242 results on '"primary glioblastoma"'
Search Results
2. A Dose-escalation Clinical Study of Intraoperative Photodynamic Therapy of Glioblastoma
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- 2024
3. Effectiveness of MR-guided LITT Therapy in Irresectable Glioblastoma (EMITT) (EMITT)
- Author
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Dutch National Health Care Institute, ZonMw: The Netherlands Organisation for Health Research and Development, and UMC Utrecht
- Published
- 2024
4. AV-GBM-1 vs Control as Adjunctive Therapy Following Surgery and RT/TMZ in Newly Diagnosed GBM
- Published
- 2023
5. The Place and Prognostic Value of TERT Promoter Mutation in Molecular Classification in Grade II-III Glial Tumors and Primary Glioblastomas
- Author
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Neslihan Kaya TERZI, Ismail YILMAZ, and Aysim Buge OZ
- Subjects
diffuse glioma ,primary glioblastoma ,tert p ,promoter mutation ,survival ,Pathology ,RB1-214 - Abstract
Objective: Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class II-IV gliomas. After 2016, two mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were identified in addition to the IDH, 1p / 19q, and ATRX status. Material and Method: We identified 84 patients with grade II-IV glioma with IDH, ATRX, 1p / 19q and TERT status. All tumor samples were subjected to molecular genetic screening (Sanger sequencing for IDH and TERT mutations, fluorescence in situ hybridization for 1p/19q status) after histological diagnosis (immunohistochemistry for IDH1 R132H, ATRX, and p53) for a more precise molecular diagnosis. The confidence intervals were calculated at the 95% confidence level, and differences at p < 0.05 were considered statistically significant. Results: Primary glioblastomas had the highest frequency of TERT promoter mutations (25 of 28, 89.2%, p=0.006) followed by oligodendrogliomas (29 of 35, 82.8%, p
- Published
- 2022
- Full Text
- View/download PDF
6. Carbon Ion Radiotherapy for Primary Glioblastoma (CLEOPATRA)
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Juergen Debus, Prof. Dr. Dr. Jürgen Debus
- Published
- 2020
7. Silico analysis of the target and possible mechanism of lomustine in the treatment of primary glioblastoma.
- Author
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Zhang, Tieying, Zhang, Dongdong, and Shi, Feng
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NOTCH genes , *MOLECULAR dynamics , *NOTCH signaling pathway , *GLIOBLASTOMA multiforme , *MOLECULAR docking , *PROTEIN-protein interactions , *CYTOPLASM , *STARTLE reaction - Abstract
Objective: The targets and mechanism of lomustine in the treatment of primary glioblastoma (PGBM) were investigated by molecular docking and molecular dynamics simulation, which provided theoretical guidance for its clinical application. Methods: We used the PharmMapper database to identify all of the targets of lomustine, and then examined the effect of lomustine on PGBM using molecular docking, molecular mechanics generalized born surface area (MMGB/SA), gene difference analysis, molecular dynamics simulation, survival analysis, and protein subcellular localization prediction. Results: A total of 243 lomustine targets and 3197 PGBM-related targets were screened. The intersection of the two was 59 active targets. Protein interaction (PPI), gene enrichment analysis, gene difference analysis, molecular docking, and molecular dynamics simulation finally screened out three effective targets of lomustine, namely HMOX1, AKT1, and EGFR, which exist mainly in the cytoplasm, nucleus, and vesicles, respectively. These three targets mainly inhibit JAK-STAT, PD-1/PD-L1, PI3K-Akt, Rap1, HIF-1, MAPK, and Fc-εRI involved in protein metabolism, the regulation of cell differentiation, the regulation of the Notch signaling pathway and glial cell activation, and other biological processes and could play a role in the treatment of PGBM. Conclusions: HMOX1, AKT1, and EGFR may represent novel therapeutic targets for lomustine in the clinical treatment of PGBM. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
8. Metabolic-related gene pairs signature analysis identifies ABCA1 expression levels on tumor-associated macrophages as a prognostic biomarker in primary IDHWT glioblastoma.
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Shiqun Wang, Lu Li, Shuguang Zuo, Lingkai Kong, Jiwu Wei, and Jie Dong
- Subjects
ISOCITRATE dehydrogenase ,GLIOBLASTOMA multiforme ,TUMOR growth ,PROGNOSIS ,BIOMARKERS - Abstract
Background: Although isocitrate dehydrogenase (IDH) mutation serves as a prognostic signature for routine clinical management of glioma, nearly 90% of glioblastomas (GBM) patients have a wild-type IDH genotype (IDHWT) and lack reliable signatures to identify distinct entities. Methods: To develop a robust prognostic signature for IDHWT GBM patients, we retrospectively analyzed 4 public datasets of 377 primary frozen tumor tissue transcriptome profiling and clinical follow-up data. Samples were divided into a training dataset (204 samples) and a validation (173 samples) dataset. A prognostic signature consisting of 21metabolism-related gene pairs (MRGPs) was developed based on the relative ranking of single-sample gene expression levels. GSEA and immune subtype analyses were performed to reveal differences in biological processes between MRGP risk groups. The single-cell RNA-seq dataset was used to examine the expression distribution of each MRG constituting the signature in tumor tissue subsets. Finally, the association of MRGs with tumor progression was biologically validated in orthotopic GBM models. Results: The metabolic signature remained an independent prognostic factor (hazard ratio, 5.71 [3.542-9.218], P < 0.001) for stratifying patients into high- and low-risk levels in terms of overall survival across subgroups with MGMTp methylation statuses, expression subtypes, and chemo/ratio therapies. Immune-related biological processes were significantly different between MRGP risk groups. Compared with the low-risk group, the high-risk group was significantly enriched in humoral immune responses and phagocytosis processes, and had more monocyte infiltration and less activated DC, NK, and gd T cell infiltration. scRNA-seq dataset analysis identified that the expression levels of 5 MRGs (ABCA1, HMOX1, MTHFD2, PIM1, and PTPRE) in TAMs increased with metabolic risk. With tumor progression, the expression level of ABCA1 in TAMs was positively correlated with the population of TAMs in tumor tissue. Downregulation of ABCA1 levels can promote TAM polarization towards an inflammatory phenotype and control tumor growth. Conclusions: The metabolic signature is expected to be used in the individualized management of primary IDHWT GBM patients. [ABSTRACT FROM AUTHOR]
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- 2022
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- View/download PDF
9. Metabolic-related gene pairs signature analysis identifies ABCA1 expression levels on tumor-associated macrophages as a prognostic biomarker in primary IDHWT glioblastoma
- Author
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Shiqun Wang, Lu Li, Shuguang Zuo, Lingkai Kong, Jiwu Wei, and Jie Dong
- Subjects
primary glioblastoma ,wild-type isocitrate dehydrogenase ,metabolic-related gene pairs ,prognosis ,tumor-associated macrophages ,ABCA1 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundAlthough isocitrate dehydrogenase (IDH) mutation serves as a prognostic signature for routine clinical management of glioma, nearly 90% of glioblastomas (GBM) patients have a wild-type IDH genotype (IDHWT) and lack reliable signatures to identify distinct entities.MethodsTo develop a robust prognostic signature for IDHWT GBM patients, we retrospectively analyzed 4 public datasets of 377 primary frozen tumor tissue transcriptome profiling and clinical follow-up data. Samples were divided into a training dataset (204 samples) and a validation (173 samples) dataset. A prognostic signature consisting of 21 metabolism-related gene pairs (MRGPs) was developed based on the relative ranking of single-sample gene expression levels. GSEA and immune subtype analyses were performed to reveal differences in biological processes between MRGP risk groups. The single-cell RNA-seq dataset was used to examine the expression distribution of each MRG constituting the signature in tumor tissue subsets. Finally, the association of MRGs with tumor progression was biologically validated in orthotopic GBM models.ResultsThe metabolic signature remained an independent prognostic factor (hazard ratio, 5.71 [3.542-9.218], P < 0.001) for stratifying patients into high- and low-risk levels in terms of overall survival across subgroups with MGMTp methylation statuses, expression subtypes, and chemo/ratio therapies. Immune-related biological processes were significantly different between MRGP risk groups. Compared with the low-risk group, the high-risk group was significantly enriched in humoral immune responses and phagocytosis processes, and had more monocyte infiltration and less activated DC, NK, and γδ T cell infiltration. scRNA-seq dataset analysis identified that the expression levels of 5 MRGs (ABCA1, HMOX1, MTHFD2, PIM1, and PTPRE) in TAMs increased with metabolic risk. With tumor progression, the expression level of ABCA1 in TAMs was positively correlated with the population of TAMs in tumor tissue. Downregulation of ABCA1 levels can promote TAM polarization towards an inflammatory phenotype and control tumor growth.ConclusionsThe metabolic signature is expected to be used in the individualized management of primary IDHWT GBM patients.
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- 2022
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10. Androgen Receptor Activity Is Associated with Worse Survival in Glioblastoma.
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Fariña-Jerónimo, Helga, de Vera, Antonia, Medina, Lilian, and Plata-Bello, Julio
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ANDROGEN receptors , *GLIOBLASTOMA multiforme , *BIOMARKERS , *PROGNOSIS , *APOPTOSIS - Abstract
Background: Some evidence about the role of the androgen receptor (AR) in pathogenesis of glioblastoma have been reported, but no study has focused on measuring the activity of the AR in GB. Therefore, the aim of this work is to study the role of AR and its activity as prognostic biomarkers in glioblastoma (GB). Methods: Molecular and clinical data from The Cancer Genome Atlas database were used. The AR-expression at protein-level was obtained from reversed phase protein array (RPPA) assays. The AR-activity was determined by calculating the AR-score, an index calculated by using the expression (at RNA-level) of 13 androgen-responsive-genes. Univariate and multivariate Cox-regression analyses were performed. Finally, a correlation analysis was conducted between protein expression data and the AR-score. Results: Two-hundred and thirty-three patients were included. RPPA data showed a mean AR abundance of 0.027(Statistical Deviation = 0.38) in GB. The univariate Cox-regression analysis showed that the AR-Score was associated with a worse prognosis (Hazard Ratio (HR) = 1.070) while the AR-expression did not show any relationship with survival (HR = 0.869). The association of the AR-score with worse overall survival (OS) was still significant in the multivariate analysis (HR = 1.054). The highest correlation coefficients between the AR-score and RPPA were identified in a group of proteins involved in apoptotic process regulation. Conclusions: GB patients with a high AR-activity present a worse prognosis in terms of OS. Thus, the activity of the AR may have a pathogenic role in GB. In this regard, the activation of the AR in GB may be associated with a dysregulation of apoptosis. [ABSTRACT FROM AUTHOR]
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- 2022
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11. The Place and Prognostic Value of TERT Promoter Mutation in Molecular Classification in Grade II-III Glial Tumors and Primary Glioblastomas.
- Author
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TERZI, Neslihan Kaya, YILMAZ, Ismail, and OZ, Aysim Buge
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PROGNOSIS , *TELOMERASE reverse transcriptase , *GLIOBLASTOMA multiforme , *FLUORESCENCE in situ hybridization , *GENETIC testing - Abstract
Objective: Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class II-IV gliomas. After 2016, two mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were identified in addition to the IDH, 1p / 19q, and ATRX status. Material and Method: We identified 84 patients with grade II-IV glioma with IDH, ATRX, 1p / 19q and TERT status. All tumor samples were subjected to molecular genetic screening (Sanger sequencing for IDH and TERT mutations, fluorescence in situ hybridization for 1p/19q status) after histological diagnosis (immunohistochemistry for IDH1 R132H, ATRX, and p53) for a more precise molecular diagnosis. The confidence intervals were calculated at the 95% confidence level, and differences at p < 0.05 were considered statistically significant. Results: Primary glioblastomas had the highest frequency of TERT promoter mutations (25 of 28, 89.2%, p=0.006) followed by oligodendrogliomas (29 of 35, 82.8%, p<0.001) while astrocytomas showed the lowest frequency (3 of 15, 20%, p=0.107), and the positivity significantly differed among these three groups (p<0.001). TERT promoter mutations were more frequent in patients older than 55 years of age at diagnosis (p=0.023). The group with TERT promoter mutations, and without IDH mutations showed the worst overall survival. However, the presence of both TERT promoter and IDH mutations, which resembled oligodendroglial progression, showed best overall survival (p=0.042). Conclusion: The discovery of TERT promoter mutations in numerous gliomas has opened the door for a better molecular classification of gliomas, and TERT status is associated with survival. Further studies will help in elucidating the value of TERT promoter mutations as biomarkers in clinical practice, and eventual therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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12. Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy.
- Author
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Nguyen, HuyTram N, Lie, Amy, Li, Tie, Chowdhury, Reshmi, Liu, Fei, Ozer, Byram, Wei, Bowen, Green, Richard M, Ellingson, Benjamin M, Wang, He-Jing, Elashoff, Robert, Liau, Linda M, Yong, William H, Nghiemphu, Phioanh L, Cloughesy, Timothy, and Lai, Albert
- Subjects
Humans ,Glioblastoma ,Brain Neoplasms ,Neoplasm Recurrence ,Local ,DNA Repair Enzymes ,DNA Modification Methylases ,Isocitrate Dehydrogenase ,Telomerase ,Tumor Suppressor Proteins ,Prognosis ,Survival Rate ,DNA Methylation ,Mutation ,Aged ,Middle Aged ,Female ,Male ,Promoter Regions ,Genetic ,Neoplasm Grading ,Chemoradiotherapy ,Biomarkers ,Tumor ,MGMT promoter methylation ,hTERT promoter mutation ,overall survival ,primary glioblastoma ,progression free survival ,progression free ,survival ,Neoplasm Recurrence ,Local ,Promoter Regions ,Genetic ,Biomarkers ,Tumor ,Brain Disorders ,Rare Diseases ,Aging ,Human Genome ,Genetics ,Brain Cancer ,Cancer ,Oncology & Carcinogenesis ,Neurosciences ,Oncology and Carcinogenesis - Abstract
BackgroundPromoter mutation in the human telomerase reverse transcriptase gene (hTERT) occurs in ~75% of primary glioblastoma (GBM). Although the mutation appears to upregulate telomerase expression and contributes to the maintenance of telomere length, its clinical significance remains unclear.MethodsWe performed hTERT promoter genotyping on 303 isocitrate dehydrogenase 1 wild-type GBM tumors treated with standard chemoradiotherapy. We also stratified 190 GBM patients from the database of The Cancer Genome Atlas (TCGA) by hTERT gene expression. We analyzed overall and progression-free survival by Kaplan-Meier and Cox regression.ResultsWe detected hTERT promoter mutation in 75% of the patients. When included as the only biomarker, hTERT mutation was not prognostic in our patient cohort by Cox regression analysis. However, when hTERT and O6-DNA methylguanine-methyltransferase (MGMT) were included together, we observed an interaction between these 2 factors. To further investigate this interaction, we performed pairwise comparison of the 4 patient subcohorts grouped by hTERT-MGMT status (MUT-M, WT-M, MUT-U, and WT-U). MGMT methylated patients showed improved survival only in the presence of hTERT promoter mutation: MUT-M versus MUT-U (overall survival of 28.3 vs 15.9 mos, log-rank P < .0001 and progression-free survival of 15.4 vs 7.86 mo, log-rank P < .0001). These results were confirmed by Cox analyses. Analogously, the cohort from TCGA demonstrated survival benefit of MGMT promoter methylation only in patients with high hTERT expression. In addition, hTERT mutation was negatively prognostic in our MGMT unmethylated patients, while the analogous association with high expression was not observed in the cohort from TCGA.ConclusionThe prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.
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- 2017
13. Genetic alteration and clonal evolution of primary glioblastoma into secondary gliosarcoma.
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Li, Jie, Zhao, Yu‐Hang, Tian, Su‐Fang, Xu, Cheng‐Shi, Cai, Yu‐Xiang, Li, Kai, Cheng, Yan‐Bing, Wang, Ze‐Fen, and Li, Zhi‐Qiang
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SOMATIC mutation , *TUMOR suppressor genes , *BRAIN tumors , *GLIOBLASTOMA multiforme , *PHENOTYPES , *GENETIC mutation , *DNA damage - Abstract
Aims: Secondary gliosarcoma (SGS) rarely arises post treatment of primary glioblastoma multiforme (GBM), and contains gliomatous and sarcomatous components. The origin and clonal evolution of SGS sarcomatous components remain uncharacterized. Therapeutic radiation is mutagenic and can induce sarcomas in patients with other tumor phenotypes, but possible causal relationships between radiotherapy and induction of SGS sarcomatous components remain unexplored. Herein, we investigated the clonal origin of SGS in a patient with primary GBM progressing into SGS post‐radiochemotherapy. Methods: Somatic mutation profile in GBM and SGS was examined using whole‐genome sequencing and deep‐whole‐exome sequencing. Mutation signatures were characterized to investigate relationships between radiochemotherapy and SGS pathogenesis. Results: A mutation cluster containing two founding mutations in tumor‐suppressor genes NF1 (variant allele frequency [VAF]: 50.0% in GBM and 51.1% in SGS) and TP53 (VAF: 26.7% in GBM and 50.8% in SGS) was shared in GBM and SGS. SGS exhibited an overpresented C>A (G>T) transversion (oxidative DNA damage signature) but no signature 11 mutations (alkylating‐agents – exposure signature). Since radiation induces DNA lesions by generating reactive oxygen species, the mutations observed in this case of SGS were likely the result of radiotherapy rather than chemotherapy. Conclusions: Secondary gliosarcoma components likely have a monoclonal origin, and the clone possessing mutations in NF1 and TP53 was likely the founding clone in this case of SGS. [ABSTRACT FROM AUTHOR]
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- 2021
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14. The predominant expression of cancer stem cell marker ALDH1A3 in tumor infiltrative area is associated with shorter overall survival of human glioblastoma
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Chao Gan, Daniela Pierscianek, Nicolai El Hindy, Yahya Ahmadipour, Kathy Keyvani, Ulrich Sure, and Yuan Zhu
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Primary glioblastoma ,ALDH1A3 ,Cancer stem cell marker ,Overall survival ,Peritumoral edema ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background ALDH1A3 is a cancer stem cell marker in neoplasms including glioblastoma (GBM). However, the comprehensive role of ALDH1A3 in GBM remains unclear. This study attempted to investigate the expression of ALDH1A3 in human GBM tissues and its association with clinical parameters. Methods Thirty primary GBM and 9 control were enrolled in this study. ALDH1A3 mRNA and protein expression levels were detected by RT2-PCR and western blot, respectively. Immunohistochemistry and immunofluorescence staining were performed to evaluate the regional and cellular expression manner of ALDH1A3. The association of ALDH1A3 expression with multiple clinical parameters was analyzed. Results ALDH1A3 protein level, but not mRNA level, in a subgroup of GBM was significantly higher than that in the control group. ALDH1A3 immunoreactivity was detected heterogeneously in individual GBMs. Fifteen of 30 cases showed a positive of ALDH1A3 immunoreactivity which was predominantly observed in the tumor infiltrative area (TI). Double immunofluorescence staining revealed a co-localization of ALDH1A3 with GFAP in glial-shaped cells and in tumor cells. ALDH1A3 immunoreactivity was often merged with CD44, but not with CD68. Moreover, ALDH1A3 expression was positively associated with the tumor edema grade and inversely with overall survival (OS) (median OS: 16 months vs 10 months), but with neither MGMT promoter methylation status nor Ki67 index in GBM. An upregulation of ALDH1A3 was accompanied by a reduced expression of STAT3β and p-STAT3β. Conclusions Inter- and intra-tumoral heterogeneous expression of ALDH1A3 was exhibited in GBMs. A high immunoreactivity of ALDH1A3 in tumor infiltrative area was associated with shorter OS, especially in patients with MGMT promoter methylation. Our findings propose ALDH1A3 not only as a predictive biomarker but also as a potential target for personalized therapy of GBM.
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- 2020
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15. Prognostic Impact of the Combination of MGMT Methylation and TERT Promoter Mutation in Glioblastoma.
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Tunthanathip, Thara, Sangkhathat, Surasak, Tanvejsilp, Pimwara, and Kanjanapradit, Kanet
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TELOMERASE reverse transcriptase , *PHYSICIANS , *GLIOBLASTOMA multiforme , *METHYLATION ,TUMOR surgery - Abstract
Background The concept of combinational analysis between the methylation of O 6 -methylguanine-DNA methyltransferase (MGMT) and telomerase reverse transcriptase promoter (pTERT) mutation in glioblastoma (GBM) has been reported. The main study objective was to determine the prognosis of patients with GBM based on MGMT/pTERT classification, while the secondary objective was to estimate the temozolomide effect on the survival time of GBM with MGMT/pTERT classification. Methods A total of 50 GBM specimens were collected after tumor resection and were selected for investigating MGMT methylation and pTERT mutation. Clinical imaging and pathological characteristics were retrospectively analyzed. Patients with MGMT/pTERT classification were analyzed using survival analysis to develop the nomogram for forecasting and individual prognosis. Results All patients underwent resection (total resection: 28%, partial resection: 64%, biopsy: 8%). Thirty-two percent of all cases received adjuvant temozolomide with radiotherapy. Sixty-four percent of the case was found methylated MGMT , and 56% of the present cohort found pTERT mutation. Following combinational analysis of biomarkers, results showed that the GBMs with methylated MGMT and wild-type pTERT had a superior prognosis compared with other subtypes. Using Cox regression analysis with multivariable analysis, the extent of resection, postoperative chemoradiotherapy, MGMT/pTERT classification were associated with a favorable prognosis. Hence, a web-based nomogram was developed for deploying individual prognostication. Conclusions The interaction of MGMT methylation and pTERT mutation was confirmed for predicting prognosis. The results from the present study could help physicians create treatment strategies for GBM patients in real-world situations. [ABSTRACT FROM AUTHOR]
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- 2021
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16. Androgen Receptor Activity Is Associated with Worse Survival in Glioblastoma
- Author
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Helga Fariña-Jerónimo, Antonia de Vera, Lilian Medina, and Julio Plata-Bello
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glioblastoma ,high grade glioma ,androgen receptor ,survival ,prognosis ,hormones ,androgens ,primary glioblastoma ,androgenic pathway ,apoptosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Some evidence about the role of the androgen receptor (AR) in pathogenesis of glioblastoma have been reported, but no study has focused on measuring the activity of the AR in GB. Therefore, the aim of this work is to study the role of AR and its activity as prognostic biomarkers in glioblastoma (GB). Methods: Molecular and clinical data from The Cancer Genome Atlas database were used. The AR-expression at protein-level was obtained from reversed phase protein array (RPPA) assays. The AR-activity was determined by calculating the AR-score, an index calculated by using the expression (at RNA-level) of 13 androgen-responsive-genes. Univariate and multivariate Cox-regression analyses were performed. Finally, a correlation analysis was conducted between protein expression data and the AR-score. Results: Two-hundred and thirty-three patients were included. RPPA data showed a mean AR abundance of 0.027(Statistical Deviation = 0.38) in GB. The univariate Cox-regression analysis showed that the AR-Score was associated with a worse prognosis (Hazard Ratio (HR) = 1.070) while the AR-expression did not show any relationship with survival (HR = 0.869). The association of the AR-score with worse overall survival (OS) was still significant in the multivariate analysis (HR = 1.054). The highest correlation coefficients between the AR-score and RPPA were identified in a group of proteins involved in apoptotic process regulation. Conclusions: GB patients with a high AR-activity present a worse prognosis in terms of OS. Thus, the activity of the AR may have a pathogenic role in GB. In this regard, the activation of the AR in GB may be associated with a dysregulation of apoptosis.
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- 2022
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17. Palliative Radiotherapy of Primary Glioblastoma.
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WITTELER, JASPAR, SCHILD, STEVEN E., and RADES, DIRK
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GLIOBLASTOMA multiforme ,THYROID cancer ,RADIOTHERAPY ,GENE expression ,TEMOZOLOMIDE - Abstract
Background/Aim: Care is often palliative when patients are not fit and complete resection of glioblastomas cannot be achieved. This study aimed to identify predictors of survival after palliative radiotherapy. Patients and Methods: Thirty-one patients irradiated after biopsy or incomplete resection of primary glioblastoma were retrospectively analyzed. Median total dose, dose per fraction and equivalent dose in 2 Gy fractions (EQD2) were 45.0 Gy, 3.0 Gy and 46.0 Gy, respectively. Median number of fractions was 15, median treatment time 3 weeks. Ten patients received temozolomide. Six factors were evaluated for survival including location of glioblastoma, Karnofsky performance score (KPS), gender, age, EQD2 and temozolomide. Results: KPS ≥60 showed a trend for improved survival (p=0.141). For other factors including EQD2, no significant association with survival was found. Conclusion: Patients with a KPS ≤50 have a poor survival prognosis and appear good candidates for short-course radiotherapy. Selected patients with better KPS may be considered for more aggressive treatments. [ABSTRACT FROM AUTHOR]
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- 2021
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18. Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas
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Omer Gokay Argadal, Melis Mutlu, Secil Ak Aksoy, Hasan Kocaeli, Berrin Tunca, Muhammet Nafi Civan, Unal Egeli, Gulsah Cecener, Ahmet Bekar, Mevlut Ozgur Taskapilioglu, Cagla Tekin, Gulcin Tezcan, and Sahsine Tolunay
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Long noncoding RNA ,MALAT1 ,biomarker ,prognosis ,IDH1/2 ,primary glioblastoma ,Biology (General) ,QH301-705.5 - Abstract
Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations.
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- 2020
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19. The delta-like ligand 4-notch signaling inhibits tumor angiogenesis but promotes tumor growth in primary glioblastoma: An immunohistochemical study
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Yao Chen, Zhi-Xiong Lin, Jin-Tao Chen, and Ming-Cheng Zheng
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Angiogenesis ,delta-like ligand 4-notch signaling ,microvessel density ,primary glioblastoma ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Delta-like ligand 4 (DLL4) is a key Notch ligand implicated in tumor angiogenesis. However, previous studies have shown that the DLL4-Notch signaling inhibits tumor angiogenesis but promotes tumor progression in primary glioblastoma. The underlying mechanism remains unknown. Methods: Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for the expression of DLL4, microvessel density (MVD), and Ki67 labeling index. The degree of tumor contrast enhancement (DTCE) on preoperative magnetic resonance imaging was also evaluated. The effect on prognosis was assessed based on Kaplan–Meier survival and Cox proportional hazard models. Results: Results showed that the DTCE was negatively correlated with DLL4 but positively correlated with MVD (r = −0.260, 0.593, P < 0.05). The Ki67 labeling index was shown to be positively correlated with both DLL4 and MVD (r = 0.346, 0.346, P < 0.05). Univariate analysis indicated a significant correlation of high DLL4 and Ki67 labeling index expression with shorter progression-free survival (PFS) and overall survival (OS) (P < 0.05). Multivariate analysis confirmed high DLL4 and MVD expression as unfavorable prognostic indicators for PFS and OS (P < 0.05), and the hazard ratio of DLL4 was higher than MVD for both PFS and OS (P < 0.05). Conclusion: We conclude that the DLL4-Notch signaling improves tumor vascular function and contributes to the survival of malignant cells, resulting in less MVD but more tumor progression in primary glioblastoma.
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- 2018
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20. Wild-type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in primary glioblastoma cells.
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Shen, Xiaopeng, Wu, Shen, Zhang, Jingyi, Li, Meng, Xu, Feng, Wang, Ao, Lei, Yang, and Zhu, Guoping
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CELL migration , *PRIMARY cell culture , *ISOCITRATE dehydrogenase , *RNA sequencing , *BRAIN tumors , *WOUND healing , *PI3K/AKT/MTOR pathway , *GLIOBLASTOMA multiforme - Abstract
Glioblastoma (GBM) is the most common type of brain cancer and has the highest mortality. Dysregulated expression of wild-type isocitrate dehydrogenase 1 (IDH1) has been demonstrated to promote the progression of primary GBM without accumulating D-2-hydroxyglutarate, which differs from IDH1 mutation-related mechanisms of tumorigenesis. Previous studies have revealed several roles of wild-type IDH1 in primary GBM, involving proliferation and apoptosis. However, the function of IDH1 in cell migration has not been investigated. In the current study, the results of bioinformatics analysis revealed that IDH1 expression was significantly upregulated in patients with primary GBM. Wound healing and Transwell assays demonstrated that IDH1 overexpression promoted cell migration in primary GBM cells and that IDH1 knockdown hindered this process. Furthermore, α-ketoglutarate (α-KG), which is the main product of IDH1-catalyzed reactions, was significantly decreased by IDH1 knockdown and upregulated by IDH1 overexpression. α-KG treatment significantly increased the migration of primary GBM cells. Additionally, RNA sequence analysis of patients with primary GBM reported significant alterations in the expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway-regulated genes, including Myc, Snail family transcriptional repressor 2 and Twist-related protein 1, which are primarily cell migration regulatory factors. Western blotting revealed that the overexpression or knockdown of IDH1 promoted or inhibited the PI3K/AKT/mTOR pathway, respectively. α-KG treatment of primary GBM cells also promoted the PI3K/AKT/mTOR pathway. Furthermore, IDH1-overexpressing and α-KG-treated U87 cells were incubated with rapamycin, an mTOR-specific inhibitor, and the results revealed that rapamycin treatment reversed the increased cell migration caused by IDH1 overexpression and α-KG treatment. The results indicated that IDH1 regulated the migration of primary GBM cells by altering α-KG levels and that the function of the IDH1/α-KG axis may rely on PI3K/AKT/mTOR pathway regulation. [ABSTRACT FROM AUTHOR]
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- 2020
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21. The predominant expression of cancer stem cell marker ALDH1A3 in tumor infiltrative area is associated with shorter overall survival of human glioblastoma.
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Gan, Chao, Pierscianek, Daniela, El Hindy, Nicolai, Ahmadipour, Yahya, Keyvani, Kathy, Sure, Ulrich, and Zhu, Yuan
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CANCER stem cells , *OLIGODENDROGLIOMAS , *TUMOR markers , *GLIOBLASTOMA multiforme , *BIOMARKERS - Abstract
Background: ALDH1A3 is a cancer stem cell marker in neoplasms including glioblastoma (GBM). However, the comprehensive role of ALDH1A3 in GBM remains unclear. This study attempted to investigate the expression of ALDH1A3 in human GBM tissues and its association with clinical parameters.Methods: Thirty primary GBM and 9 control were enrolled in this study. ALDH1A3 mRNA and protein expression levels were detected by RT2-PCR and western blot, respectively. Immunohistochemistry and immunofluorescence staining were performed to evaluate the regional and cellular expression manner of ALDH1A3. The association of ALDH1A3 expression with multiple clinical parameters was analyzed.Results: ALDH1A3 protein level, but not mRNA level, in a subgroup of GBM was significantly higher than that in the control group. ALDH1A3 immunoreactivity was detected heterogeneously in individual GBMs. Fifteen of 30 cases showed a positive of ALDH1A3 immunoreactivity which was predominantly observed in the tumor infiltrative area (TI). Double immunofluorescence staining revealed a co-localization of ALDH1A3 with GFAP in glial-shaped cells and in tumor cells. ALDH1A3 immunoreactivity was often merged with CD44, but not with CD68. Moreover, ALDH1A3 expression was positively associated with the tumor edema grade and inversely with overall survival (OS) (median OS: 16 months vs 10 months), but with neither MGMT promoter methylation status nor Ki67 index in GBM. An upregulation of ALDH1A3 was accompanied by a reduced expression of STAT3β and p-STAT3β.Conclusions: Inter- and intra-tumoral heterogeneous expression of ALDH1A3 was exhibited in GBMs. A high immunoreactivity of ALDH1A3 in tumor infiltrative area was associated with shorter OS, especially in patients with MGMT promoter methylation. Our findings propose ALDH1A3 not only as a predictive biomarker but also as a potential target for personalized therapy of GBM. [ABSTRACT FROM AUTHOR]- Published
- 2020
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22. Adult Primary Gliosarcoma: Epidemiology
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Hamidi, Maryam, Moody, John, Kozak, Kevin, Hayat, M. A., Series editor, and Hayat, M.A., editor
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- 2014
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23. Tumor-induced mortality in adult primary supratentorial glioblastoma multiforme with different age subgroups.
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Shu, Chang, Yan, Xiaoling, Zhang, Xuebin, Wang, Qiong, Cao, Sen, and Wang, Jinhuan
- Abstract
Aim: To assess the independent determinants of tumor-induced mortality in different age subgroups after considering competing risk (CR). Methods: Data were extracted from the SEER database. The independent determinants of tumor-induced mortality were defined by CR analysis and validated by conditional inference trees. A CR nomogram was created based on the proportional subdistribution hazard model. Results: The different age subgroups had their own independent determinants of tumor-induced mortality. Using these variables, a CR nomogram was built with good discrimination and calibration. Conclusion: When conducting population-based cohort studies, a CR analysis is recommended for cancers with short survival and high mortality. A CR nomogram represents the first attempt at a predictive model for quantifying tumor-induced mortality. [ABSTRACT FROM AUTHOR]
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- 2019
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24. ARL4C stabilized by AKT/mTOR pathway promotes the invasion of PTEN‐deficient primary human glioblastoma.
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Chen, Qian, Weng, Hai‐Yan, Tang, Xiao‐Peng, Lin, Yong, Yuan, Ye, Li, Qian, Tang, Zhuo, Wu, Hai‐Bo, Yang, Shuai, Li, Yong, Zhao, Xi‐Long, Fu, Wen‐Juan, Niu, Qin, Feng, Hua, Zhang, Xia, Wang, Yan, Bian, Xiu‐Wu, and Yao, Xiao‐Hong
- Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency in primary human glioblastoma (GBM) is associated with increased invasiveness and poor prognosis with unknown mechanisms. Therefore, how loss of PTEN promotes GBM progression remains to be elucidated. Herein, we identified that ADP‐ribosylation factor like‐4C (ARL4C) was highly expressed in PTEN‐deficient human GBM cells and tissues. Mechanistically, loss of PTEN stabilized ARL4C protein due to AKT/mTOR pathway‐mediated inhibition of ARL4C ubiquitination. Functionally, ARL4C enhanced the progression of GBM cells in vitro and in vivo. Moreover, microarray profiling and GST pull‐down assay identified that ARL4C accelerated tumor progression via RAC1‐mediated filopodium formation. Importantly, targeting PTEN potently inhibited GBM tumor progression in vitro and in vivo, whereas overexpression of ARL4C reversed the tumor progression impaired by PTEN overexpression. Clinically, analyses with patients' specimens validated a negative correlation between PTEN and ARL4C expression. Elevated ARL4C expression but PTEN deficiency in tumor was associated with poorer disease‐free survival and overall survival of GBM patients. Taken together, ARL4C is critical for PTEN‐deficient GBM progression and acts as a novel prognostic biomarker and a potential therapeutic candidate. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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25. Extracranial multiorgan metastasis from primary glioblastoma: A case report
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Haorun Wang, Shenjie Li, Ligang Chen, Jian-Mei Wang, Xing-Zhao Luan, Haiping He, Jie Zhou, and Wei Xiang
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Primary Glioblastoma ,Oncology ,medicine.medical_specialty ,business.industry ,General Medicine ,Extracranial metastasis ,Multiple organ metastasis ,medicine.disease ,Metastasis ,Primary glioblastoma ,Internal medicine ,Case report ,medicine ,business ,Glioblastoma - Abstract
BACKGROUND Glioblastoma has a high degree of malignancy and poor prognosis. It is common to have in situ recurrence and intracranial metastasis, while extracranial metastasis is rare, and extracranial multiorgan metastasis is extremely rare. We report a case of glioblastoma with extracranial multiorgan metastasis, which will strengthen clinicians’ attention to the extracranial metastasis of glioblastoma and its treatment. CASE SUMMARY A male patient visited our hospital for treatment of dizziness and headache. Magnetic resonance imaging of the brain revealed a space-occupying lesion in the right temporoparietal occipital region. Chest computed tomography and abdominal ultrasound were normal, and no space-occupying lesions were observed in other organs of the body. The patient underwent surgery and diagnosed with glioblastoma. Postoperative concurrent radiotherapy and chemotherapy were completed. During the follow-up, the tumor was found to have metastasized to the scalp and neck, and a second tumor resection was performed. Postoperative follow-up revealed extracranial metastases to multiple extracranial organs including skull, scalp, ribs, spine, liver and lung. His family members refused further treatment, and requested only symptomatic treatment such as pain relief, and the patient died of systemic multiple organ failure. Survival time from diagnosis to death was 13 mo and from extracranial metastasis to death was 6 mo. CONCLUSION Glioblastoma extracranial metastasis is extremely rare, clinicians should always pay attention to its existence. The mechanism of glioblastoma extracranial metastasis is still unclear, and genetic and molecular studies are required.
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- 2021
26. Prognostic Impact of the Combination of MGMT Methylation and TERT Promoter Mutation in Glioblastoma
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Surasak Sangkhathat, Pimwara Tanvejsilp, Kanet Kanjanapradit, and Thara Tunthanathip
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Oncology ,medicine.medical_specialty ,Methyltransferase ,medicine.medical_treatment ,Neurosciences. Biological psychiatry. Neuropsychiatry ,survival ,o6-methylguanine-dna methyltransferase ,Internal medicine ,medicine ,Telomerase reverse transcriptase ,neoplasms ,Survival analysis ,Temozolomide ,business.industry ,Proportional hazards model ,General Neuroscience ,telomerase reverse transcriptase ,O-6-methylguanine-DNA methyltransferase ,Nomogram ,digestive system diseases ,Radiation therapy ,primary glioblastoma ,prognosis ,Neurology (clinical) ,business ,RC321-571 ,medicine.drug - Abstract
Background The concept of combinational analysis between the methylation of O6-methylguanine-DNA methyltransferase (MGMT) and telomerase reverse transcriptase promoter (pTERT) mutation in glioblastoma (GBM) has been reported. The main study objective was to determine the prognosis of patients with GBM based on MGMT/pTERT classification, while the secondary objective was to estimate the temozolomide effect on the survival time of GBM with MGMT/pTERT classification. Methods A total of 50 GBM specimens were collected after tumor resection and were selected for investigating MGMT methylation and pTERT mutation. Clinical imaging and pathological characteristics were retrospectively analyzed. Patients with MGMT/pTERT classification were analyzed using survival analysis to develop the nomogram for forecasting and individual prognosis. Results All patients underwent resection (total resection: 28%, partial resection: 64%, biopsy: 8%). Thirty-two percent of all cases received adjuvant temozolomide with radiotherapy. Sixty-four percent of the case was found methylated MGMT, and 56% of the present cohort found pTERT mutation. Following combinational analysis of biomarkers, results showed that the GBMs with methylated MGMT and wild-type pTERT had a superior prognosis compared with other subtypes. Using Cox regression analysis with multivariable analysis, the extent of resection, postoperative chemoradiotherapy, MGMT/pTERT classification were associated with a favorable prognosis. Hence, a web-based nomogram was developed for deploying individual prognostication. Conclusions The interaction of MGMT methylation and pTERT mutation was confirmed for predicting prognosis. The results from the present study could help physicians create treatment strategies for GBM patients in real-world situations.
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- 2021
27. The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival.
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Shu, Chang, Wang, Jinhuan, Wang, Qiong, and Yan, Xiaoling
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GLIOBLASTOMA multiforme , *TELOMERASE reverse transcriptase , *METHYLATION , *MAGNETIC resonance imaging , *NECROSIS , *GLIOMAS - Abstract
Abstract: Purpose: This study aimed to integrate the TERT promoter mutation status, MGMT promoter methylation status, MRI‐derived features, and clinical features into a survival analysis model to better understand adult primary glioblastoma prognosis‐related markers. Method: A total of 304 adult glioblastoma samples collected after surgical resection were selected for retrospective analysis, and Sanger sequencing was performed to detect IDH and TERT promoter mutations. The methylation of the MGMT promoter was analyzed by pyrosequencing, and MRI‐derived and clinical features were dichotomized into easily acquired variables. Random survival forest analysis, Kaplan‐Meier analysis, Cox proportional hazard regression, and LASSO regression were performed for the survival analysis, and ROC analysis and Pearson's chi‐squared test were employed for the correlation analysis. Results: Wild‐type IDH was present in 89.8% of the adult glioblastoma samples, and TERT promoter mutations and MGMT promoter methylation were observed in 66.42% and 38.49% of all adult primary glioblastomas, respectively. Age and MGMT promoter methylation were identified as independent prognostic biomarkers, and the TERT promoter mutation status and MGMT promoter methylation status, when combined with other tumor‐related factors, generated several different survival subgroups. None of the factors investigated in this study predicted the MGMT promoter status, and MRI‐detected necrosis was positively associated with TERT promoter mutations. Conclusion: MGMT promoter methylation and TERT promoter mutations, combined with MRI‐derived and clinical features, revealed different survival subgroups with distinct responses to current treatments, and this information increases the ability to predict the survival of adult primary glioblastoma patients. MRI‐detected necrosis often indicates the presence of TERT promoter mutations. [ABSTRACT FROM AUTHOR]
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- 2018
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28. The Non-Coding Oncofetal H19 Gene in Brain Tumors
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Fellig, Y., Amit, D., Matouk, I. J., Kopolovic, J., Erdmann, V. A., Hochberg, A., Erdmann, Volker A., editor, Reifenberger, Guido, editor, and Barciszewski, Jan, editor
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- 2009
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29. Genetic Evolution of Glioblastoma Stem-Like Cells From Primary to Recurrent Tumor.
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Orzan, Francesca, De Bacco, Francesca, Crisafulli, Giovanni, Pellegatta, Serena, Mussolin, Benedetta, Siravegna, Giulia, D'Ambrosio, Antonio, Comoglio, Paolo M., Finocchiaro, Gaetano, and Boccaccio, Carla
- Abstract
Glioblastoma (GBM) is a lethal tumor that displays remarkable genetic heterogeneity. It is also known that GBM contains a cell hierarchy driven by GBM stem-like cells (GSCs), responsible for tumor generation, therapeutic resistance, and relapse. An important and still open issue is whether phylogenetically related GSCs can be found in matched primary and recurrent GBMs, and reflect tumor genetic evolution under therapeutic pressure. To address this, we analyzed the mutational profile of GSCs isolated from either human primary GBMs (primary GSCs) or their matched tumors recurring after surgery and chemoradiotherapy (recurrent GSCs). We found that recurrent GSCs can accumulate temozolomide-related mutations over primary GSCs, following both linear and branched patterns. In the latter case, primary and recurrent GSCs share a common set of lesions, but also harbor distinctive mutations indicating that primary and recurrent GSCs derive from a putative common ancestor GSC by divergent genetic evolution. Interestingly, TP53 mutations distinctive of recurrent GSCs were detectable at low frequency in the corresponding primary tumors and likely marked pre-existent subclones that evolved under therapeutic pressure and expanded in the relapsing tumor. Consistently, recurrent GSCs displayed in vitro greater therapeutic resistance than primary GSCs. Overall, these data indicate that (a) phylogenetically related GSCs are found in matched primary and recurrent GBMs and (b) recurrent GSCs likely pre-exist in the untreated primary tumor and are both mutagenized and positively selected by chemoradiotherapy. Stem Cells 2017;35:2218-2228 [ABSTRACT FROM AUTHOR]
- Published
- 2017
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30. A Crowdsourced Consensus on Supratotal Resection Versus Gross Total Resection for Anatomically Distinct Primary Glioblastoma
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Brad E. Zacharia, Andrew S. Venteicher, Jon D. Weingart, Michael E. Ivan, Ezequiel Goldschmidt, Michael Lim, Ray M Chu, Raymond Sawaya, Mateo Ziu, Gary L. Gallia, Jason P. Sheehan, Mitchel S. Berger, Yoshua Esquenazi, John S. Yu, Brian V. Nahed, Adam N. Mamelak, Adham M. Khalafallah, Edjah K. Nduom, Debraj Mukherjee, Bob S. Carter, Maureen Rakovec, Christopher M. Jackson, and Chetan Bettegowda
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Primary Glioblastoma ,medicine.medical_specialty ,Randomization ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,medicine.disease ,Gross Total Resection ,Resection ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,030220 oncology & carcinogenesis ,medicine ,Surgery ,Neurology (clinical) ,Radiology ,Tumor location ,business ,030217 neurology & neurosurgery ,Glioblastoma - Abstract
BACKGROUND Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P
- Published
- 2021
31. Coexistence of TERT C228T mutation and MALAT1 dysregulation in primary glioblastoma: new prognostic and therapeutic targets
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Muhammet Nafi Civan, Ahmet Bekar, Mevlut Ozgur Taskapilioglu, Omer Gokay Argadal, Pinar Eser Ocak, Secil Ak Aksoy, Ismail Seckin Kaya, Sahsine Tolunay, Cagla Tekin, Melis Mutlu, Berrin Tunca, and Hasan Kocaeli
- Subjects
Adult ,Male ,IDH1 ,Death-associated protein 6 ,Molecular classification ,Biomarkers, Tumor ,Humans ,Medicine ,Telomerase ,ATRX ,Aged ,Primary Glioblastoma ,MALAT1 ,Brain Neoplasms ,business.industry ,General Medicine ,Middle Aged ,Prognosis ,TERT C228T ,Neurology ,Mutation ,Mutation (genetic algorithm) ,Cancer research ,Female ,RNA, Long Noncoding ,sense organs ,Neurology (clinical) ,Glioblastoma ,business - Abstract
Objective: This study was designed to conduct molecular classification based on IDH1/2, TERT, ATRX, and DAXX changes in pediatric and adult primary glioblastoma (GB) and to analyze the potential interaction of LncRNA MALAT1 in the determined homogeneous subgroups. Methods: We analyzed the expression profiles of ATRX/DAXX and MALAT1 using the qRT-PCR method and IDH and TERT mutation status using DNA sequencing analysis in 85 primary pediatric and adult GB patients. Results: IDH1 mutation was observed in 5 (5.88%) and TERT mutation in 65 (76.47%) primary pediatric and adult GB patients. ATRX and DAXX were detected in 18 (21.18%) and 7 (8.24%) patients. TERT mutation and loss of ATRX/DAXX were associated with short overall survival (p < 0.001, p < 0.001, respectively). Patients carrying especially TERT C228T mutation had worse prognosis (p < 0.001). Six subgroups were obtained from the genetic analysis. Among the subgroups, MALAT1 was highly expressed in group A that had a single TERT mutation as compared to that in groups D and E (p = 0.001 and p < 0.001, respectively); further, high MALAT1 expression was associated with worse prognosis in patients with C228T mutation (p < 0.001). Conclusions: Our findings highlight that the presence of TERT C228T mutation and expression of MALAT1 can be used as primary targets during the follow-up of primary GB patients and in the development of new treatment strategies.
- Published
- 2021
32. CHANGES IN THE MGMT GENE EXPRESSION IN PATIENTS WITH PRIMARY GLIOBLASTOMA AFTER RELAPSE. INFLUENCE OF CLINICAL CHARACTERISTICS AND MGMT EXPRESSION ON SURVIVAL OF PATIENTS
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M. V. Matsko, S. S. Sklyar, A. Yu. Ulitin, D. E. Matsko, E. N. Imyanitov, A. G. Ievleva, V. I. Ni, N. M. Volkov, A. A. Zrelov, A. O. Baksheeva, and D. V. Galkina
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Oncology ,Cancer Research ,medicine.medical_specialty ,IDH1 ,medicine.medical_treatment ,temozolomide ,glioblastoma recurrence ,IDH2 ,mutations idh1/idh2 genes, mgmt gene ,Internal medicine ,Gene expression ,medicine ,Progression-free survival ,neoplasms ,RC254-282 ,Chemotherapy ,Temozolomide ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,extent of resection ,Radiation therapy ,primary glioblastoma ,business ,Adjuvant ,progression-free survival ,medicine.drug - Abstract
Background . Over the past 10–15 years, there has been a clearer understanding of the processes occurring in cells of the primary glioblastoma. However, the change in MGMT gene expression and its role after disease relapse remain understudied. Purpose : to study changes in MGMT gene expression in case of recurrent primary glioblastoma after the standard therapy; to determine influence of clinical factors and MGMt gene expression on relapse-free survival of patients. Materials and Methods . We carried out a prospective analysis of clinical and molecular genetic characteristics of 21 patients aged from 28 to 63 with primary glioblastoma before and after recurrence. Relative mRna expression of MGMT gene and mutations in IDH1/IDH2 genes were determined in surgical biopsies using PCR techniques. after the first surgery, all patients received radiation therapy (60 Gy) and chemotherapy with adjuvant temozolomide (2–18 cycles). the second-line chemotherapy was performed in 17 (80.9 %) patients, and 8 patients received (47 %, 8/17) temozolomide. Results. the relationship between the progression-free survival (PFs) and mRna expression of MGMT gene (73.5 vs 33 weeks, p=0.013) and objective response to therapy (88 vs 36 weeks, p=0.046) was found. The number of cycles of first-line chemotherapy with temozolomide influenced the duration of the first PFs (65 weeks vs 21.5 weeks, p=0,07). the first PFs was not affected by patients’ age (p=0.64), sex (p=0.17), Karnofsky performance scale index (p=0.43), extent of brain damage (p=0.41) and extent of the resection (p=0.27). after onset of relapse, mRna expression of MGMT gene remained the same, being 66.7 % (14/21). The increased expression was observed in 23.8 % (5/21) of cases, and decreased gene expression was observed in 9.5 % (2/21) of cases. the second PFs was affected by the extent of tumor resection, although there were no statistically significant differences (p=0.52). the effect of mRna expression of MGMT gene on the median second PFs was not revealed (p=0.39). no objective response to therapy was found in patients with a low mRna expression of MGMT gene. Conclusion . Recurrent glioblastoma becomes more resistant to further therapy. With the development of tumor recurrence, the predictive value of MGMT gene is lost and the role of the extent of cytoreductive surgery increases.
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- 2021
33. Molecular Abnormalities in Gliomas
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Goussia, A. C., Polyzoidis, K., Kyritsis, A. P., and Drevelegas, Antonios, editor
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- 2002
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34. Palliative Radiotherapy of Primary Glioblastoma
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Jaspar Witteler, Dirk Rades, and Steven E. Schild
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Complete resection ,General Biochemistry, Genetics and Molecular Biology ,Palliative radiotherapy ,Survival prognosis ,Internal medicine ,Biopsy ,Temozolomide ,medicine ,Humans ,Antineoplastic Agents, Alkylating ,Retrospective Studies ,Pharmacology ,Primary Glioblastoma ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Prognosis ,Incomplete Resection ,Radiation therapy ,Glioblastoma ,business ,Research Article ,medicine.drug - Abstract
Background/aim Care is often palliative when patients are not fit and complete resection of glioblastomas cannot be achieved. This study aimed to identify predictors of survival after palliative radiotherapy. Patients and methods Thirty-one patients irradiated after biopsy or incomplete resection of primary glioblastoma were retrospectively analyzed. Median total dose, dose per fraction and equivalent dose in 2 Gy fractions (EQD2) were 45.0 Gy, 3.0 Gy and 46.0 Gy, respectively. Median number of fractions was 15, median treatment time 3 weeks. Ten patients received temozolomide. Six factors were evaluated for survival including location of glioblastoma, Karnofsky performance score (KPS), gender, age, EQD2 and temozolomide. Results KPS ≥60 showed a trend for improved survival (p=0.141). For other factors including EQD2, no significant association with survival was found. Conclusion Patients with a KPS ≤50 have a poor survival prognosis and appear good candidates for short-course radiotherapy. Selected patients with better KPS may be considered for more aggressive treatments.
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- 2021
35. Insular primary glioblastomas with IDH mutations: Clinical and biological specificities.
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Hata, Nobuhiro, Hatae, Ryusuke, Yoshimoto, Koji, Murata, Hideki, Kuga, Daisuke, Akagi, Yojiro, Sangatsuda, Yuhei, Suzuki, Satoshi O., Iwaki, Toru, Mizoguchi, Masahiro, and Iihara, Koji
- Subjects
- *
ISOCITRATE dehydrogenase , *GLIOMAS , *OLIGODENDROGLIA , *ASTROCYTES , *DIAGNOSIS , *PROGNOSIS - Abstract
Isocitrate dehydrogenase ( IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype ( IDH-wt) pGBMs. IDH-mutant ( IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs. [ABSTRACT FROM AUTHOR]
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- 2017
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36. High expression of TIG3 predicts poor survival in patients with primary glioblastoma.
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Hongxiang Wang, Hanchong Xu, Tao Xu, Cong Tan, Mei Jiang, Yihong Chen, Xinyu Hu, Jinxu Zhou, Junyan Shen, Rong Qin, Daiyu Hu, Qilin Huang, Min Wang, Lian Wang, Dongxia Duan, Yong Yan, and Juxiang Chen
- Subjects
GLIOBLASTOMA multiforme ,GLIOMAS ,CANCER prognosis ,ASTROCYTOMAS ,GENE expression - Abstract
TIG3 (tazarotene-induced gene 3) has been reported to suppress the progression of several malignancies, where this gene is universally downregulated. However, the expression of TIG3 in primary glioblastoma and its relevance to patient's prognosis have not been elaborated. Thus, this study was aimed to evaluate TIG3 expression level in primary glioblastoma and investigate the prognostic value of TIG3 for patients. The Cancer Genome Atlas database was first utilized to analyze the expression and prognostic potential of TIG3 in 528 glioblastoma cases. Compared with control group, glioblastoma showed significantly elevated TIG3 expression (p < 0.001). Log-rank analysis revealed that higher expression of TIG3 was associated with shorter overall survival (358vs 383 days, p = 0.039). Furthermore, TIG3 protein expression detected by immunohistochemistry confirmed positive correlation of TIG3 expression and glioma grade and upregulation of TIG3 in our cohort of 101 primary glioblastoma patients compared to 16 normal brains. Finally, Kaplan-Meier analysis and Cox regression analysis identified high TIG3 expression as an independent risk factor for overall survival of primary glioblastoma patients (overall survival, 10 vs 13 months, p = 0.033; hazard ratio = 1.542, p = 0.046). Together, this study indicated that increased expression of TIG3 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients. We then hypothesize that TIG3 may function in a different pattern in glioblastoma. [ABSTRACT FROM AUTHOR]
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- 2017
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37. Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications
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Ichiro Nakano, Dagoberto Estevez-Ordonez, James Mooney, Gustavo Chagoya, Ahmed Ibrahim, Adeel Ilyas, and Joshua D. Bernstock
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Primary Glioblastoma ,0303 health sciences ,business.industry ,medicine.medical_treatment ,General Medicine ,Tumor initiation ,Therapeutic resistance ,medicine.disease ,Phenotype ,nervous system diseases ,Radiation therapy ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Glioma ,Cancer research ,Medicine ,Stem cell ,business ,neoplasms ,030304 developmental biology ,Glioblastoma - Abstract
Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.
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- 2020
38. Postoperative standard chemoradiotherapy benefits primary glioblastoma patients of all ages
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You Zhai, Yuemei Feng, Tao Jiang, Haoyu Jiang, Ruoyu Huang, Wei Zhang, Yuanhao Chang, Guanzhang Li, Zheng Wang, Zhiliang Wang, and Renpeng Li
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Neurosurgical Procedures ,0302 clinical medicine ,Risk Factors ,Original Research ,Brain Neoplasms ,Age Factors ,Brain ,Standard of Care ,adjuvant therapy ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Progression-Free Survival ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Female ,medicine.medical_specialty ,Clinical Decision-Making ,lcsh:RC254-282 ,03 medical and health sciences ,Glioma ,Internal medicine ,medicine ,Adjuvant therapy ,Biomarkers, Tumor ,Humans ,Radiology, Nuclear Medicine and imaging ,Pathological ,genomic alteration ,Aged ,Primary Glioblastoma ,Chemotherapy ,business.industry ,glioblastoma ,Cancer ,Clinical Cancer Research ,Chemoradiotherapy, Adjuvant ,medicine.disease ,030104 developmental biology ,age ,prognosis ,business ,Chemoradiotherapy ,Glioblastoma - Abstract
Background Glioblastoma is the most malignant tumor of the central nervous system. Several prediction models have been produced to aid in prognosis assessment. Age, a primary decision factor for prognosis, is associated with increased genomic alterations, however the exact link between increased age and poor prognosis is unknown. Objective In this study, we aimed to reveal the underlying cause of poor prognosis in elderly patients. Methods This study included data on 616 primary GBM tumor samples from the CGGA and TCGA databases and 41 nontumor brain tissue samples obtained from http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53890. Hallmarks and clinicopathological characteristics were evaluated in both tumor and nontumor brain tissues. The association between choice of treatment regimen and age was measured using ANOVA and Student's t test. Results Age was a robust predictor of poor prognosis in glioma. No age‐related hallmarks of cancer were detected, including pathological characteristics or mutations. However, treatment choice was strongly significantly different between old and young patients. Combined chemo‐radiation therapy could benefit old and young GBM patients, however, old patients are currently less likely to choose it. Conclusion The vast divergence in prognosis between young and old GBM patients is largely caused by choice of treatment rather than age‐related tumor genomic characteristics. Postoperative standard radio‐ and chemotherapy provide strong benefits to primary glioblastoma patients of all ages., The main reason of poorer prognosis in elder patients was conservative treatment choosing, while standard radio‐ and chemotherapy should be generalized in all age grade of patients.
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- 2020
39. A novel series of phenolic temozolomide (TMZ) esters with 4 to 5-fold increased potency, compared to TMZ, against glioma cells irrespective of MGMT expression
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Amal Shervington, Oliver Ingham, and Leroy Alexander Shervington
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Primary Glioblastoma ,0303 health sciences ,Glioblastoma cell ,Temozolomide ,Standard of care ,Chemistry ,General Chemical Engineering ,B230 ,Mgmt expression ,General Chemistry ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Glioma ,medicine ,Cancer research ,Potency ,neoplasms ,030304 developmental biology ,medicine.drug ,Glioblastoma - Abstract
The standard of care treatment for patients diagnosed with glioblastoma multiforme (GBM) is temozolomide (TMZ). Tumour resistance to TMZ results in significantly limited clinical effectiveness. There is therefore an inherent need for alternatives to TMZ capable of overcoming resistance associated with MGMT and MMR. In the present study, a series of ester and amide analogues of TMZ, modified at position 8 on the imidazole ring, were prepared and investigated for antiproliferative properties. It was found that phenolic ester analogues of TMZ displayed increased potency, of up to 5-fold, against specified glioblastoma cell lines. The encouraging results displayed by the phenolic TMZ esters prompted further investigations against patient-derived primary glioblastoma cultures. The primary cultures, BTNW914 and BTNW374, were MGMT positive and MGMT negative, respectively. Lead phenolic TMZ esters were found to decrease viability in primary cells at clinically relevant concentrations, irrespective of MGMT expression. Furthermore, TMZ was found to be ineffective against the same primary cells at clinically relevant concentrations. The novel phenyl ester analogues of TMZ, described in this study, could have potential chemotherapeutic properties for the treatment of GBM, overcoming the resistance associated with the expression of MGMT.
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- 2020
40. NIMG-59. RADIOMICS-PREDICTED T CELL DYNAMICS STRATIFY SURVIVAL AFTER DENDRITIC CELL VACCINE THERAPY FOR PRIMARY GLIOBLASTOMA
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Leland S. Hu, Ian F. Parney, Gustavo De Leon, Kamila M. Bond, Javier Urcuyo, Kamala Clark-Swanson, Andrea Hawkins-Daarud, Nhan L. Tran, Kristin R. Swanson, Christopher Sereduk, Kyle W. Singleton, and Lee Curtin
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Primary Glioblastoma ,Cancer Research ,business.industry ,Dendritic Cell Vaccine Therapy ,T cell ,Dynamics (mechanics) ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.anatomical_structure ,Oncology ,Radiomics ,Cancer research ,Medicine ,Neurology (clinical) ,business - Abstract
INTRODUCTION Dendritic cells (DCs) are potent antigen presenting cells that can be exploited to initiate an adaptive anti-tumoral immune response. DC vaccine clinical trials for primary glioblastoma (GBM) have reported prolonged progression-free survival without any impact on overall survival (OS). We report a radiomics approach that identifies a subpopulation of patients with prolonged OS in clinical trial MC1272. METHODS Twenty adults with primary GBM undergoing standard-of-care therapy were enrolled in MC1272. Autologous DCs were pulsed with allogenic GBM cell lines to generate vaccines that were administered for up to twelve cycles. Standard brain imaging was obtained at the initiation of treatment and two months afterwards. An independent cohort of image-localized biopsies underwent RNA sequencing followed by cellular deconvolution to estimate T cell abundance. A machine learning model was trained to predict intratumoral T cell abundance from imaging features, and the model was applied to MC1272 patient imaging. RESULTS Voxelwise predictions of T cell abundance were generated for each patient’s pre- and post-treatment images. The difference in total intratumoral T cell abundance between imaging timepoints classified patients into increasing or decreasing T cell groups. Patients whose T cells increased had longer OS (median, 21 months) than those whose T cells decreased (median, 10 months; p=0.0035). The significance remained in a Cox proportional hazards analysis that adjusted for patient age and sex (p=0.011). CONCLUSIONS A spatially-resolved radiomics model detected that an intratumoral T cell influx after DC vaccine therapy was associated with prolonged OS. The “post-treatment” imaging in this study was obtained a mere two months after DC vaccine initiation, suggesting that our radiomics model can provide an early indication of treatment responsiveness and prognosis in these patients.
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- 2021
41. Primary glioblastoma of the cauda equina with molecular and histopathological characterization: Case report
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Hayden Scott, Analiz Rodriguez, Christopher P. Wardell, Rebekah G. Langston, Murat Gokden, Angela Palmer, and T. Glenn Pait
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Primary Glioblastoma ,Pathology ,medicine.medical_specialty ,Nerve root ,business.industry ,glioblastoma ,Cauda equina ,medicine.disease ,medicine.anatomical_structure ,cauda equina ,medicine ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Molecular Tumor Board Case Report ,nerve root entry zone ,business ,Glioblastoma - Published
- 2021
42. Prognostic Impact of the Combination of
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Thara, Tunthanathip, Surasak, Sangkhathat, Pimwara, Tanvejsilp, and Kanet, Kanjanapradit
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O 6 -methylguanine-DNA methyltransferase ,telomerase reverse transcriptase ,Original Article ,primary glioblastoma ,prognosis ,neoplasms ,survival ,digestive system diseases - Abstract
Background The concept of combinational analysis between the methylation of O 6 -methylguanine-DNA methyltransferase ( MGMT ) and telomerase reverse transcriptase promoter ( pTERT ) mutation in glioblastoma (GBM) has been reported. The main study objective was to determine the prognosis of patients with GBM based on MGMT/pTERT classification, while the secondary objective was to estimate the temozolomide effect on the survival time of GBM with MGMT/pTERT classification. Methods A total of 50 GBM specimens were collected after tumor resection and were selected for investigating MGMT methylation and pTERT mutation. Clinical imaging and pathological characteristics were retrospectively analyzed. Patients with MGMT/pTERT classification were analyzed using survival analysis to develop the nomogram for forecasting and individual prognosis. Results All patients underwent resection (total resection: 28%, partial resection: 64%, biopsy: 8%). Thirty-two percent of all cases received adjuvant temozolomide with radiotherapy. Sixty-four percent of the case was found methylated MGMT , and 56% of the present cohort found pTERT mutation. Following combinational analysis of biomarkers, results showed that the GBMs with methylated MGMT and wild-type pTERT had a superior prognosis compared with other subtypes. Using Cox regression analysis with multivariable analysis, the extent of resection, postoperative chemoradiotherapy, MGMT/pTERT classification were associated with a favorable prognosis. Hence, a web-based nomogram was developed for deploying individual prognostication. Conclusions The interaction of MGMT methylation and pTERT mutation was confirmed for predicting prognosis. The results from the present study could help physicians create treatment strategies for GBM patients in real-world situations.
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- 2021
43. P14.87 Significance of clinical and molecular-genetic factors for prognosis in 574 adult patients with primary glioblastoma
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A Dalechina, S. Zolotova, Anvar Kurmukov, Andrey Golanov, and A. Belyashova
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Primary Glioblastoma ,Cancer Research ,medicine.diagnostic_test ,Adult patients ,business.industry ,medicine.medical_treatment ,O-6-methylguanine-DNA methyltransferase ,Magnetic resonance imaging ,Methylation ,Genome ,Radiation therapy ,Poster Presentations ,Oncology ,Mutation (genetic algorithm) ,medicine ,Cancer research ,Neurology (clinical) ,business - Abstract
BACKGROUND Despite advances in the characterization of genomic alterations in glioblastoma patient survival remains poor. The aim of this single center retrospective study was to estimate prognostic factors affecting to survival for optimizing personalized treatment strategy in glioblastoma patients. MATERIAL AND METHODS 574 consecutive patients with primary glioblastoma treated at the Burdenko National Medical Research Center of Neurosurgery from 2014 to 2019 were included in this study (314 male /260 female). Survival data was analyzed using Kaplan-Meier with log-rank tests to assess statistical significance. A linear regression model was built to predict overall survival. RESULTS Older patients (> 45 years) had the worse prognosis than patients ≤ 45 (p = 2.37 * 10^-6). Female patients had advantages in overall survival (p = 0.014). Time interval from surgery to the starting of radiotherapy longer than 4 weeks was associated with worse overall survival (p = 0.062). Patients with positive IDH1/2 and MGMT had better prognosis than patients with wild type and MGMT negative (p = 0.000841, p = 0.000138, respectively). We revealed that there were significant differences in overall survival between patients who had progression on the first (p = 0.000312), second (p = 0.001046) and third (p = 0.00223) follow-up MRI after radiotherapy. Median survival times (from the date of surgery) were 17, 20, 23 months, respectively. The feature importance in the linear regression model was patient’s age, IDH1/2 mutation, MGMT promoter methylation status, progression on the first follow-up MRI and sex. CONCLUSION Older patient’s age, prolonged time between surgery and RT starting, male sex, negative IDH1/2 and MGMT, progression on the first MRI were associated with poor overall survival in glioblastoma patients. Our results suggested additional clinical, radiomics and molecular-genetic data should be added to improve the overall survival prediction. The results have been obtained under the support of the RFBR grant 18-29-01054
- Published
- 2021
44. Genetic alteration and clonal evolution of primary glioblastoma into secondary gliosarcoma
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Jie Li, Cheng-Shi Xu, Su-Fang Tian, Ze-Fen Wang, Yu-Hang Zhao, Yan-Bing Cheng, Zhi-Qiang Li, Kai Li, and Yu-Xiang Cai
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Gliosarcoma ,Clone (cell biology) ,clonal evolution ,Biology ,medicine.disease_cause ,Somatic evolution in cancer ,Germline mutation ,stomatognathic system ,secondary gliosarcoma ,Physiology (medical) ,medicine ,Humans ,Pharmacology (medical) ,Transversion ,Gene ,radiotherapy ,Pharmacology ,mutation signature ,Mutation ,Brain Neoplasms ,Original Articles ,Middle Aged ,medicine.disease ,Phenotype ,Psychiatry and Mental health ,Cancer research ,Female ,Original Article ,primary glioblastoma ,Glioblastoma - Abstract
Aims Secondary gliosarcoma (SGS) rarely arises post treatment of primary glioblastoma multiforme (GBM), and contains gliomatous and sarcomatous components. The origin and clonal evolution of SGS sarcomatous components remain uncharacterized. Therapeutic radiation is mutagenic and can induce sarcomas in patients with other tumor phenotypes, but possible causal relationships between radiotherapy and induction of SGS sarcomatous components remain unexplored. Herein, we investigated the clonal origin of SGS in a patient with primary GBM progressing into SGS post‐radiochemotherapy. Methods Somatic mutation profile in GBM and SGS was examined using whole‐genome sequencing and deep‐whole‐exome sequencing. Mutation signatures were characterized to investigate relationships between radiochemotherapy and SGS pathogenesis. Results A mutation cluster containing two founding mutations in tumor‐suppressor genes NF1 (variant allele frequency [VAF]: 50.0% in GBM and 51.1% in SGS) and TP53 (VAF: 26.7% in GBM and 50.8% in SGS) was shared in GBM and SGS. SGS exhibited an overpresented C>A (G>T) transversion (oxidative DNA damage signature) but no signature 11 mutations (alkylating‐agents – exposure signature). Since radiation induces DNA lesions by generating reactive oxygen species, the mutations observed in this case of SGS were likely the result of radiotherapy rather than chemotherapy. Conclusions Secondary gliosarcoma components likely have a monoclonal origin, and the clone possessing mutations in NF1 and TP53 was likely the founding clone in this case of SGS., This study presents the first comprehensive genomic profile and clonal architecture of tumor evolution from glioblastoma multiforme to Secondary gliosarcoma (SGS). The data support not only the monoclonal origin of gliomatous and sarcomatous components in SGS but also the causal relationship between therapeutic radiation and SGS pathogenesis.
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- 2021
45. A case of multicentric gliomas in both supra- and infratentorial regions with different histology: a case report.
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Akihiro Inoue, Takanori Ohnishi, Shohei Kohno, Yosuke Mizuno, Riko Kitazawa, Yawara Nakamura, and Shiro Ohue
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GLIOMAS , *INFRATENTORIAL brain tumors , *HISTOLOGY , *HISTOPATHOLOGY , *MAGNETIC resonance imaging , *EPIDERMAL growth factor receptors , *GADOLINIUM - Abstract
Background: Multicentric gliomas are well-separated tumors in different locations of the brain, without anatomical continuity between lesions. We report a rare case of multicentric gliomas that occurred in both supra- and infratentorial regions with different histopathology. Case presentation: A 27-year-old man was admitted to our hospital with mild motor weakness of the right leg. Magnetic resonance imaging (MRI) showed a large tumor occupying the left insula, extending to the left basal ganglia, so tumor resection was performed. Histological diagnosis was diffuse astrocytoma. Tumor cells showed sporadic immunoreactivity for p53 and negative immunostaining for epidermal growth factor receptor (EGFR). Postoperative course was uneventful, and adjuvant therapy was not performed. At 7 months after surgery, MRI disclosed a left cerebellar tumor displaying an irregular ring formation on enhancement with gadolinium (Gd) and marked peritumoral edema. MRI studies including T2-weighted imaging demonstrated that this paravermian tumor had no contact with the initial left insular tumor. In addition, MRI studies of the whole neuraxis, cytological examination of the cerebrospinal fluid, and neurological findings demonstrated that no dissemination had occurred through the subarachnoid space or as intracerebral metastases. Therefore, the second surgery was performed. Histological diagnosis was glioblastoma. Immunohistochemistry revealed that most tumor cells were positively stained for both p53 and EGFR but negatively stained for isocitrate dehydrogenase 1 (IDH1). Conclusions: We reported a case of multicentric gliomas occurring in both supra- and infratentorial regions with different histopathology. Immunohistochemical examinations suggest that different genetic pathways may participate in the occurrence of these tumors. [ABSTRACT FROM AUTHOR]
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- 2016
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46. The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study.
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Zhang, Jin-feng, Chen, Yao, Qiu, Xian-xin, Tang, Wen-long, Zhang, Jian-dong, Huang, Jian-huang, Lin, Guo-shi, Wang, Xing-fu, and Lin, Zhi-xiong
- Abstract
Delta-like ligand-4 (DLL4)-Notch signaling is known to play a pivotal role in the regulation of tumor angiogenesis. We had previously found that DLL4 was overexpressed, while Notch1 receptor, which binds to DLL4 during angiogenesis, was absent in the majority of human primary glioblastomas. Thus, DLL4-Notch signaling pathway in the regulation of tumor angiogenesis in primary glioblastoma remains unknown. Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for expression of components of DLL4-Notch signaling, vascular endothelial growth factor (VEGF), and microvessel density (MVD). Immunohistochemistry results showed that the positive staining of DLL4 and Notch4 was primarily distributed in tumor vascular endothelial cells but rarely detected in tumor cells. However, VEGF, hairy/enhancer of split-1 (HES1; a target gene of Notch signaling), and Notch1-3 expression was seen in both tumor vascular endothelial cells and tumor cells. Univariate analysis showed that the expression levels of VEGF and DLL4, HES1, and Notch4 in tumor endothelial cells were significantly associated with MVD in primary glioblastoma ( P < 0.001). Binary logistic regression analysis showed that high expression levels of DLL4, HES1, and Notch4 in tumor endothelial cells were associated with a decrease of MVD in primary glioblastoma, while MVD increased with elevated VEGF expression in contrast. In addition, DLL4, Notch4, and HES1 expression were positively correlated in tumor vascular endothelial cells ( P < 0.05). We conclude that the vascular DLL4-Notch4 signaling and VEGF signaling complementing each other plays an important role in the progression of tumor angiogenesis in primary glioblastoma. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]
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- 2016
- Full Text
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47. CD133 and BMI1 expressions and its prognostic role in primary glioblastoma.
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SIBIN, M. K., LAVANYA, C. H., BHAT, DHANANJAYA I., RAO, NARASINGA, GEETHASHREE, N., VIBHUTI, W., and CHETAN, G. K.
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GENE expression , *STEM cells , *MESSENGER RNA , *GLIOBLASTOMA multiforme , *PATIENTS , *GENETICS , *DISEASES - Abstract
Glioblastoma is the most common malignant brain tumour, generated by bulk of malignant cancer stem cells, which express various stem cell factors like CD133, BMI1 and nestin. There are several studies which show the importance of CD133 in cancer, but the function and interaction with other major oncogenes and tumour suppressor genes is still not understood. This study aimed to analyse the expression of CD133 mRNA and its correlations with BMI1 protein expression and TP53 mutations in newly diagnosed glioblastoma patients and its role in prognosis. Overexpression of CD133 mRNA and BMI1 protein was found in 47.6 and 76.2% patients respectively and TP53 mutations was seen in 57.1% of patients in our study. There was no correlation among TP53 mutations and expressions of CD133 and BMI1. We found that high level of BMI1 expression was favourable for the patient survival (P = 0.0075) and high CD133 mRNA expression was unfavourable for the patient survival (P = 0.0226). CD133 mRNA and BMI1 protein expression could independently predict the glioblastoma patient survival in multivariate analysis. In conclusion, the overexpression of these stem cell markers is a common event in glioblastoma progression and could be used as potential prognostic markers. [ABSTRACT FROM AUTHOR]
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- 2015
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48. An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) with BCNU Wafers in the Surgical Management of Primary Glioblastoma
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Kieren Allinson, Sarah Jefferies, Katharina Wanek, Alina Finch, Nicholas Counsell, Thomas Santarius, Keyoumars Ashkan, Colin Watts, Mark Phillips, Paul Smith, Laura Clifton-Hadley, Athanasios Zisakis, Stephen J. Price, Ting Ting Zhang, Peter Collins, Michael D. Jenkinson, Daniel Scoffings, Tomasz Matys, Price, Stephen J [0000-0002-7535-3009], Allinson, Kieren [0000-0003-3468-2110], Apollo - University of Cambridge Repository, and Price, Stephen J. [0000-0002-7535-3009]
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Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Article ,chemoRT ,03 medical and health sciences ,0302 clinical medicine ,Histological diagnosis ,Medicine ,BCNU wafers ,Amino-Levulinic Acid ,RC254-282 ,Primary Glioblastoma ,Chemotherapy ,Bcnu wafer ,business.industry ,glioblastoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Surgery ,Oncology ,Tolerability ,5-aminolevulinic acid ,030220 oncology & carcinogenesis ,feasibility trial ,business ,030217 neurology & neurosurgery ,Chemoradiotherapy ,Glioblastoma - Abstract
Simple Summary This reseach explored the safety and feasibility of combining local chemotherapy with fluorescence-guided resection in patients with a brain cancer, glioblastoma. The aim was to determine if the combination of fluorescence-guided surgery using 5-aminolevulinic acid and BCNU wafers left in the tumour cavity at the end of the operation was safe and did not prevent patients getting subsequent chemo-radiotherapy. The results showed that combining local chemotherapy with fluorescence-guided resection was tolerable in terms of surgical morbidity and overall toxicity. However, any potential therapeutic benefit requires further investigation, preferably with improved local delivery technologies. Abstract Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4–9.8) and median overall survival was 14.7 months (95% CI: 11.7–16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.
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- 2021
49. Effect of Long-term Adjuvant Temozolomide Chemotherapy on Primary Glioblastoma Patient Survival
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Huang B, Liang R, and Yu Z
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Primary Glioblastoma ,Oncology ,medicine.medical_specialty ,Chemotherapy ,Temozolomide ,business.industry ,medicine.medical_treatment ,Patient survival ,Term (time) ,Text mining ,Internal medicine ,medicine ,business ,Adjuvant ,medicine.drug - Abstract
Objective: Glioblastoma multiforme (GBM) is the most common primary malignant central nervous system (CNS) tumor. The Stupp regimen is the standard treatment , although the optimal number of temozolomide (TMZ) treatment cycles remains controversial. We compared the effects of standard 6 cycles versus >6 cycles of TMZ chemotherapy post-surgery with concurrent chemoradiotherapy on primary GBM patient survival. Patients and Methods: We performed a single center retrospective study of GBM patients that underwent total resection, concurrent chemoradiotherapy, and at least 6 cycles of adjuvant TMZ chemotherapy from June 2011 to August 2018. Patients were divided into 2 groups based on adjuvant TMZ treatment plan: Group A(n=27): standard 6-cycle adjuvant TMZ therapy and Group B(n=26): >6 cycles of adjuvant TMZ therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Continuous variables were analyzed by ANOVA, and the Kaplan-Meier method was used to evaluate PFS and OS. Univariate and multivariate COX analyses determined correlation between survival rates and covariates.Results: After follow-up, median PFS was 15 months in in Group A (95%CI 9.5-20.5) and 20.1 months in Group B (95%CI 15.9-24.4). Group A median OS was 19.4 months (95%CI 15.5-23.2), compared to 25.6 months in Group B (95%CI 20.4-30.8). The 2-year survival rate of Groups A and B was 36% was 66%, respectively (P=0.02). and 5-year survival was 7% in both. Multivariate COX regression analysis showed association between patient PFS and long-period adjuvant chemotherapy, but not OS. Conclusions: Long-term adjuvant TMZ chemotherapy benefits PFS and 2-year survival rate but not OS. We do not suggest prolonging TMZ maintenance therapy beyond six cycles in patients with glioblastoma after total resection.
- Published
- 2021
50. Acute Visual Loss Related to Retinal Vascular Occlusion Secondary to Visual Pathway Primary Glioblastoma
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Germán A Reyes-Botero, Beatriz Lopera-Marín, Beatriz Pineda-Arrieta, Marta L Muñoz-Cardona, Feliza Restrepo, Francisco Londoño-Ocampo, Yuliana Llano-Naranjo, Esteban E Preciado-Mesa, and Lina Garcia
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Primary Glioblastoma ,Retinal Vascular Occlusion ,medicine.medical_specialty ,Optic Neuritis ,Brain Neoplasms ,business.industry ,Biopsy ,Visual Acuity ,Middle Aged ,Blindness ,Ophthalmology ,Acute Disease ,Retinal Vein Occlusion ,Humans ,Medicine ,Female ,Visual Pathways ,Neurology (clinical) ,Glioblastoma ,business - Published
- 2020
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