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Frontiers in Microbiology 2024Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been...
Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been proposed as a potential cause of neurodegeneration. While studies have extensively tackled the interaction between autophagy and HSV-1 in neurons, research in glial cells is currently limited. Our studies demonstrate that HSV-1 inhibits, but not completely blocks, the formation of autophagosomes in human oligodendroglioma- and astrocytoma- derived cell lines. These findings have been confirmed in murine oligodendrocyte precursor cells (OPCs). Finally, this study investigates the impact of autophagy on HSV-1 infection in glial cells. While the lack of basal autophagy in LC3B knockout glial cells does not have a significant effect on viral infection, cells without the autophagy-related protein ATG5 exhibit reduced viral production. The absence of ATG5 leads to a decrease in the transcription and replication of viral genes, as well as a delay in the initial stages of the formation of HSV-1 replication compartments. These findings indicate that while autophagy may not play a significant role in antiviral defense in glial cells, HSV-1 may be inhibiting autophagy to exploit non-canonical functions of certain components of the autophagic machinery, such as ATG5, to benefit its lifecycle.
PubMed: 38915300
DOI: 10.3389/fmicb.2024.1411655 -
BioRxiv : the Preprint Server For... Apr 2024Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1 /IDH2 ) and 1p/19q co-deletions. Previously, we reported...
Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1 /IDH2 ) and 1p/19q co-deletions. Previously, we reported that in IDH1 gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDH -specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1 oligodendroglioma. We demonstrated an IDH1 -specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1 and should be considered in the future.
PubMed: 38903086
DOI: 10.1101/2024.04.27.591426 -
Cancers May 2024Mutation in the telomerase reverse transcriptase promoter ( )is commonly observed in various malignancies, such as central nervous system (CNS) tumors, malignant...
Mutation in the telomerase reverse transcriptase promoter ( )is commonly observed in various malignancies, such as central nervous system (CNS) tumors, malignant melanoma, bladder cancer, and thyroid carcinoma. These mutations are recognized as significant poor prognostic factors for these tumors. In this investigation, a total of 528 cases of adult-type diffuse gliomas diagnosed at a single institution were reclassified according to the 2021 WHO classifications of CNS tumors, 5th edition (WHO2021). The study analyzed clinicopathological and genetic features, including mutations in each tumor. The impact of known prognostic factors on patient outcomes was analyzed through Kaplan-Meier survival and Cox regression analysis. mutations were predominantly identified in 94.1% of oligodendrogliomas (ODG), followed by 66.3% in glioblastoma, IDH-wildtype (GBM-IDHwt), and 9.2% of astrocytomas, IDH-mutant (A-IDHm). When considering A-IDHm and GBM as astrocytic tumors (Group 1) and ODGs (Group 2), mutations emerged as a significant adverse prognostic factor ( = 0.013) in Group 1. However, within each GBM-IDHwt and A-IDHm, the presence of mutations did not significantly impact patient prognosis ( = 0.215 and 0.268, respectively). Due to the high frequency of mutations in Group 2 (ODG) and their consistent prolonged survival, a statistical analysis to evaluate their impact on overall survival was deemed impractical. When considering status, the combined -mutated and -unmethylated group exhibited the worst prognosis in OS ( = 0.018) and PFS ( = 0.034) of GBM. This study confirmed that the classification of tumors according to the WHO2021 criteria effectively reflected prognosis. Both uni- and multivariate analyses in GBM, age, methylation, and / homozygous deletion were statistically significant prognostic factors while in univariate analysis in A-IDHm, grade 4, the Ki-67 index and amplifications were statistically significant prognostic factors. This study suggests that it is important to classify and manage tumors based on their genetic characteristics in adult-type diffuse gliomas.
PubMed: 38893152
DOI: 10.3390/cancers16112032 -
Clinical Proteomics Jun 2024Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis,...
BACKGROUND
Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival.
METHODS
Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays.
RESULTS
High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas.
CONCLUSIONS
GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas.
PubMed: 38879494
DOI: 10.1186/s12014-024-09492-7 -
BMC Neurology Jun 2024Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient...
BACKGROUND
Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management.
METHODS
Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications.
RESULTS
457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups.
CONCLUSIONS
Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.
Topics: Humans; Male; Female; Glioma; Middle Aged; Retrospective Studies; Prognosis; Adult; Brain Neoplasms; Aged; Cohort Studies; Young Adult
PubMed: 38877400
DOI: 10.1186/s12883-024-03703-2 -
PNAS Nexus Jun 2024Molecular genetics is highly related with prognosis of high-grade glioma. Accordingly, the latest WHO guideline recommends that molecular subgroups of the genes,...
Molecular genetics is highly related with prognosis of high-grade glioma. Accordingly, the latest WHO guideline recommends that molecular subgroups of the genes, including IDH, 1p/19q, MGMT, TERT, EGFR, Chromosome 7/10, CDKN2A/B, need to be detected to better classify glioma and guide surgery and treatment. Unfortunately, there is no preoperative or intraoperative technology available for accurate and comprehensive molecular subgrouping of glioma. Here, we develop a deep learning-assisted fiber-optic Raman diagnostic platform for accurate and rapid molecular subgrouping of high-grade glioma. Specifically, a total of 2,354 fingerprint Raman spectra was obtained from 743 tissue sites (astrocytoma: 151; oligodendroglioma: 150; glioblastoma (GBM): 442) of 44 high-grade glioma patients. The convolutional neural networks (ResNet) model was then established and optimized for molecular subgrouping. The mean area under receiver operating characteristic curves (AUC) for identifying the molecular subgroups of high-grade glioma reached 0.904, with mean sensitivity of 83.3%, mean specificity of 85.0%, mean accuracy of 83.3%, and mean time expense of 10.6 s. The diagnosis performance using ResNet model was shown to be superior to PCA-SVM and UMAP models, suggesting that high dimensional information from Raman spectra would be helpful. In addition, for the molecular subgroups of GBM, the mean AUC reached 0.932, with mean sensitivity of 87.8%, mean specificity of 83.6%, and mean accuracy of 84.1%. Furthermore, according to saliency maps, the specific Raman features corresponding to tumor-associated biomolecules (e.g. nucleic acid, tyrosine, tryptophan, cholesteryl ester, fatty acid, and collagen) were found to contribute to the accurate molecular subgrouping. Collectively, this study opens up new opportunities for accurate and rapid molecular subgrouping of high-grade glioma, which would assist optimal surgical resection and instant post-operative decision-making.
PubMed: 38860145
DOI: 10.1093/pnasnexus/pgae208 -
Neuro-oncology Advances 2024Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy...
BACKGROUND
Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population.
METHODS
Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%.
RESULTS
Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects.
CONCLUSIONS
Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.
PubMed: 38855053
DOI: 10.1093/noajnl/vdae078 -
Annals of Medicine and Surgery (2012) Jun 2024Primary spinal cord oligodendrogliomas (PSO) are sporadic tumors that arise from oligodendrocytes in the central nervous system (CNS). They can affect adults and...
INTRODUCTION
Primary spinal cord oligodendrogliomas (PSO) are sporadic tumors that arise from oligodendrocytes in the central nervous system (CNS). They can affect adults and children and make up about 2% of all intramedullary (IM) spinal tumors. Here, the authors present the second case in the literature of a primary spinal oligodendroglioma with intracranial extension.
PRESENTATION
A 28-year-old right-handed female presented to our emergency room severely malaised with left-sided hemiparesis, numbness, tingling, and urinary retention with positive Babinski and negative Hoffmann. MRI showed a widespread heterogeneous mass extending from the medulla to C7 with syringomyelia inferior to the mass. The mass was removed surgically, and her neurological condition improved rapidly. The gross, pathological exams, and immunohistochemistry confirmed the diagnosis of oligodendroglioma.
DISCUSSION
Up until 2017, there have been 60 documented cases of PSO in the literature and we have found two more cases in our search between 2017 and 2023. Also, there has been only one case recorded with an intracranial extension, making our case the 63rd PSO case and the second one with cranial extension.
CONCLUSION
The golden standard for imaging is MRI. Surgical excision is the main treatment in the literature. Single-stage laminectomy showed promising results and surgical resection was the critical intervention to which the patient responded. This matches what was stated in the literature that surgery is the primary mode of treatment in PSO patients.
PubMed: 38846823
DOI: 10.1097/MS9.0000000000002099 -
Radiology Case Reports Aug 2024Intraoperative magnetic resonance imaging (iMRI) is a powerful tool used to verify maximal safe resection of gliomas. However, unsuspected new or incidental findings can...
Intraoperative magnetic resonance imaging (iMRI) is a powerful tool used to verify maximal safe resection of gliomas. However, unsuspected new or incidental findings can present difficult clinical scenarios. Here we present a case of a large supratentorial glioma resection where new, incidental bilateral cerebellar hemispheric enhancement was noted on iMRI. A 52-year-old male with a large intra-axial mass spanning the right temporal and parietal lobes underwent a craniotomy for tumor resection utilizing iMRI. Imaging displayed new, remote, bilateral cerebellar enhancement. Upon completion of surgery, the patient was extubated and was at his neurological baseline. An immediate CT scan showed no abnormalities in the cerebellum, and the duration of his hospital stay was unaffected by this finding. An MRI 24 hours after the procedure demonstrated complete resolution of the enhancement. New, remote contrast enhancement in the cerebellum raises concerns for the potentially emergent, well-defined pathology known as remote cerebellar hemorrhage (RCH). However, here we describe a case where these findings turned out to be clinically insignificant, CT-negative, and self-limiting. Therefore, here we call this finding remote non-hemorrhagic cerebellar contrast enhancement (RNHCCE) to differentiate it from RCE, and we discuss nuances and management considerations for differentiating the two.
PubMed: 38841601
DOI: 10.1016/j.radcr.2024.04.091 -
Health Science Reports Jun 2024Brain tumors are common, requiring physicians to have a precise understanding of them for accurate diagnosis and treatment. Considering that various histological tumor...
BACKGROUND AND AIM
Brain tumors are common, requiring physicians to have a precise understanding of them for accurate diagnosis and treatment. Considering that various histological tumor types present different cellularity, we conducted this research to examine the role of apparent diffusion coefficient (ADC) values in the differential diagnosis and pathologic grading of brain tumor types.
METHODS
In this cross-sectional study, we gathered pathology reports of histological samples of adult brain tumors. The tissue sample of brain tumors were examined histologically by a pathologist. The magnetic resonance imaging data of these patients were interpreted by a neuroradiologist. The measured ADC values and ADC ratios were calculated. Standard mean ADC values were expressed as 10 mm/s. The findings were compared according to the histological diagnosis of each tumor.
RESULTS
Sixty-eight patients were included in the study: 34 (50%) were male, and 34 (50%) were female. The average age of the patients was 51.69 + 16.40 years. In the examination of tumor type, 16 (23.5%) were astrocytoma, 9 (13.2%) were oligodendroglioma, 20 (29.4%) were glioblastoma, 4 (5.9%) were medulloblastoma, and 19 (27.9%) were metastatic tumors. the average value of ADC was statistically significantly different according to the pathological type of tumor ( < 0.001). The two-by-two comparison of average ADC among tumor types revealed significant differences, except for oligodendroglioma and glioblastoma (-value = 0.87) and glioblastoma and medulloblastoma (-value = 0.347). The average value of ADC and ADC ratio was statistically significantly different according to the pathological grade of the tumor ( < 0.001). In the two-by-two comparison of average ADC between all pathological grades of the tumor showed a significance difference except for Grade I and Grade II (-value = 0.355). The mean value of ADC and ADC ratio for glioblastoma and metastatic tumors showed no significant difference.
CONCLUSION
The assessment of brain tumor grade through ADC examination will help to estimate prognosis and devising suitable therapeutic strategies.
PubMed: 38841116
DOI: 10.1002/hsr2.2110