical platform...
Current technologies to subtype glioblastoma (GBM), the most lethal brain tumor, require highly invasive brain biopsies. Here, we develop a dedicated analytical platform to achieve direct and multiplexed profiling of circulating RNAs in extracellular vesicles for blood-based GBM characterization. The technology, termed 'enzyme ZIF-8 complexes for regenerative and catalytic digital detection of RNA' (EZ-READ), leverages an RNA-responsive transducer to regeneratively convert and catalytically enhance signals from rare RNA targets. Each transducer comprises hybrid complexes - protein enzymes encapsulated within metal organic frameworks - to configure strong catalytic activity and robust protection. Upon target RNA hybridization, the transducer activates directly to liberate catalytic complexes, in a target-recyclable manner; when partitioned within a microfluidic device, these complexes can individually catalyze strong chemifluorescence reactions for digital RNA quantification. The EZ-READ platform thus enables programmable and reliable RNA detection, across different-sized RNA subtypes (miRNA and mRNA), directly in sample lysates. When clinically evaluated, the EZ-READ platform established composite signatures for accurate blood-based GBM diagnosis and subtyping.
Topics: Humans; MicroRNAs; Brain Neoplasms; RNA, Messenger; Nucleic Acid Hybridization; Glioblastoma
PubMed: 37460561
DOI: 10.1038/s41467-023-39844-0 -
Frontiers in Immunology 2024
Topics: Humans; Glioblastoma; Immunotherapy; Brain Neoplasms; Immune Checkpoint Inhibitors; Treatment Outcome; Animals
PubMed: 38715607
DOI: 10.3389/fimmu.2024.1407930 -
Neuro-oncology Sep 2023
Topics: Humans; Glioma; Brain Neoplasms; Isocitrate Dehydrogenase; Mutation; Astrocytoma; Cyclin-Dependent Kinase Inhibitor p16
PubMed: 37329568
DOI: 10.1093/neuonc/noad095 -
Acta Neuropathologica Communications Nov 2023As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount...
As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.
Topics: Humans; Brain Neoplasms; Retrospective Studies; Glioma; Astrocytoma; Mutation; Temozolomide; Genomics; Isocitrate Dehydrogenase
PubMed: 37932833
DOI: 10.1186/s40478-023-01669-9 -
Radiology and Oncology Sep 2023Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with... (Review)
Review
BACKGROUND
Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with an intensity of 1 V/cm to 3 V/cm. Its purpose is to inhibit cancer cell proliferation and induce cell death. Despite promising outcomes from clinical trials, TTFields have received FDA approval for the treatment of glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Nevertheless, global acceptance of TTFields remains limited. To enhance its clinical application in other types of cancer and gain a better understanding of its mechanisms of action, this review aims to summarize the current research status by examining existing literature on TTFields' clinical trials and mechanism studies.
CONCLUSIONS
Through this comprehensive review, we seek to stimulate novel ideas and provide physicians, patients, and researchers with a better comprehension of the development of TTFields and its potential applications in cancer treatment.
Topics: Humans; Glioblastoma; Mesothelioma, Malignant; Cell Death; Cell Proliferation
PubMed: 37665740
DOI: 10.2478/raon-2023-0044 -
Journal of Radiation Research Sep 2023Radiotherapy is one of the cornerstone of the glioblastoma treatment paradigm. However, the resistance of tumor cells to radiation results in poor survival. The...
Radiotherapy is one of the cornerstone of the glioblastoma treatment paradigm. However, the resistance of tumor cells to radiation results in poor survival. The mechanism of radioresistance has not been fully elucidated. This study aimed to screen the differential expressed genes related with radiosensitivity. The differentially expressed genes were screened based on RNA sequencing in 15 pairs of primary and recurrent glioblastoma that have undergone radiotherapy. Candidate genes were validated in 226 primary and 134 recurrent glioblastoma (GBM) obtained from the Chinese Glioma Genome Atlas (CGGA) database. RNA and protein expression were verified by Quantitative Real-time PCR (qPCR) and western blot in irradiated GBM cell lines. The candidate gene was investigated to explore the relationship between mRNA levels and clinical characteristics in the CGGA and The Cancer Genome Atlas dataset. Kaplan-Meier survival analysis and Cox regression analysis were used for survival analysis. Gene ontology and KEGG pathway analysis were used for bioinformatics analysis. Four genes (TMEM59L, Gelsolin, ZBTB7A and ATX) were screened. TMEM59L expression was significantly elevated in recurrent glioblastoma and lower in normal brain tissue. We selected TMEM59L as the target gene for further study. The increasing of TMEM59L expression induced by radiation was confirmed by mRNA and western blot in irradiated GBM cell. Further investigation revealed that high expression of TMEM59L was enriched in IDH mutant and MGMT methylated gliomas and associated with a better prognosis. Gene ontology and KEGG pathway analysis revealed that TMEM59L was closely related to the DNA damage repair and oxidative stress respond process. We speculated that the high expression of TMEM59L might enhance radiotherapy sensitivity by increasing ROS-induced DNA damage and inhibiting DNA damage repair process.
Topics: Humans; Glioblastoma; Cell Line, Tumor; Brain Neoplasms; Transcription Factors; Neoplasm Recurrence, Local; DNA-Binding Proteins; Glioma; RNA, Messenger; Radiation Tolerance
PubMed: 37439405
DOI: 10.1093/jrr/rrad053 -
European Journal of Cancer (Oxford,... Aug 2023Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features...
BACKGROUND
Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined.
METHODS
European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich.
RESULTS
At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours.
CONCLUSIONS
Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.
Topics: Humans; Female; Young Adult; Adult; Middle Aged; Aged; Male; Glioblastoma; Isocitrate Dehydrogenase; DNA Methylation; Neoplasm Recurrence, Local; Prognosis; Brain Neoplasms; DNA Modification Methylases; DNA Repair Enzymes; Retrospective Studies
PubMed: 37277265
DOI: 10.1016/j.ejca.2023.05.002 -
International Journal of Molecular... Aug 2023Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by...
Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by hijacking neuronal mechanisms and interacting with non-neuronal cell types, such as astrocytes and endothelial cells. To enter the interstitial space of the brain parenchyma, GBM cells significantly shrink their volume and extend the invadopodia and lamellipodia by modulating their membrane conductance repertoire. However, the changes in the compartment-specific ionic dynamics involved in this process are still not fully understood. Here, using noninvasive perforated patch-clamp and live imaging approaches on various GBM cell lines during a wound-healing assay, we demonstrate that the sodium-calcium exchanger (NCX) is highly expressed in the lamellipodia compartment, is functionally active during GBM cell migration, and correlates with the overexpression of large conductance K+ channel (BK) potassium channels. Furthermore, a NCX blockade impairs lamellipodia formation and maintenance, as well as GBM cell migration. In conclusion, the functional expression of the NCX in the lamellipodia of GBM cells at the migrating front is a conditio sine qua non for the invasion strategy of these malignant cells and thus represents a potential target for brain tumor treatment.
Topics: Humans; Glioblastoma; Sodium-Calcium Exchanger; Endothelial Cells; Cell Movement; Brain
PubMed: 37628853
DOI: 10.3390/ijms241612673