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Chang T, Wu Y, Quan Y, Chen S, Liao J, Zhao W, Li Y, Fang Y, Zong Y, Liu Y, Jiang N, Mao Q, He J, Yang Y. Glioma-induced neural functional remodeling in the hand motor cortex: precise mapping with ECoG grids during awake craniotomy. Int J Surg 2025; 111:2849-2861. [PMID: 39903573 DOI: 10.1097/js9.0000000000002277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 12/27/2024] [Indexed: 02/06/2025]
Abstract
BACKGROUND The dilemma of achieving 'onco-functional balance' in gliomas affecting the motor cortex highlights the importance of functionally-guided resection strategies. While accurate mapping of eloquent areas often requires frequent electrical stimulation, this practice can lead to side effects like seizures and postoperative deficits. To enhance safety in functional mapping, we studied how gliomas impact hand movement areas and assessed the effectiveness of cortical electrical activity for functional mapping in this setting. MATERIALS AND METHODS We recruited patients with gliomas affecting the motor cortex and individuals with an unaffected motor cortex for awake craniotomy. During the procedures, electrocorticography (ECoG) grids were employed to record signals under three conditions: resting state, finger movements, and wrist movements. We then quantified the distances from the positively stimulated sites to the specific anatomical landmarks. Additionally, we analyzed the relationship between the ECoG power features and the stimulation responses. RESULTS The cortical layout for finger activity in the motor cortex glioma (MCG) group was more dispersed and overlapped, typically clustering near the central sulcus and Sylvian fissure. The predictive performance of ECoG mapping exhibited significant variability across different frequency bands and clinical scenarios. Specifically, the area under the curve (AUC) for the non-MCG group during the resting state reached its peak, with a value of 0.802 for Gamma3 (95% CI = 0.729-0.875) and 0.865 for broadband (95% CI = 0.804-0.926). In contrast, the MCG group achieved the highest AUC during wrist movements, with Gamma3 at 0.785 (95% CI = 0.719-0.849) and broadband at 0.824 (95% CI = 0.753-0.890). CONCLUSION Gliomas in the motor cortex disrupt the distribution of hand activity, complicating intraoperative functional mapping. As a novel and reliable approach, ECoG technique can complement and guide direct cortical stimulation for precise mapping, potentially reducing its frequency, minimizing the risk of functional deficits, and achieving a balance between maximal tumor resection and neurological preservation.
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Affiliation(s)
- Tao Chang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yihan Wu
- National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Med-X Center for Manufacturing, Sichuan University, Chengdu, Sichuan, China
| | - Yuxin Quan
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Siliang Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiawei Liao
- National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Med-X Center for Manufacturing, Sichuan University, Chengdu, Sichuan, China
| | - Wenyu Zhao
- National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Med-X Center for Manufacturing, Sichuan University, Chengdu, Sichuan, China
| | - Yu Li
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yuan Fang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yixuan Zong
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yanhui Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ning Jiang
- National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Med-X Center for Manufacturing, Sichuan University, Chengdu, Sichuan, China
| | - Qing Mao
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiayuan He
- National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Med-X Center for Manufacturing, Sichuan University, Chengdu, Sichuan, China
| | - Yuan Yang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
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Lizunou Y, Potthoff AL, Schäfer N, Waha A, Borger V, Herrlinger U, Vatter H, Schuss P, Schneider M. Cerebellar glioblastoma in adults: a comparative single-center matched pair analysis and systematic review of the literature. J Cancer Res Clin Oncol 2024; 150:432. [PMID: 39340649 PMCID: PMC11438707 DOI: 10.1007/s00432-024-05959-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024]
Abstract
PURPOSE The rarity of cerebellar glioblastoma presents a significant challenge in clinical practice due to the lack of extensive prognostic data on long-term survival rates, rendering it an underrepresented entity compared to its supratentorial counterpart. This study aims to analyze potential differences in survival outcome between patients with cerebellar and supratentorial glioblastomas. METHODS From 2009 to 2020, 8 patients underwent surgical treatment for cerebellar glioblastoma at the authors' institution. These patients were individually matched with a cohort of 205 consecutive patients from our institutional database with supratentorial glioblastoma, taking into account key prognostic parameters. Progression-free survival (PFS) and overall survival (OS) rates were compared. Additionally, we performed a systematic literature review to compile further survival data on cerebellar glioblastoma patients. RESULTS The median OS for cerebellar glioblastoma patients was 18 months (95% CI 11-25). The balanced matched-pair analysis showed no significant difference in survival when compared to patients with supratentorial glioblastoma, exhibiting a median OS of 23 months (95% CI 0-62) (p = 0.63). Respective values for PFS were 8 months (95% CI 4-12) for cerebellar and 7 months (95% CI 0-16) for supratentorial glioblastoma (p = 0.2). The systematic review revealed that median OS for cerebellar glioblastoma in current literature ranges from 7 to 21 months. CONCLUSIONS The present findings indicate that patients with supra- and infratentorial glioblastoma do not significantly differ in regard to survival outcome parameters. This similarity in prognosis might encourage clinicians to consider surgical interventions for both supra- and infratentorial glioblastoma in a similar manner.
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Affiliation(s)
- Yauhen Lizunou
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.
| | | | - Niklas Schäfer
- Department of Neurology, Devision of Neurooncology, University Hospital Bonn, Bonn, Germany
| | - Andreas Waha
- Department of Neuropathology, University Hospital Bonn, Bonn, Germany
| | - Valeri Borger
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Ulrich Herrlinger
- Department of Neurology, Devision of Neurooncology, University Hospital Bonn, Bonn, Germany
| | - Hartmut Vatter
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Patrick Schuss
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
- Department of Neurosurgery, Unfallkrankenhaus Berlin, Berlin, Germany
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Xu F, Hua X, Wang M, Cao W, Wang S, Xu C, Chen J, Gao Y, Chen L, Ni W. Racial and social-economic inequalities in systemic chemotherapy use among adult glioblastoma patients following surgery and radiotherapy. Sci Rep 2024; 14:19079. [PMID: 39154028 PMCID: PMC11330508 DOI: 10.1038/s41598-024-68962-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/30/2024] [Indexed: 08/19/2024] Open
Abstract
Not all patients with glioblastoma multiforme (GBM) eligible for systemic chemotherapy after upfront surgery and radiotherapy finally receive it. The information on patients with GBM was retrieved from the surveillance, epidemiology, and end results database. Patients who underwent upfront surgery or biopsy and external beam radiotherapy between 2010 and 2019 were eligible for systemic chemotherapy. The available patient and tumor characteristics were assessed using multivariable logistic regression and chi-squared test. Out of the 16,682 patients eligible, 92.1% underwent systemic chemotherapy. The characteristics linked to the lowest systemic chemotherapy utilization included tumors of the brain stem/cerebellum (P = 0.01), former years of diagnosis (P = 0.001), ≥ 80 years of age (P < 0.001), Hispanic, Non-Hispanic Asian, Pacific Islander, or Black race (P < 0.001), non-partnered status (P < 0.001), and low median household income (P = 0.006). Primary tumor site, year of diagnosis, age, race, partnered status, and median household income correlated with the omission of systemic chemotherapy in GBM in adult patients.
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Affiliation(s)
- Fei Xu
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Xin Hua
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Mengdi Wang
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Weiguo Cao
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Shubei Wang
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Cheng Xu
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Jiayi Chen
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Yunsheng Gao
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China.
| | - Linlin Chen
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China.
| | - Weiqiong Ni
- Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China.
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Chang T, Zhang R, Gan J, Yang Y, Liu Y, Ju Y, Niu X, Mao Q. Investigating distinct clinical features and constructing a nomogram model for survival probability in adults with cerebellar high-grade gliomas. BMC Cancer 2024; 24:836. [PMID: 39003457 PMCID: PMC11245792 DOI: 10.1186/s12885-024-12580-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 06/28/2024] [Indexed: 07/15/2024] Open
Abstract
BACKGROUND The clinical features of cerebellar high-grade gliomas (cHGGs) in adults have not been thoroughly explored. This large-scale, population-based study aimed to comprehensively outline these traits and construct a predictive model. METHODS Patient records diagnosed with gliomas were collected from various cohorts and analyzed to compare the features of cHGGs and supratentorial HGGs (sHGGs). Cox regression analyses were employed to identify prognostic factors for overall survival and to develop a nomogram for predicting survival probabilities in patients with cHGGs. Multiple machine learning methods were applied to evaluate the efficacy of the predictive model. RESULTS There were significant differences in prognosis, with SEER-cHGGs showing a median survival of 7.5 months and sHGGs 14.9 months (p < 0.001). Multivariate Cox regression analyses revealed that race, WHO grade, surgical procedures, radiotherapy, and chemotherapy were independent prognostic factors for cHGGs. Based on these factors, a nomogram was developed to predict 1-, 3-, and 5-year survival probabilities, with AUC of 0.860, 0.837, and 0.810, respectively. The model's accuracy was validated by machine learning approaches, demonstrating consistent predictive effectiveness. CONCLUSIONS Adult cHGGs are distinguished by distinctive clinical features different from those of sHGGs and are associated with an inferior prognosis. Based on these risk factors affecting cHGGs prognosis, the nomogram prediction model serves as a crucial tool for clinical decision-making in patient care.
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Affiliation(s)
- Tao Chang
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Zhang
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Jiahao Gan
- Clinical Medicine School, Traditional Chinese Medicine of Jiangxi University, Jiangxi, China
| | - Yuan Yang
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Yanhui Liu
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Ju
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaodong Niu
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.
- Department of Neurosurgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, China.
| | - Qing Mao
- Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.
- Department of Neurosurgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, China.
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Noronha C, Ribeiro AS, Carvalho R, Mendes N, Reis J, Faria CC, Taipa R, Paredes J. Cadherin Expression Profiles Define Glioblastoma Differentiation and Patient Prognosis. Cancers (Basel) 2024; 16:2298. [PMID: 39001361 PMCID: PMC11240393 DOI: 10.3390/cancers16132298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 07/16/2024] Open
Abstract
Cadherins are cell-cell adhesion proteins which have been strongly implicated in cancer invasion, dissemination and metastasis capacity; thus, they are key players in the epithelial-to-mesenchymal transition (EMT) program. However, their role in glioblastoma (GBM), a primary central nervous system aggressive tumor, remains to be clarified. N-, E- and P-cadherin expression was analyzed on a large series of GBMs, characterized with clinical, imaging and neuropathological parameters, as well as with patients' survival data. In addition, cadherins' expression was studied in match-recurrent cases. Using TCGA data, cadherin expression profiles were also evaluated according to GBM transcription subtypes. N-cadherin expression was observed in 81.5% of GBM, followed by E-cadherin in 31% and P-cadherin in 20.8%. Upon tumor recurrence, P-cadherin was the only significantly upregulated cadherin compared with the primary tumor, being positive in 65.8% of the cases. Actually, P-cadherin gain was observed in 51.4% of matched primary-recurrent cases. Cadherins' co-expression was also explored. Interestingly, E- and N-cadherin co-expression identified a GBM subgroup with frequent epithelial differentiation and a significant survival benefit. On the other hand, subgroups with P-cadherin expression carried the worse prognosis. P- and N-cadherin co-expression correlated with the presence of a mesenchymal phenotype. Expressions of isolated P-cadherin or E- and P-cadherin co-expression were associated with imaging characteristics of aggressiveness, to highly heterogeneous tumors, an d to worse patient survival. Classical cadherins co-expression subgroups present consistent clinical, imaging, neuropathological and survival differences, which probably reflect different states of an EMT-like program in GBM.
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Affiliation(s)
- Carolina Noronha
- Neurosurgery Department, Hospital de Santo António, Centro Hospitalar e Universitário do Porto, 4050-366 Porto, Portugal
- Cancer Metastasis, i3S, Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
- FMUP-Faculty of Medicine, University of Porto, 4200-135 Porto, Portugal
| | - Ana Sofia Ribeiro
- Cancer Metastasis, i3S, Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Rita Carvalho
- Cancer Metastasis, i3S, Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Nuno Mendes
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- Histology and Electron Microscopy, i3S, Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
| | - Joaquim Reis
- Neurosurgery Department, Hospital de Santo António, Centro Hospitalar e Universitário do Porto, 4050-366 Porto, Portugal
| | - Claudia C Faria
- Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisbon, Portugal
- IMM-Instituto de Medicina Molecular João Lobo Antunes, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal
| | - Ricardo Taipa
- Neuropathology Department, Hospital de Santo António, Centro Hospitalar Universitário de Santo António, 4050-342 Porto, Portugal
- UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-346 Porto, Portugal
- ITR-Laboratory for Integrative and Translational Research in Population Health, 4050-600 Porto, Portugal
| | - Joana Paredes
- Cancer Metastasis, i3S, Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
- FMUP-Faculty of Medicine, University of Porto, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
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Kumaria A, Leggate AJ, Dow GR, Ingale HA, Robertson IJA, Byrne PO, Basu S, Macarthur DC, Smith SJ. A common tumour in a rare location: a single centre case series of cerebellar glioblastoma. Br J Neurosurg 2024:1-6. [PMID: 38741545 DOI: 10.1080/02688697.2024.2348598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 04/23/2024] [Indexed: 05/16/2024]
Abstract
Although glioblastoma is the commonest primary brain tumour in adults, its location in the cerebellum is extremely rare. We present thirteen cases (3 female, 10 male; median age at presentation 56 [age range 21-77]) of surgically managed, histologically confirmed, primary cerebellar glioblastoma (cGB) over a 17 year period (2005-2022). Pre-operative radiological diagnosis was challenging given cGB rarity, although MRI demonstrated ring enhancement in all cases. Surgical management included posterior fossa craniectomy and debulking in 11 cases and burr hole biopsy in two. CSF diversion was necessary in four cases. No evidence of IDH or ATRX gene mutations was found when tested. Survival ranged from 1 to 22 months after diagnosis (mean 10.9 months). We also seek to understand why glioblastoma is rare in this location and discuss potential reasons for this. We hypothesise that increasing anatomical distance from germinal regions and decreased local endogenous neural stem cell activity (which has been associated with glioblastoma) may explain why glioblastoma is rare in the cerebellum. We hereby seek to add to the limited literature on cGB as this is the largest UK cGB series to date.
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Affiliation(s)
- Ashwin Kumaria
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | - Alex J Leggate
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | - Graham R Dow
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | - Harshal A Ingale
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | | | - Paul O Byrne
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | - Surajit Basu
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | | | - Stuart J Smith
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
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Lasica N, Arnautovic K, Tadanori T, Vulekovic P, Kozic D. An integrative survival analysis and a systematic review of the cerebellopontine angle glioblastomas. Sci Rep 2023; 13:4442. [PMID: 36932101 PMCID: PMC10023706 DOI: 10.1038/s41598-023-30677-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/28/2023] [Indexed: 03/19/2023] Open
Abstract
Glioblastomas presenting topographically at the cerebellopontine angle (CPA) are exceedingly rare. Given the specific anatomical considerations and their rarity, overall survival (OS) and management are not discussed in detail. The authors performed an integrative survival analysis of CPA glioblastomas. A literature search of PubMed, Scopus, and Web of Science databases was performed per PRISMA guidelines. Patient data including demographics, clinical features, neuroimaging, management, follow-up, and OS were extracted. The mean age was 39 ± 26.2 years. The mean OS was 8.9 months. Kaplan-Meier log-rank test and univariate Cox proportional-hazards model identified hydrocephalus (log-rank, p = 0.034; HR 0.34; 95% CI 0.12-0.94; p = 0.038), chemotherapy (log-rank, p < 0.005; HR 5.66; 95% CI 1.53-20.88; p = 0.009), and radiotherapy (log-rank, p < 0.0001; HR 12.01; 95% CI 3.44-41.89; p < 0.001) as factors influencing OS. Hydrocephalus (HR 3.57; 95% CI 1.07-11.1; p = 0.038) and no adjuvant radiotherapy (HR 0.12; 95% CI 0.02-0.59; p < 0.01) remained prognostic on multivariable analysis with fourfold and twofold higher risk for the time-related onset of death, respectively. This should be considered when assessing the risk-to-benefit ratio for patients undergoing surgery for CPA glioblastoma.
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Affiliation(s)
- Nebojsa Lasica
- Clinic of Neurosurgery, University Clinical Center of Vojvodina, Hajduk Veljkova 1-9, 21000, Novi Sad, Serbia.
- Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
| | - Kenan Arnautovic
- Semmes Murphey Clinic, Memphis, TN, USA
- Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tomita Tadanori
- Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Petar Vulekovic
- Clinic of Neurosurgery, University Clinical Center of Vojvodina, Hajduk Veljkova 1-9, 21000, Novi Sad, Serbia
- Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Dusko Kozic
- Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
- Center for Diagnostic Imaging, Oncology Institute of Vojvodina, Sremska Kamenica, Serbia
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Raghu ALB, Chen JA, Valdes PA, Essayed WI, Claus E, Arnaout O, Smith TR, Chiocca EA, Peruzzi PP, Bernstock JD. Cerebellar High-Grade Glioma: A Translationally Oriented Review of the Literature. Cancers (Basel) 2022; 15:174. [PMID: 36612169 PMCID: PMC9818238 DOI: 10.3390/cancers15010174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022] Open
Abstract
World Health Organization (WHO) grade 4 gliomas of the cerebellum are rare entities whose understanding trails that of their supratentorial counterparts. Like supratentorial high-grade gliomas (sHGG), cerebellar high-grade gliomas (cHGG) preferentially affect males and prognosis is bleak; however, they are more common in a younger population. While current therapy for cerebellar and supratentorial HGG is the same, recent molecular analyses have identified features and subclasses of cerebellar tumors that may merit individualized targeting. One recent series of cHGG included the subclasses of (1) high-grade astrocytoma with piloid features (HGAP, ~31% of tumors); (2) H3K27M diffuse midline glioma (~8%); and (3) isocitrate dehydrogenase (IDH) wildtype glioblastoma (~43%). The latter had an unusually low-frequency of epidermal growth factor receptor (EGFR) and high-frequency of platelet-derived growth factor receptor alpha (PDGFRA) amplification, reflecting a different composition of methylation classes compared to supratentorial IDH-wildtype tumors. These new classifications have begun to reveal insights into the pathogenesis of HGG in the cerebellum and lead toward individualized treatment targeted toward the appropriate subclass of cHGG. Emerging therapeutic strategies include targeting the mitogen-activated protein kinases (MAPK) pathway and PDGFRA, oncolytic virotherapy, and immunotherapy. HGGs of the cerebellum exhibit biological differences compared to sHGG, and improved understanding of their molecular subclasses has the potential to advance treatment.
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Affiliation(s)
- Ashley L. B. Raghu
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Oxford Functional Neurosurgery Group, Nuffield Departments of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK
| | - Jason A. Chen
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Pablo A. Valdes
- Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Walid Ibn Essayed
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Elizabeth Claus
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Omar Arnaout
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Timothy R. Smith
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - E. Antonio Chiocca
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Pier Paolo Peruzzi
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Joshua D. Bernstock
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Szczepaniak J, Sosnowska M, Wierzbicki M, Witkowska-Pilaszewicz O, Strojny-Cieslak B, Jagiello J, Fraczek W, Kusmierz M, Grodzik M. Reduced Graphene Oxide Modulates the FAK-Dependent Signaling Pathway in Glioblastoma Multiforme Cells In Vitro. MATERIALS (BASEL, SWITZERLAND) 2022; 15:ma15175843. [PMID: 36079225 PMCID: PMC9457042 DOI: 10.3390/ma15175843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/28/2022] [Accepted: 08/19/2022] [Indexed: 05/27/2023]
Abstract
Aggressive invasiveness is a common feature of malignant gliomas, despite their high level of tumor heterogeneity and possible diverse cell origins. Therefore, it is important to explore new therapeutic methods. In this study, we evaluated and compared the effects of graphene (GN) and reduced graphene oxides (rGOs) on a highly invasive and neoplastic cell line, U87. The surface functional groups of the GN and rGO flakes were characterized by X-ray photoelectron spectroscopy. The antitumor activity of these flakes was obtained by using the neutral red assay and their anti-migratory activity was determined using the wound healing assay. Further, we investigated the mRNA and protein expression levels of important cell adhesion molecules involved in migration and invasiveness. The rGO flakes, particularly rGO/ATS and rGO/TUD, were found highly toxic. The migration potential of both U87 and Hs5 cells decreased, especially after rGO/TUD treatment. A post-treatment decrease in mobility and FAK expression was observed in U87 cells treated with rGO/ATS and rGO/TUD flakes. The rGO/TUD treatment also reduced β-catenin expression in U87 cells. Our results suggest that rGO flakes reduce the migration and invasiveness of U87 tumor cells and can, thus, be used as potential antitumor agents.
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Affiliation(s)
- Jaroslaw Szczepaniak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Malwina Sosnowska
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Mateusz Wierzbicki
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Olga Witkowska-Pilaszewicz
- Department of Large Animal Diseases and Clinic, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
| | - Barbara Strojny-Cieslak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Joanna Jagiello
- Graphene and Composites Research Group, Łukasiewicz Research Network-Institute of Microelectronics and Photonics, 01-919 Warsaw, Poland
| | - Wiktoria Fraczek
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
| | - Marcin Kusmierz
- Analytical Laboratory, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Skłodowska University, 3 Maria Curie-Skłodowska Square, 20-031 Lublin, Poland
| | - Marta Grodzik
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences (WULS-SGGW), 02-787 Warsaw, Poland
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10
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Daisy Precilla S, Biswas I, Kuduvalli SS, Anitha TS. Crosstalk between PI3K/AKT/mTOR and WNT/β-Catenin signaling in GBM - Could combination therapy checkmate the collusion? Cell Signal 2022; 95:110350. [PMID: 35525406 DOI: 10.1016/j.cellsig.2022.110350] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/11/2022] [Accepted: 04/30/2022] [Indexed: 12/12/2022]
Abstract
Glioblastoma multiforme is one of the calamitous primary glial brain tumors with extensive heterogeneity at cellular and molecular levels. While maximal surgical resection trailed by radio and chemotherapy employing temozolomide remains the gold-standard treatment for malignant glioma patients, the overall prognosis remains dismal and there exists an unmet need for effective therapeutic strategies. In this context, we hypothesize that proper understanding of signaling pathways responsible for glioblastoma multiforme proliferation would be the first trump card while searching for novel targeted therapies. Among the pathways aberrantly activated, PI3K/AKT/mTOR is the most significant pathway, that is clinically implicated in malignancies such as high-grade glioma. Further, the WNT/β-Catenin cascade is well-implicated in several malignancies, while its role in regulating glioma pathogenesis has only emerged recently. Nevertheless, oncogenic activation of both these pathways is a frequent event in malignant glioma that facilitates tumor proliferation, stemness and chemo-resistance. Recently, it has been reported that the cross-talk of PI3K/AKT/mTOR pathway with multiple signaling pathways could promote glioma progression and reduce the sensitivity of glioma cells to the standard therapy. However, very few studies had focused on the relationship between PI3K/AKT/mTOR and WNT/β-Catenin pathways in glioblastoma multiforme. Interestingly, in homeostatic and pathologic circumstances, both these pathways depict fine modulation and are connected at multiple levels by upstream and downstream effectors. Thus, gaining deep insights on the collusion between these pathways would help in discovering unique therapeutic targets for glioblastoma multiforme management. Hence, the current review aims to address, "the importance of inter-play between PI3K/AKT/mTOR and WNT/β-Catenin pathways", and put forward, "the possibility of combinatorially targeting them", for glioblastoma multiforme treatment enhancement.
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Affiliation(s)
- S Daisy Precilla
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Indrani Biswas
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Shreyas S Kuduvalli
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - T S Anitha
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India.
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11
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Glioblastoma Microenvironment and Cellular Interactions. Cancers (Basel) 2022; 14:cancers14041092. [PMID: 35205842 PMCID: PMC8870579 DOI: 10.3390/cancers14041092] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/31/2022] [Accepted: 02/16/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary This paper summarizes the crosstalk between tumor/non-tumor cells and other elements of the glioblastoma (GB) microenvironment. In tumor pathology, glial cells result in the highest number of cancers, and GB is considered the most lethal tumor of the central nervous system (CNS). The tumor microenvironment (TME) is a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be a key factor for the ineffective treatment since the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. A deeper understanding of cell–cell interactions in the TME and with the tumor cells could be the basis for a more efficient therapy. Abstract The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell–cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.
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12
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Noronha C, Ribeiro AS, Taipa R, Castro DS, Reis J, Faria C, Paredes J. Cadherin Expression and EMT: A Focus on Gliomas. Biomedicines 2021; 9:biomedicines9101328. [PMID: 34680444 PMCID: PMC8533397 DOI: 10.3390/biomedicines9101328] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 12/13/2022] Open
Abstract
Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.
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Affiliation(s)
- Carolina Noronha
- Neurosurgery Department, Hospital de Santo António, Centro Hospitalar Universitario do Porto, 4099-001 Porto, Portugal; (C.N.); (J.R.)
- Cancer Metastasis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Ana Sofia Ribeiro
- Cancer Metastasis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
| | - Ricardo Taipa
- Neuropathology Unit, Hospital de Santo António, Centro Hospitalar Universitario do Porto, 4099-001 Porto, Portugal;
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Diogo S. Castro
- Stem Cells & Neurogenesis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
| | - Joaquim Reis
- Neurosurgery Department, Hospital de Santo António, Centro Hospitalar Universitario do Porto, 4099-001 Porto, Portugal; (C.N.); (J.R.)
- Anatomy Department, Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Cláudia Faria
- Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, 1649-028 Lisboa, Portugal;
- IMM—Instituto de Medicina Molecular Joao Lobo Antunes, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Joana Paredes
- Cancer Metastasis Group, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Correspondence:
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13
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Yamamuro S, Yazawa G, Shiokawa R, Kajiwara R, Negishi H, Sumi K, Yoshino A. Erroneous resection of a cerebellar infarction – Lesson learned. INTERDISCIPLINARY NEUROSURGERY 2021. [DOI: 10.1016/j.inat.2021.101196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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14
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Chandra A, Lopez-Rivera V, Dono A, Brandel MG, Lewis C, O'Connor KP, Sheth SA, Ballester LY, Aghi MK, Esquenazi Y. Comparative Analysis of Survival Outcomes and Prognostic Factors of Supratentorial versus Cerebellar Glioblastoma in the Elderly: Does Location Really Matter? World Neurosurg 2020; 146:e755-e767. [PMID: 33171326 DOI: 10.1016/j.wneu.2020.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Cerebellar glioblastomas (cGBMs) are rare tumors that are uncommon in the elderly. In this study, we compare survival outcomes and identify prognostic factors of cGBM compared with the supratentorial (stGBM) counterpart in the elderly. METHODS Data from the SEER 18 registries were used to identify patients with a glioblastoma (GBM) diagnosis between 2000 and 2016. The log-rank method and a multivariable Cox proportional hazards regression model were used for analysis. RESULTS Among 110 elderly patients with cGBM, the median age was 74 years (interquartile range [IQR], 69-79 years), 39% were female and 83% were white. Of these patients, 32% underwent gross total resection, 73% radiotherapy, and 39% chemotherapy. Multivariable analysis of the unmatched and matched cohort showed that tumor location was not associated with survival; in the unmatched cohort, insurance status (hazard ratio [HR], 0.11; IQR, 0.02-0.49; P = 0.004), gross total resection (HR, 0.53; IQR, 0.30-0.91; P = 0.022), and radiotherapy (HR, 0.33; IQR, 0.18-0.61; P < 0.0001) were associated with better survival. Patients with cGBM and stGBM undergoing radiotherapy (7 months vs. 2 months; P < 0.001) and chemotherapy (10 months vs. 3 months; P < 0.0001) had improved survival. Long-term mortality was lower for cGBM in the elderly at 24 months compared with the stGBM cohort (P = 0.007). CONCLUSIONS In our study, elderly patients with cGBM and stGBM have similar outcomes in overall survival, and those undergoing maximal resection with adjuvant therapies, independent of tumor location, have improved outcomes. Thus, aggressive treatment should be encouraged for cGBM in geriatric patients to confer the same survival benefits seen in stGBM. Single-institutional and multi-institutional studies to identify patient-level prognostic factors are warranted to triage the best surgical candidates.
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Affiliation(s)
- Ankush Chandra
- Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - Victor Lopez-Rivera
- Department of Neurology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Antonio Dono
- Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Michael G Brandel
- Department of Neurosurgery, University of California San Diego, La Jolla, California, USA
| | - Cole Lewis
- Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA
| | - Kyle P O'Connor
- Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA
| | - Sunil A Sheth
- Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Leomar Y Ballester
- Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Manish K Aghi
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - Yoshua Esquenazi
- Department of Neurosurgery, Memorial Hermann Hospital-TMC, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
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15
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Cho HJ, Zhao J, Jung SW, Ladewig E, Kong DS, Suh YL, Lee Y, Kim D, Ahn SH, Bordyuh M, Kang HJ, Sa JK, Seo YJ, Kim ST, Lim DH, Dho YS, Lee JI, Seol HJ, Choi JW, Park WY, Park CK, Rabadan R, Nam DH. Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma. Neuro Oncol 2020; 21:47-58. [PMID: 30085274 DOI: 10.1093/neuonc/noy123] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features. Methods We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs. Results Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target. Conclusions Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients. Key Points 1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.
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Affiliation(s)
- Hee Jin Cho
- Institute for Refractory Cancer Research, Seoul, Korea.,Research Institute for Future Medicine, Seoul, Korea
| | - Junfei Zhao
- Department of Systems Biology, Columbia University, New York, New York, USA.,Department of Biomedical Informatics, Columbia University, New York, New York, USA
| | - Sang Won Jung
- Institute for Refractory Cancer Research, Seoul, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
| | - Erik Ladewig
- Department of Systems Biology, Columbia University, New York, New York, USA.,Department of Biomedical Informatics, Columbia University, New York, New York, USA
| | - Doo-Sik Kong
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yeon-Lim Suh
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yeri Lee
- Institute for Refractory Cancer Research, Seoul, Korea.,Research Institute for Future Medicine, Seoul, Korea
| | - Donggeon Kim
- Institute for Refractory Cancer Research, Seoul, Korea.,Research Institute for Future Medicine, Seoul, Korea
| | - Sun Hee Ahn
- Institute for Refractory Cancer Research, Seoul, Korea
| | - Mykola Bordyuh
- Department of Systems Biology, Columbia University, New York, New York, USA.,Department of Biomedical Informatics, Columbia University, New York, New York, USA
| | - Hyun Ju Kang
- Institute for Refractory Cancer Research, Seoul, Korea.,Research Institute for Future Medicine, Seoul, Korea
| | - Jason K Sa
- Institute for Refractory Cancer Research, Seoul, Korea.,Research Institute for Future Medicine, Seoul, Korea
| | - Yun Jee Seo
- Institute for Refractory Cancer Research, Seoul, Korea
| | - Sung Tae Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Do Hoon Lim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yun-Sik Dho
- Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Il Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Jun Seol
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Won Choi
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woong-Yang Park
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
| | - Chul-Kee Park
- Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Raul Rabadan
- Department of Systems Biology, Columbia University, New York, New York, USA.,Department of Biomedical Informatics, Columbia University, New York, New York, USA
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Seoul, Korea.,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
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16
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Zhou X, Zhang S, Niu X, Li T, Zuo M, Yang W, Li M, Li J, Yang Y, Wang X, Mao Q, Liu Y. Risk Factors for Early Mortality Among Patients with Glioma: A Population-Based Study. World Neurosurg 2020; 136:e496-e503. [PMID: 31954903 DOI: 10.1016/j.wneu.2020.01.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 01/07/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The present study evaluated the early death and factors associated with early mortality in patients with glioma. METHODS The data used for analysis in the present study was extracted from the Surveillance, Epidemiology, and End Results data set. RESULTS A total of 58,700 patients with glioma were enrolled in the present study. The proportion of patient death within 1 month and 3 months after the diagnosis was 9.24% and 19.15% for all patients, respectively. The factors significantly associated with death within 1 month after tumor resection on multivariate analysis included age at diagnosis, year of diagnosis, tumor location, histological features, tumor size, and the absence of gross total resection, radiotherapy, and chemotherapy. We also observed similar findings in the evaluation of the factors associated with 3-month mortality. CONCLUSION The early deaths rates, including 1 and 3 months after tumor resection in patients with glioma, have decreased slightly during the previous 40 years. The risk factors for early mortality included advanced age, male sex, tumor located in the lateral ventricle, cerebellum, or brainstem, receipt of biopsy only, no chemotherapy or radiotherapy, and specific histopathological types.
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Affiliation(s)
- Xingwang Zhou
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Shuxin Zhang
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - XiaoDong Niu
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Tengfei Li
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Mingrong Zuo
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Wanchun Yang
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Mao Li
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Junhong Li
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Yuan Yang
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Xiang Wang
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Qing Mao
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China
| | - Yanhui Liu
- Department of Neurosurgery, West China Hospital, Chengdu, People's Republic of China.
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17
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Reinhardt A, Stichel D, Schrimpf D, Koelsche C, Wefers AK, Ebrahimi A, Sievers P, Huang K, Casalini MB, Fernández-Klett F, Suwala A, Weller M, Gramatzki D, Felsberg J, Reifenberger G, Becker A, Hans VH, Prinz M, Staszewski O, Acker T, Dohmen H, Hartmann C, Paulus W, Heß K, Brokinkel B, Schittenhelm J, Buslei R, Deckert M, Mawrin C, Hewer E, Pohl U, Jaunmuktane Z, Brandner S, Unterberg A, Hänggi D, Platten M, Pfister SM, Wick W, Herold-Mende C, Korshunov A, Reuss DE, Sahm F, Jones DTW, Capper D, von Deimling A. Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities. Acta Neuropathol Commun 2019; 7:163. [PMID: 31661039 PMCID: PMC6816155 DOI: 10.1186/s40478-019-0801-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 08/30/2019] [Indexed: 11/29/2022] Open
Abstract
In this multi-institutional study we compiled a retrospective cohort of 86 posterior fossa tumors having received the diagnosis of cerebellar glioblastoma (cGBM). All tumors were reviewed histologically and subjected to array-based methylation analysis followed by algorithm-based classification into distinct methylation classes (MCs). The single MC containing the largest proportion of 25 tumors diagnosed as cGBM was MC anaplastic astrocytoma with piloid features representing a recently-described molecular tumor entity not yet included in the WHO Classification of Tumours of the Central Nervous System (WHO classification). Twenty-nine tumors molecularly corresponded to either of 6 methylation subclasses subsumed in the MC family GBM IDH wildtype. Further we identified 6 tumors belonging to the MC diffuse midline glioma H3 K27 M mutant and 6 tumors allotted to the MC IDH mutant glioma subclass astrocytoma. Two tumors were classified as MC pilocytic astrocytoma of the posterior fossa, one as MC CNS high grade neuroepithelial tumor with BCOR alteration and one as MC control tissue, inflammatory tumor microenvironment. The methylation profiles of 16 tumors could not clearly be assigned to one distinct MC. In comparison to supratentorial localization, the MC GBM IDH wildtype subclass midline was overrepresented, whereas the MCs GBM IDH wildtype subclass mesenchymal and subclass RTK II were underrepresented in the cerebellum. Based on the integration of molecular and histological findings all tumors received an integrated diagnosis in line with the WHO classification 2016. In conclusion, cGBM does not represent a molecularly uniform tumor entity, but rather comprises different brain tumor entities with diverse prognosis and therapeutic options. Distinction of these molecular tumor classes requires molecular analysis. More than 30% of tumors diagnosed as cGBM belong to the recently described molecular entity of anaplastic astrocytoma with piloid features.
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18
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Malignant Glioma in the Cerebellum Presenting as Multiple Small Lesions. Case Rep Oncol Med 2019; 2019:6725127. [PMID: 30723560 PMCID: PMC6339752 DOI: 10.1155/2019/6725127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/26/2018] [Accepted: 12/04/2018] [Indexed: 11/17/2022] Open
Abstract
Malignant glioma, the most common malignant primary brain tumor in adults, usually occurs in supratentorial space as a single mass lesion, and cerebellar location and multiple appearance are uncommon. We report a case of a 69-year-old female with three lesions simultaneously found in the cerebellum on magnetic resonance images (MRIs) after suffering from gait disturbance. Two lesions were around 15 mm in size and the other one was observed as a spotty enhancement. Although MRI findings suggested brain metastases, whole body examinations denied any primary malignancies. Biopsy for one lesion in the cerebellum was performed, which resulted in pathological diagnosis of malignant astrocytoma. The lesions were considered multicentric glioma based on MRI definition. The treatment with temozolomide and whole brain radiation was completed. Although the patient was discharged in an independent state with the shrinkage of the tumors, she unexpectedly died following sudden loss of consciousness from an unknown cause one month after discharge. The coincidence of cerebellar location and multicentricity characterized by smallness is quite rare in glioma patients, and such MRI findings might be misleading for the diagnosis. We describe the details of the case and discuss the pathogenesis of this unique presentation of malignant glioma with the literatures.
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Hong B, Banan R, Christians A, Nakamura M, Lalk M, Lehmann U, Hartmann C, Krauss JK. Cerebellar glioblastoma: a clinical series with contemporary molecular analysis. Acta Neurochir (Wien) 2018; 160:2237-2248. [PMID: 30203362 DOI: 10.1007/s00701-018-3673-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 09/04/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Glioblastomas (GBM) are localized in only less than 1% of patients in the cerebellum. Therefore, tumor characteristics, survival, and the efficacy of therapies are not yet well defined. The present study aims to characterize the molecular features of cerebellar GBM (GBMc) in 8 patients treated with contemporary modality in our institution. METHODS Patients' treatment history, progression-free survival (PFS), and overall survival (OS) were analyzed. All histopathological specimens were re-investigated. EGFR amplification was determined by FISH, H3F3A, and HIST1H3B mutation status and MGMT promoter methylation after bisulfite treatment by pyrosequencing and BRAF V600E by pyrosequencing and immunohistochemistry. TERT promoter mutations were analyzed by Sanger sequencing, CDKN2A/B deletions by digital PCR. The expression of IDH1 R132H, ATRX, and p53 was determined through immunohistochemistry. RESULTS Six adults and two children (mean age 36 years) underwent tumor resection via medial or lateral suboccipital craniotomy. The median overall survival (mOS) of the adult patients was 7 months. GBMc from two children demonstrated a H3F3A K27M mutation. One of these also harbored a BRAF V600E mutation and has already had a PFS of 74 months. Mutated IDH1 R132H protein was expressed in 2 GBM from adult patients with previous supratentorial anaplastic astrocytoma. One patient carried a TERT promoter mutation. Another patient initially presented with a thalamic pilocytic astrocytoma. The cerebellar tumor revealed neither a BRAF V600E nor a H3F3A mutation but a homozygous CDKN2A/B deletion. CONCLUSIONS GBM located in the cerebellum can be found in all age groups. We provide novel molecular genetic data on these rare tumors. Mutated IDH1 R132H protein and H3F3A K27M mutations indicate that a substantial number of GBMc are "metastatic" or "diaschismatic" lesions. Mutation of BRAF V600E may have a stronger biological significance than H3F3A K27M alterations. In a subset of patients, GBM may arise primarily as a distinct entity in the cerebellum.
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Matsumura N, Ikota H, Yamazaki T, Nakata S, Nobusawa S, Hirato J, Yoshimoto Y, Yokoo H. Cerebellar high-grade astrocytoma with IDH mutations in the elderly: A report of two cases. Neuropathology 2018; 38:411-416. [PMID: 29635724 DOI: 10.1111/neup.12468] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 03/01/2018] [Accepted: 03/06/2018] [Indexed: 11/27/2022]
Abstract
Cerebellar high-grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH-mutated cerebellar high-grade glioma with unusual histological features and uncommon patient ages. One case was an 83-year-old man, whose tumor was predominantly composed of densely packed round-to-polygonal epithelioid cells. The other was a 75-year-old woman's high-grade astrocytoma characterized by cord-like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH-mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2-mutation. Although the number is limited, IDH-mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.
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Affiliation(s)
- Nozomi Matsumura
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hayato Ikota
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Tatsuya Yamazaki
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoshi Nakata
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Neurosurgery, Gunma University Hospital, Maebashi, Japan
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Junko Hirato
- Department of Diagnostic Pathology, Gunma University Hospital, Maebashi, Japan
| | - Yuhei Yoshimoto
- Department of Neurosurgery, Gunma University Hospital, Maebashi, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
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Abstract
Cerebellar glioblastoma multiforme (cGBM) is rare in adults, accounting for <1% of all patients with glioblastoma multiforme (GBM). The accurate diagnosis of cGBM is important for establishing a suitable therapeutic schedule. However, the diagnosis of cerebellar GBM is not usually suspected preoperatively because of its rarity. Generally, patients with cGBMs typically presented with symptoms of raised intracranial pressure, and infrequently cerebellar symptoms such as gait ataxia and disequilibrium. Nevertheless, the authors reported a cGMB patient, with his clinical presentations and imaging characteristics mimicking a vestibular schwannoma. To the best of our knowledge, this is the first reported patient with cGBM mimicking a vestibular schwannoma. Furthermore, the diagnosis, treatment, and prognosis for cGBM were broadly investigated.
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22
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Picart T, Barritault M, Berthillier J, Meyronet D, Vasiljevic A, Frappaz D, Honnorat J, Jouanneau E, Poncet D, Ducray F, Guyotat J. Characteristics of cerebellar glioblastomas in adults. J Neurooncol 2017; 136:555-563. [DOI: 10.1007/s11060-017-2682-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 11/11/2017] [Indexed: 12/16/2022]
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Nakata S, Nobusawa S, Yamazaki T, Osawa T, Horiguchi K, Hashiba Y, Yaoita H, Matsumura N, Ikota H, Hirato J, Yoshimoto Y, Yokoo H. Histone H3 K27M mutations in adult cerebellar high-grade gliomas. Brain Tumor Pathol 2017; 34:113-119. [PMID: 28547652 DOI: 10.1007/s10014-017-0288-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 05/19/2017] [Indexed: 12/31/2022]
Abstract
Adult cerebellar high-grade gliomas (HGG) are rare and their molecular basis has not been fully elucidated. Although a diffuse midline glioma H3 K27M-mutant, a recently characterized variant of HGG, was reported to occasionally occur in the cerebellum, adult cases were rarely tested for this mutation; only five mutant cases have been reported to date. It currently remains unknown whether H3 K27M-mutant cerebellar gliomas share common histological features or have a uniformly dismal prognosis. In the present study, we assessed the prevalence of histone H3 K27M mutations in ten adult cerebellar HGG, identifying two H3F3A-mutant cases. One case was a 70-year-old female with a cystic lesion. Histologically, the tumor was considered to be glioblastoma; however, a part of the tumor exhibiting low proliferative activity appeared to be consistent with long-standing H3 K27M-mutant tumors in the literature. Another case was a 69-year-old male. The tumor showed a distinct circumscribed histology with minimal astrocytic differentiation, suggesting a nosological issue in the diagnosis of diffuse midline glioma. More cerebellar tumors need to be tested for H3 K27M mutations to clarify the clinical and histopathological spectra of this tumor.
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Affiliation(s)
- Satoshi Nakata
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
- Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Japan.
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Tatsuya Yamazaki
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Tadashi Osawa
- Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Keishi Horiguchi
- Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yasuhiro Hashiba
- Department of Neurosurgery, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Hiroyuki Yaoita
- Department of Neurosurgery, Ota Memorial Hospital, Ota, Japan
| | - Nozomi Matsumura
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Hayato Ikota
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Junko Hirato
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
- Department of Pathology, Gunma University Hospital, Maebashi, Japan
| | - Yuhei Yoshimoto
- Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
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Nana AW, Yang PM, Lin HY. Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression. Asian Pac J Cancer Prev 2016; 16:6813-23. [PMID: 26514451 DOI: 10.7314/apjcp.2015.16.16.6813] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor β (TGFβ) superfamily is a large group of structurally related proteins including TGFβ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The TGFβ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulin- like growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (αvβ3, α5β1) and GBM initiating cells (GICs) as well as inducing a GBM mesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the TGFβ subfamily yields advantageous results, enhancing BMPs production is also beneficial.
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Affiliation(s)
- Andre Wendindonde Nana
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan E-mail :
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Takahashi Y, Makino K, Nakamura H, Hide T, Yano S, Kamada H, Kuratsu JI. Clinical characteristics and pathogenesis of cerebellar glioblastoma. Mol Med Rep 2014; 10:2383-8. [PMID: 25199771 DOI: 10.3892/mmr.2014.2549] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 05/25/2014] [Indexed: 11/05/2022] Open
Abstract
Cerebellar glioblastomas (GBMs) are rare, with neither their pathogenesis nor prognosis being completely understood. The present study aimed to clarify the clinical characteristics of cerebellar GBMs by comparison with supratentorial GBMs, focusing particularly on the pathogenesis. The clinical factors between cerebellar (n=10) and supratentorial (n=216) GBMs were compared. Additionally, p53 and epidermal growth factor receptor (EGFR) levels were investigated in six patients by immunostaining as well as the isocitrate dehydrogenase 1 (IDH1) status of five patients by direct sequencing. Eight males and two females participated in the present study, the mean age at diagnosis was 56.6 years and the range 37-75 years. Four patients presented with hydrocephalus and one with brainstem involvement, and two patients were diagnosed with neurofibromatosis type 1. Two patients had previously received radiotherapy, eight patients received postoperative radiotherapy and seven chemotherapy. The mean Karnofsky performance status (KPS) score was lower in patients with cerebellar GBMs compared to those with supratentorial GBM; however, the survival times did not differ between the two groups. All of the cases of six cerebellar GBMs were p53‑positive and EGFR‑negative, as detected by immunostaining, consistent with secondary GBM. However, no IDH1 mutations were detected in any of the five cases of cerebellar GBMs analyzed, indicating that these tumors were not of the secondary type. The KPS score with cerebellar GBMs may be lower due to hydrocephalus, which was ameliorated by surgery but may have impacted the survival rate. It was confirmed that cerebellar GBMs were identical to supratentorial GBMs with respect to its clinical features, with the possible exception of the KPS score. The present study's genetic analyses indicated that cerebellar GBMs may develop via a pathway different from that of either primary or secondary GBM.
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Affiliation(s)
- Yoshinobu Takahashi
- Department of Neurosurgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Keishi Makino
- Department of Neurosurgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideo Nakamura
- Department of Neurosurgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Takuichiro Hide
- Department of Neurosurgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Shigetoshi Yano
- Department of Neurosurgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hajime Kamada
- Department of Neurosurgery, Hokuto Hospital, Obihiro, Hokkaido 080-0039, Japan
| | - Jun-Ichi Kuratsu
- Department of Neurosurgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
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26
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Milinkovic VP, Skender Gazibara MK, Manojlovic Gacic EM, Gazibara TM, Tanic NT. The impact of TP53 and RAS mutations on cerebellar glioblastomas. Exp Mol Pathol 2014; 97:202-7. [PMID: 25036404 DOI: 10.1016/j.yexmp.2014.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 07/15/2014] [Indexed: 11/27/2022]
Abstract
Cerebellar glioblastoma (cGBM) is a rare, inadequately characterized disease, without detailed information on its molecular basis. This is the first report analyzing both TP53 and RAS alterations in cGBM. TP53 mutations were detected in more than half of the samples from our cohort, mainly in hotspot codons. There were no activating mutations in hotspot codons 12/13 and 61 of KRAS and HRAS genes in cGBM samples but we detected alterations in other parts of exons 2 and 3 of these genes, including premature induction of STOP codon. This mutation was present in 3 out of 5 patients. High incidence of RAS mutations, as well as significantly longer survival of cGBM patients compared to those with supratentorial GBM suggest that cGBM may have different mechanisms of occurrence. Our results suggest that inactivation of TP53 and RAS may play an important role in the progression of cerebellar GBM.
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Affiliation(s)
- Vedrana P Milinkovic
- University of Belgrade, Institute for Biological Research "Sinisa Stankovic", Department of Neurobiology, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia.
| | - Milica K Skender Gazibara
- University of Belgrade, School of Medicine, Institute of Pathology, Doktora Subotica 1, 11000 Belgrade, Serbia
| | - Emilija M Manojlovic Gacic
- University of Belgrade, School of Medicine, Institute of Pathology, Doktora Subotica 1, 11000 Belgrade, Serbia
| | - Tatjana M Gazibara
- University of Belgrade, School of Medicine, Institute of Epidemiology, Visegradska 26, 11000 Belgrade, Serbia
| | - Nikola T Tanic
- University of Belgrade, Institute for Biological Research "Sinisa Stankovic", Department of Neurobiology, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia
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27
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Jeswani S, Nuño M, Folkerts V, Mukherjee D, Black KL, Patil CG. Comparison of survival between cerebellar and supratentorial glioblastoma patients: surveillance, epidemiology, and end results (SEER) analysis. Neurosurgery 2014; 73:240-6; discussion 246; quiz 246. [PMID: 23615082 DOI: 10.1227/01.neu.0000430288.85680.37] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Cerebellar glioblastoma multiforme (cGBM) is rare, and although there is a general belief that these tumors have a worse prognosis than supratentorial GBM (sGBM), few studies have been published to support this belief. OBJECTIVE To investigate the effect of cerebellar location on survival through a case-control design comparing overall survival time of cGBM and sGBM patients. METHODS The Surveillance, Epidemiology, and End Results (SEER) registry was used to identify 132 patients with cGBM (1973-2008). Each cGBM patient was matched with an sGBM patient from among 20,848 sGBM patients on the basis of age, extent of resection, decade of diagnosis, and radiation therapy using propensity score matching. RESULTS Within the cGBM, 37% were older than 65 years of age, 62% were men, and 87% were white. Most patients underwent surgery and radiation (74%), whereas only 26% underwent surgical resection only. The median survival time for the cGBM and sGBM matched cohort was 8 months; however, the survival distributions differed (log-rank P = .04). Survival time for cGBM vs sGBM at 2 years was 21.5% vs 8.0%, and 12.7% vs 5.3% at 3 years. Multivariate analysis of survival among cGBM patients showed that younger age (P < .0001) and having radiation therapy (P < .0001) were significantly associated with reduced hazard of mortality. Among all patients, multivariate analysis showed that tumor location (P = .03), age (P < .0001), tumor size (P = .009), radiation (P < .0001), and resection (P < .0001) were associated with survival time in the unmatched cohort. CONCLUSION Median survival time for cGBM and sGBM patients was 8 months, but cGBM patients had a survival time advantage as the study progressed. These findings suggest that cGBM patients should be treated as aggressively as sGBM patients with surgical resection and radiation therapy.
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Affiliation(s)
- Sunil Jeswani
- Center for Neurosurgical Outcomes Research, Maxine Dunitz Neurosurgical Institute Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California
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Matsuda M, Onuma K, Satomi K, Nakai K, Yamamoto T, Matsumura A. Exophytic cerebellar glioblastoma in the cerebellopontine angle: case report and review of the literature. J Neurol Surg Rep 2014; 75:e67-72. [PMID: 25083393 PMCID: PMC4110129 DOI: 10.1055/s-0033-1364167] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 11/15/2013] [Indexed: 01/05/2023] Open
Abstract
We report the unique case of a 69-year-old man with a cerebellar glioblastoma showing an exophytic growth pattern. Magnetic resonance imaging revealed a heterogeneously gadolinium-enhancing tumor in the right cerebellopontine angle. The preoperative differential diagnoses included an intraaxial tumor, such as high-grade glioma, and an extraaxial tumor, such as a meningioma or neurinoma. The tumor with a clear boundary was subtotally removed, except for the adhesion site to the petrosal vein, and the histologic diagnosis was glioblastoma. Immunohistochemical analyses demonstrated that the tumor cells were immunopositive for epidermal growth factor receptor and immunonegative for p53 mutation and IDH1 R132H, indicating that it had different genetic features from a typical cerebellar glioblastoma. Conventional radiotherapy with 60 Gy concurrent with temozolomide was performed, and the condition of the patient has remained stable for 24 months since the operation. Exophytic cerebellar glioblastoma should be considered in the differential diagnosis of cerebellopontine angle tumor.
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Affiliation(s)
- Masahide Matsuda
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kuniyuki Onuma
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kaishi Satomi
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kei Nakai
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tetsuya Yamamoto
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akira Matsumura
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Modrek AS, Bayin NS, Placantonakis DG. Brain stem cells as the cell of origin in glioma. World J Stem Cells 2014; 6:43-52. [PMID: 24567787 PMCID: PMC3927013 DOI: 10.4252/wjsc.v6.i1.43] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 11/06/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineage-tracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.
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Babu R, Sharma R, Karikari IO, Owens TR, Friedman AH, Adamson C. Outcome and prognostic factors in adult cerebellar glioblastoma. J Clin Neurosci 2013; 20:1117-21. [PMID: 23706183 DOI: 10.1016/j.jocn.2012.12.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 12/01/2012] [Indexed: 11/25/2022]
Abstract
Cerebellar glioblastoma multiforme (GBM) occurs rarely in adults, accounting for 0.4-3.4% of all GBM. Current studies have all involved small patient numbers, limiting the clear identification of prognostic factors. Additionally, while few studies have compared cerebellar GBM to their supratentorial counterparts, there is conflicting data regarding their relative prognosis. To better characterize outcome and identify patient and treatment factors which affect survival, the authors analyzed cases of adult cerebellar GBM from the Surveillance, Epidemiology, and End Results database. A total of 247 adult patients with cerebellar GBM were identified, accounting for 0.67% of all adult GBM. Patients with cerebellar GBM were significantly younger than those with supratentorial tumors (56.6 versus 61.8 years, p < 0.0001), but a larger percentage of patients with supratentorial GBM were Caucasian (91.7% versus 85.0%, p < 0.0001). Overall median survival did not differ between those with cerebellar and supratentorial GBM (7 versus 8 months, p = 0.24), with similar rates of long-term (greater than 2 years) survival (13.4% versus 10.6%, p = 0.21). Multivariate analysis revealed age greater than 40 years (hazard ratio [HR]: 2.20; 95% confidence interval [CI]: 1.47-3.28; p = 0.0001) to be associated with worse patient survival, while the use of radiotherapy (HR: 0.33; 95% CI: 0.24-0.47; p < 0.0001) and surgical resection (HR: 0.66; 95% CI: 0.45-0.96; p = 0.028) were seen to be independent favorable prognostic factors. In conclusion, patients with cerebellar GBM have an overall poor prognosis, with radiotherapy and surgical resection significantly improving survival. As with supratentorial GBM, older age is a poor prognostic factor. The lack of differences between supratentorial and cerebellar GBM with respect to overall survival and prognostic factors suggests these tumors to be biologically similar.
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Affiliation(s)
- Ranjith Babu
- Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
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Adams H, Chaichana KL, Avendaño J, Liu B, Raza SM, Quiñones-Hinojosa A. Adult cerebellar glioblastoma: understanding survival and prognostic factors using a population-based database from 1973 to 2009. World Neurosurg 2013; 80:e237-43. [PMID: 23395851 DOI: 10.1016/j.wneu.2013.02.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 02/01/2013] [Indexed: 10/27/2022]
Abstract
OBJECTIVE Glioblastoma (GB) is rarely found in the cerebellum. Because of its rarity, it is poorly understood if cerebellar GB (CGB) behaves similarly to supratentorial GB. Studies have been limited to case reports and small case series. A better understanding of CGB may help guide treatment strategies. METHODS Surveillance, Epidemiology and End Results database was analyzed from 1973 to 2009 for all adult patients with GB located in the cerebellum. Stepwise multivariate proportional hazards regression analyses were used to identify factors independently associated with survival. RESULTS Two hundred eight (0.9%) patients with CGB were identified from 23,329 GB patients with known locality. The mean age was 58 years. Median survival was 8 months, with 1-, 2- and 5-year survival rates of 21%, 13%, and 2%. When compared to supratentorial GB, CGB occurred in younger patients (58 ± 16 vs. 61 ± 13 years, P = 0.001), less commonly in Whites (85.6% vs. 91.3%, P = 0.005), and were smaller (3.7 ± 1.1 vs. 4.5 ± 1.7 cm, P = 0.001). A cerebellar location independently predicted poorer survival when compared to other GB locations (P = 0.048). In multivariate analysis for patients with CGB, younger age (P < 0.001), Asian or Pacific Islander race (P = 0.046), and radiation therapy (P < 0.001) were independently associated with prolonged survival. CONCLUSION CGBs are difficult to analyze using institutional series because of their rarity. This study shows they are clinically different from supratentorial GB. Among patients with CGB, radiation therapy may prolong survival. This may help guide treatment strategies aimed at prolonging survival for patients with these extremely rare lesions.
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Affiliation(s)
- Hadie Adams
- Department of Neurosurgery and Oncology, Neuro-Oncology Surgical Outcomes Research Laboratory, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Tucker-Burden C, Chappa P, Krishnamoorthy M, Gerwe BA, Scharer CD, Heimburg-Molinaro J, Harris W, Usta SN, Eilertson CD, Hadjipanayis CG, Stice SL, Brat DJ, Nash RJ. Lectins identify glycan biomarkers on glioblastoma-derived cancer stem cells. Stem Cells Dev 2012; 21:2374-86. [PMID: 22435486 DOI: 10.1089/scd.2011.0369] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Despite aggressive therapy with surgery, radiotherapy, and chemotherapy, nearly all patients succumb to disease within 2 years. Several studies have supported the presence of stem-like cells in brain tumor cultures that are CD133-positive, are capable of self-renewal, and give rise to all cell types found within the tumor, potentially perpetuating growth. CD133 is a widely accepted marker for glioma-derived cancer stem cells; however, its reliability has been questioned, creating a need for other identifiers of this biologically important subpopulation. We used a panel of 20 lectins to identify differences in glycan expression found in the glycocalyx of undifferentiated glioma-derived stem cells and differentiated cells that arise from them. Fluorescently labeled lectins that specifically recognize α-N-acetylgalactosamine (GalNAc) and α-N-acetylglucosamine (GlcNAc) differentially bound to the cell surface based on the state of cellular differentiation. GalNAc and GlcNAc were highly expressed on the surface of undifferentiated cells and showed markedly reduced expression over a 12-day duration of differentiation. Additionally, the GalNAc-recognizing lectin Dolichos biflorus agglutinin was capable of specifically selecting and sorting glioma-derived stem cell populations from an unsorted tumor stock and this subpopulation had proliferative properties similar to CD133(+) cells in vitro and also had tumor-forming capability in vivo. Our preliminary results on a single cerebellar GBM suggest that GalNAc and GlcNAc are novel biomarkers for identifying glioma-derived stem cells and can be used to isolate cancer stem cells from unsorted cell populations, thereby creating new cell lines for research or clinical testing.
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Affiliation(s)
- Carol Tucker-Burden
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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