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Gecici NN, Habib A, Mallela AN, Rich JN, Drappatz J, Mantica M, Abdullah KG, Zinn PO. Ventricular Entry During Glioblastoma Resection is Associated With Reduced Survival and Increased Risk of Distant Recurrence. Neurosurgery 2025:00006123-990000000-01554. [PMID: 40178259 DOI: 10.1227/neu.0000000000003431] [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: 09/18/2024] [Accepted: 12/10/2024] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Although subventricular zone (SVZ) involvement is known to correlate with more aggressive tumor behavior and reduced survival in glioblastoma (GBM), the role of ventricular entry (VE) on outcomes is less clear and remains debated. This study aims to investigate the impact of VE on outcomes and overall survival (OS) in GBM. METHODS A retrospective analysis of patients with newly diagnosed supratentorial GBMtreated between 2013 and 2023 at the University of Pittsburgh Medical Center was performed. SVZ involvement, size, and extent of resection were identified through preoperative and postoperative imaging. VE was identified through operative notes and postoperative imaging review. RESULTS A total of 282 patients met inclusion criteria. VE occurred in 38.3% (n = 108) of patients and was more common in those with SVZ-contacting tumors (P < .001). Patients who had VE had significantly lower median OS compared with non-VE (12 months vs 18 months, P < .001). VE was identified as an independent risk factor for decreased OS in patients with GBM, after adjusting for well-known prognostic factors and SVZ contact (hazard ratios: 1.62 [1.12-2.34], P = .001). Only patients who had VE developed postoperative hydrocephalus (n = 4, 1.4%, P = .021) and had external ventricular drain placed (n = 6, 2.1%, P = .003). Distant parenchymal recurrence and leptomeningeal dissemination (LMD) rates were significantly higher in the VE group compared with the non-VE group (63.9% vs 39.7%, P < .001, and 23.1% vs 13.2%, P = .035), and VE emerged as an independent predictor of distant recurrences/LMDs in multivariable logistic regression (odds ratio: 4.7 [2.11-10.4], P < .001). CONCLUSION Our data suggest that VE during GBM resection is a significant independent risk factor for decreased survival and increased distant recurrence/LMD. While maximizing tumor resection remains critical, neurosurgeons must consider the potential adverse outcomes associated with VE because it may diminish the survival benefits of gross-total resection. Prospective studies are warranted to better understand the risks and benefits of VE in GBM surgery.
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Affiliation(s)
- Neslihan Nisa Gecici
- Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Cini NT, Pennisi M, Genc S, Spandidos DA, Falzone L, Mitsias PD, Tsatsakis A, Taghizadehghalehjoughi A. Glioma lateralization: Focus on the anatomical localization and the distribution of molecular alterations (Review). Oncol Rep 2024; 52:139. [PMID: 39155859 PMCID: PMC11358673 DOI: 10.3892/or.2024.8798] [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: 07/21/2023] [Accepted: 07/31/2024] [Indexed: 08/20/2024] Open
Abstract
It is well known how the precise localization of glioblastoma multiforme (GBM) predicts the direction of tumor spread in the surrounding neuronal structures. The aim of the present review is to reveal the lateralization of GBM by evaluating the anatomical regions where it is frequently located as well as the main molecular alterations observed in different brain regions. According to the literature, the precise or most frequent lateralization of GBM has yet to be determined. However, it can be said that GBM is more frequently observed in the frontal lobe. Tractus and fascicles involved in GBM appear to be focused on the corticospinal tract, superior longitudinal I, II and III fascicles, arcuate fascicle long segment, frontal strait tract, and inferior fronto‑occipital fasciculus. Considering the anatomical features of GBM and its brain involvement, it is logical that the main brain regions involved are the frontal‑temporal‑parietal‑occipital lobes, respectively. Although tumor volumes are higher in the right hemisphere, it has been determined that the prognosis of patients diagnosed with cancer in the left hemisphere is worse, probably reflecting the anatomical distribution of some detrimental alterations such as TP53 mutations, PTEN loss, EGFR amplification, and MGMT promoter methylation. There are theories stating that the right hemisphere is less exposed to external influences in its development as it is responsible for the functions necessary for survival while tumors in the left hemisphere may be more aggressive. To shed light on specific anatomical and molecular features of GBM in different brain regions, the present review article is aimed at describing the main lateralization pathways as well as gene mutations or epigenetic modifications associated with the development of brain tumors.
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Affiliation(s)
- Nilgun Tuncel Cini
- Department of Anatomy, Faculty of Medicine, Bilecik Şeyh Edebali University, Bilecik 11230, Turkey
| | - Manuela Pennisi
- Department of Biomedical and Biotechnological Sciences, University of Catania, I-95123 Catania, Italy
| | - Sidika Genc
- Department of Pharmacology, Faculty of Medicine, Bilecik Şeyh Edebali University, Bilecik 11230, Turkey
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences, University of Catania, I-95123 Catania, Italy
| | - Panayiotis D. Mitsias
- Department of Neurology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Aristides Tsatsakis
- Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
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Papacocea SI, Vrinceanu D, Dumitru M, Manole F, Serboiu C, Papacocea MT. Molecular Profile as an Outcome Predictor in Glioblastoma along with MRI Features and Surgical Resection: A Scoping Review. Int J Mol Sci 2024; 25:9714. [PMID: 39273661 PMCID: PMC11395592 DOI: 10.3390/ijms25179714] [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: 07/25/2024] [Revised: 09/06/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Glioblastoma (GBM) is one of the most aggressive malignant tumors of the brain. We queried PubMed for articles about molecular predictor markers in GBM. This scoping review aims to analyze the most important outcome predictors in patients with GBM and to compare these factors in terms of absolute months of survival benefit and percentages. Performing a gross total resection for patients with GBM undergoing optimal chemo- and radiotherapy provides a significant benefit in overall survival compared to those patients who received a subtotal or partial resection. However, compared to IDH-Wildtype GBMs, patients with IDH-Mutant 1/2 GBMs have an increased survival. MGMT promoter methylation status is another strong outcome predictor for patients with GBM. In the reviewed literature, patients with methylated MGMT promoter lived approximately 50% to 90% longer than those with an unmethylated MGMT gene promoter. Moreover, KPS is an important predictor of survival and quality of life, demonstrating that we should refrain from aggressive surgery in important brain areas. As new therapies (such as TTFs) emerge, we are optimistic that the overall median survival will increase, even for IDH-Wildtype GBMs. In conclusion, molecular profiles are stronger outcome predictors than the extent of neurosurgical resection for GBM.
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Affiliation(s)
- Serban Iancu Papacocea
- Neurosurgery Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (S.I.P.); (M.T.P.)
| | - Daniela Vrinceanu
- ENT Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Mihai Dumitru
- ENT Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Felicia Manole
- ENT Department, Faculty of Medicine, University of Oradea, 410073 Oradea, Romania;
| | - Crenguta Serboiu
- Cellular Biology and Histology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Marius Toma Papacocea
- Neurosurgery Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (S.I.P.); (M.T.P.)
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Tsuchiya T, Kawauchi D, Ohno M, Miyakita Y, Takahashi M, Yanagisawa S, Osawa S, Fujita S, Omura T, Narita Y. Risk Factors of Distant Recurrence and Dissemination of IDH Wild-Type Glioblastoma: A Single-Center Study and Meta-Analysis. Cancers (Basel) 2024; 16:2873. [PMID: 39199644 PMCID: PMC11352485 DOI: 10.3390/cancers16162873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 09/01/2024] Open
Abstract
Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) is a highly aggressive brain tumor with a high recurrence rate despite adjuvant treatment. This study aimed to evaluate the risk factors for non-local recurrence of GBM. In the present study, we analyzed 104 GBMs with a single lesion (non-multifocal or multicentric). Univariate analysis revealed that subventricular zone (SVZ) involvement was significantly associated with non-local recurrence (hazard ratio [HR]: 2.09 [1.08-4.05]). Tumors in contact with the trigone of the lateral ventricle tended to develop subependymal dissemination (p = 0.008). Ventricular opening via surgery did not increase the risk of non-local recurrence in patients with SVZ involvement (p = 0.190). A systematic review was performed to investigate the risk of non-local recurrence, and 21 studies were identified. A meta-analysis of previous studies confirmed SVZ involvement (odds ratio [OR]: 1.30 [1.01-1.67]) and O-6-methylguanine DNA methyltransferase promoter methylation (OR: 1.55 [1.09-2.20]) as significant risk factors for local recurrence. A time-dependent meta-analysis revealed a significant association between SVZ involvement and dissemination (HR: 1.69 [1.09-2.63]), while no significant association was found for distant recurrence (HR: 1.29 [0.74-2.27]). Understanding SVZ involvement and specific tumor locations associated with non-local recurrence provides critical insights for the management of GBM.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan; (T.T.); (D.K.); (M.O.); (Y.M.); (M.T.); (S.Y.); (S.O.); (S.F.); (T.O.)
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Norton ES, Whaley LA, Jones VK, Brooks MM, Russo MN, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann YW, Lam TT, Chaichana KL, Anastasiadis PZ, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. SCIENCE ADVANCES 2024; 10:eadn1607. [PMID: 39110807 PMCID: PMC11305394 DOI: 10.1126/sciadv.adn1607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.
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Affiliation(s)
- Emily S. Norton
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
- Regenerative Sciences Training Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Lauren A. Whaley
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Vanessa K. Jones
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Mieu M. Brooks
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Marissa N. Russo
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Dmytro Morderer
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Erik Jessen
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | | | - Natanael Zarco
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Anna Carrano
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Wilfried Rossoll
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Yan W. Asmann
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
| | - TuKiet T. Lam
- Keck MS and Proteomics Resource, Yale School of Medicine, New Haven, CT 06510, USA
- Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06510, USA
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Cruz-Garza JG, Bhenderu LS, Taghlabi KM, Frazee KP, Guerrero JR, Hogan MK, Humes F, Rostomily RC, Horner PJ, Faraji AH. Electrokinetic convection-enhanced delivery for infusion into the brain from a hydrogel reservoir. Commun Biol 2024; 7:869. [PMID: 39020197 PMCID: PMC11255224 DOI: 10.1038/s42003-024-06404-1] [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: 06/22/2023] [Accepted: 05/31/2024] [Indexed: 07/19/2024] Open
Abstract
Electrokinetic convection-enhanced delivery (ECED) utilizes an external electric field to drive the delivery of molecules and bioactive substances to local regions of the brain through electroosmosis and electrophoresis, without the need for an applied pressure. We characterize the implementation of ECED to direct a neutrally charged fluorophore (3 kDa) from a doped biocompatible acrylic acid/acrylamide hydrogel placed on the cortical surface. We compare fluorophore infusion profiles using ECED (time = 30 min, current = 50 µA) and diffusion-only control trials, for ex vivo (N = 18) and in vivo (N = 12) experiments. The linear intensity profile of infusion to the brain is significantly higher in ECED compared to control trials, both for in vivo and ex vivo. The linear distance of infusion, area of infusion, and the displacement of peak fluorescence intensity along the direction of infusion in ECED trials compared to control trials are significantly larger for in vivo trials, but not for ex vivo trials. These results demonstrate the effectiveness of ECED to direct a solute from a surface hydrogel towards inside the brain parenchyma based predominantly on the electroosmotic vector.
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Affiliation(s)
- Jesus G Cruz-Garza
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
- Center for Neural Systems Restoration, Houston Methodist Research Institute, Houston, TX, USA.
| | - Lokeshwar S Bhenderu
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
- Center for Neural Systems Restoration, Houston Methodist Research Institute, Houston, TX, USA.
- Texas A&M University College of Medicine, Houston, TX, USA.
| | - Khaled M Taghlabi
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neural Systems Restoration, Houston Methodist Research Institute, Houston, TX, USA
| | - Kendall P Frazee
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
- School of Engineering, Texas A&M, College Station, TX, USA
| | - Jaime R Guerrero
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Matthew K Hogan
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neural Systems Restoration, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Frances Humes
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Robert C Rostomily
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Philip J Horner
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neural Systems Restoration, Houston Methodist Research Institute, Houston, TX, USA
- Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Amir H Faraji
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
- Center for Neural Systems Restoration, Houston Methodist Research Institute, Houston, TX, USA.
- Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
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7
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Norton ES, Whaley LA, Jones VK, Brooks MM, Russo MN, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann YW, Lam TT, Chaichana KL, Anastasiadis PZ, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553966. [PMID: 37662251 PMCID: PMC10473635 DOI: 10.1101/2023.08.19.553966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM. Highlights Periventricular GBM is more malignant and disrupts neurogenesis in a rodent model.Cell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs.NPCs induce upregulated CTSB expression in GBM, promoting tumor progression.GBM stalls neurogenesis and promotes NPC senescence via CTSB.
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DTI Abnormalities Related to Glioblastoma: A Prospective Comparative Study with Metastasis and Healthy Subjects. Curr Oncol 2022; 29:2823-2834. [PMID: 35448204 PMCID: PMC9027882 DOI: 10.3390/curroncol29040230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
(1) Background: Glioblastoma multiforme (GBM) shows complex mechanisms of spreading of the tumor cells, up to remote areas, and little is still known of these mechanisms, thus we focused on MRI abnormalities observable in the tumor and the brain adjacent to the lesion, up to the contralateral hemisphere, with a special interest on tensor diffusion imaging informing on white matter architecture; (2) Material and Methods: volumes, macroscopic volume (MV), brain-adjacent-tumor (BAT) volume and abnormal color-coded DTI volume (aCCV), and region-of-interest samples (probe volumes, ipsi, and contra lateral to the lesion), with their MRI characteristics, apparent diffusion coefficient (ADC), fractional anisotropy (FA) values, and number of fibers (DTI fiber tracking) were analyzed in patients suffering GBM (n = 15) and metastasis (n = 9), and healthy subjects (n = 15), using ad hoc statistical methods (type I error = 5%) (3) Results: GBM volumes were larger than metastasis volumes, aCCV being larger in GBM and BAT ADC was higher in metastasis, ADC decreased centripetally in metastasis, FA increased centripetally either in GBM or metastasis, MV and BAT FA values were higher in GBM, ipsi FA values of GBM ROIs were higher than those of metastasis, and the GBM ipsi number of fibers was higher than the GBM contra number of fibers; (4) Conclusions: The MV, BAT and especially the aCCV, as well as their related water diffusion characteristics, could be useful biomarkers in oncology and functional oncology.
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Tierling S, Jürgens-Wemheuer WM, Leismann A, Becker-Kettern J, Scherer M, Wrede A, Breuskin D, Urbschat S, Sippl C, Oertel J, Schulz-Schaeffer WJ, Walter J. Bisulfite profiling of the MGMT promoter and comparison with routine testing in glioblastoma diagnostics. Clin Epigenetics 2022; 14:26. [PMID: 35180887 PMCID: PMC8857788 DOI: 10.1186/s13148-022-01244-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 02/07/2022] [Indexed: 11/26/2022] Open
Abstract
Background Promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is an acknowledged predictive epigenetic marker in glioblastoma multiforme and anaplastic astrocytoma. Patients with methylated CpGs in the MGMT promoter benefit from treatment with alkylating agents, such as temozolomide, and show an improved overall survival and progression-free interval. A precise determination of MGMT promoter methylation is of importance for diagnostic decisions. We experienced that different methods show partially divergent results in a daily routine. For an integrated neuropathological diagnosis of malignant gliomas, we therefore currently apply a combination of methylation-specific PCR assays and pyrosequencing. Results To better rationalize the variation across assays, we compared these standard techniques and assays to deep bisulfite sequencing results in a cohort of 80 malignant astrocytomas. Our deep analysis covers 49 CpG sites of the expanded MGMT promoter, including exon 1, parts of intron 1 and a region upstream of the transcription start site (TSS). We observed that deep sequencing data are in general in agreement with CpG-specific pyrosequencing, while the most widely used MSP assays published by Esteller et al. (N Engl J Med 343(19):1350–1354, 2000. 10.1056/NEJM200011093431901) and Felsberg et al. (Clin Cancer Res 15(21):6683–6693, 2009. 10.1158/1078-0432.CCR-08-2801) resulted in partially discordant results in 22 tumors (27.5%). Local deep bisulfite sequencing (LDBS) revealed that CpGs located in exon 1 are suited best to discriminate methylated from unmethylated samples. Based on LDBS data, we propose an optimized MSP primer pair with 83% and 85% concordance to pyrosequencing and LDBS data. A hitherto neglected region upstream of the TSS, with an overall higher methylation compared to exon 1 and intron 1 of MGMT, is also able to discriminate the methylation status. Conclusion Our integrated analysis allows to evaluate and redefine co-methylation domains within the MGMT promoter and to rationalize the practical impact on assays used in daily routine diagnostics. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-022-01244-4.
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Affiliation(s)
- Sascha Tierling
- Fak.NT Life Sciences, Department of Genetics/Epigenetics, Saarland University, Campus, Building A2 4, 66041, Saarbrücken, Germany.
| | | | - Alea Leismann
- Fak.NT Life Sciences, Department of Genetics/Epigenetics, Saarland University, Campus, Building A2 4, 66041, Saarbrücken, Germany
| | - Julia Becker-Kettern
- Institute of Neuropathology, Medical Faculty of the Saarland University, Homburg, Germany
| | - Michael Scherer
- Fak.NT Life Sciences, Department of Genetics/Epigenetics, Saarland University, Campus, Building A2 4, 66041, Saarbrücken, Germany.,Department of Bioinformatics and Genomics, Centre for Genomic Regulation, Barcelona, Spain
| | - Arne Wrede
- Institute of Neuropathology, Medical Faculty of the Saarland University, Homburg, Germany
| | - David Breuskin
- Institute for Neurosurgery, Medical Faculty of the Saarland University, Homburg, Germany
| | - Steffi Urbschat
- Institute for Neurosurgery, Medical Faculty of the Saarland University, Homburg, Germany
| | - Christoph Sippl
- Institute for Neurosurgery, Medical Faculty of the Saarland University, Homburg, Germany
| | - Joachim Oertel
- Institute for Neurosurgery, Medical Faculty of the Saarland University, Homburg, Germany
| | | | - Jörn Walter
- Fak.NT Life Sciences, Department of Genetics/Epigenetics, Saarland University, Campus, Building A2 4, 66041, Saarbrücken, Germany
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Bruhn H, Blystad I, Milos P, Malmström A, Dahle C, Vrethem M, Henriksson R, Lind J. Initial cognitive impairment predicts shorter survival of patients with glioblastoma. Acta Neurol Scand 2022; 145:94-101. [PMID: 34514585 DOI: 10.1111/ane.13529] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization. METHODS Medical records of 189 GBM patients were reviewed regarding the first medical appointment, presenting symptom/s, date of diagnostic radiology and survival. Tumour size, localization and treatment data were retrieved. Overall survival was calculated using Kaplan-Meier and Mann-Whitney U test. Cox regression was used for risk estimation. RESULTS Cognitive impairment as the initial symptom was often misinterpreted in primary health care leading to a delayed diagnosis. Initial global symptoms (66% of all patients) were associated with reduced survival compared to no global symptoms (median 8.4 months vs. 12.6 months). Those with the most common cognitive dysfunctions: change of behaviour, memory impairment and/or disorientation had a reduced median survival to 6.4 months. In contrast, seizures (32%) were associated with longer survival (median 11.2 months vs. 8.3 months). Global symptoms were associated with larger tumours than seizures, but tumour size had no linear association with survival. The setting of the first medical appointment was evenly distributed between primary health care and emergency units. CONCLUSION Patients with GBM presenting with cognitive symptoms are challenging to identify, have larger tumours and reduced survival. In contrast, epileptic seizures as the first symptom are associated with longer survival and smaller tumours.
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Affiliation(s)
- Helena Bruhn
- Department of Neurology Region Jönköping County Jönköping Sweden
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
| | - Ida Blystad
- Department of Radiology in Linköping and Department of Health, Medicine and Caring Sciences Linköping University Linköping Sweden
- Centre for Medical Image Science and Visualization (CMIV) Linköping University Linköping Sweden
| | - Peter Milos
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
- Department of Neurosurgery Linköping University Hospital Linköping Sweden
| | - Annika Malmström
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
- Department of Advanced Home Care Linköping University Linköping Sweden
| | - Charlotte Dahle
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
| | - Magnus Vrethem
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
| | - Roger Henriksson
- Department of Radiation Sciences Umeå University Hospital Umeå Sweden
| | - Jonas Lind
- Department of Neurology Region Jönköping County Jönköping Sweden
- Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden
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11
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Mohammadi A, Pour Abbasi MS, Khorrami S, Khodamoradi S, Mohammadi Goldar Z, Ebrahimzadeh F. The TRIM proteins in cancer: from expression to emerging regulatory mechanisms. Clin Transl Oncol 2021; 24:460-470. [PMID: 34643877 DOI: 10.1007/s12094-021-02715-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022]
Abstract
New clinical evidence suggests that dysregulation of the ubiquitin-mediated destruction of tumor suppressors or oncogene products is probably engaged in the etiology of leukemia and carcinoma. The superfamily of tripartite motif (TRIM)-containing protein family is among the biggest recognized single protein RING finger E3 ubiquitin ligases that are considered vital carcinogenesis regulators, which is not shocking since TRIM proteins are engaged in various biological processes, including cell growth, development, and differentiation; hence, TRIM proteins' alterations may influence apoptosis, cell proliferation, and transcriptional regulation. In this review article, the various mechanisms through which TRIM proteins exert their role in the most prevalent malignancies including lung, prostate, colorectal, liver, breast, brain cancer, and leukemia are summarized.
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Affiliation(s)
- A Mohammadi
- Department of Genetics Islamic, Azad University of Marand, Marand, Iran
| | | | - S Khorrami
- Tehran University of Medical Sciences, Tehran, Iran
| | - S Khodamoradi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Z Mohammadi Goldar
- Department of Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - F Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Mistry AM, Kelly PD, Gallant JN, Mummareddy N, Mobley BC, Thompson RC, Chambless LB. Comparative Analysis of Subventricular Zone Glioblastoma Contact and Ventricular Entry During Resection in Predicting Dissemination, Hydrocephalus, and Survival. Neurosurgery 2020; 85:E924-E932. [PMID: 31058968 DOI: 10.1093/neuros/nyz144] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 01/12/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Ventricular entry during glioblastoma resection and tumor contact with the subventricular zone (SVZ) have both been shown to associate with development of hydrocephalus, leptomeningeal dissemination, distant parenchymal recurrence, and decreased survival. However, prior studies did not analyze these variables together in a single-patient population; therefore, it is unknown which is an independent predictor of these outcomes. OBJECTIVE To conduct a comparative outcome analysis of surgical ventricular entry and SVZ contact by glioblastoma in a retrospective cohort of 232 patients. METHODS Outcomes studied included hydrocephalus, leptomeningeal dissemination, distant tumor recurrences, and progression-free (PFS) and overall (OS) survival. The Cox proportional regression analyses were adjusted for age at diagnosis, preoperative Karnofsky performance status score, extent of resection, temozolomide and radiation treatments, and tumor molecular status (specifically, IDH1/2 mutation and MGMT promoter methylation). RESULTS Surgical ventricular entry, SVZ-contacting glioblastoma, hydrocephalus, leptomeningeal dissemination, and distant recurrences were observed in 85 (36.6%), 114 (49.1%), 19 (8.2%), 78 (33.6%), and 59 (25.4%) patients, respectively. Multivariate, adjusted analysis revealed SVZ tumor contact-but not ventricular entry-associated with hydrocephalus (hazard ratio, HR, 4.20 [1.13-15.7], P = .03), leptomeningeal dissemination (HR 1.93 [1.14-3.28], P = .01), PFS (HR 2.10 [1.53-2.88], P < .001), and OS (HR 1.90 [1.35-2.67], P < .001). Distant recurrences were not associated with either. No interaction between the 2 variables was statistically noted. CONCLUSION SVZ contact by glioblastoma was independently associated with the development of hydrocephalus, leptomeningeal dissemination, and decreased survival. SVZ tumor contact was associated with ventricular entry during surgical resections, which did not independently correlate with these outcomes.
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Affiliation(s)
- Akshitkumar M Mistry
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Patrick D Kelly
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | - Bret C Mobley
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Reid C Thompson
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Lola B Chambless
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
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13
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van Dijken BRJ, Jan van Laar P, Li C, Yan JL, Boonzaier NR, Price SJ, van der Hoorn A. Ventricle contact is associated with lower survival and increased peritumoral perfusion in glioblastoma. J Neurosurg 2019; 131:717-723. [PMID: 30485234 DOI: 10.3171/2018.5.jns18340] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 05/02/2018] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The purpose of this study was to prospectively investigate outcome and differences in peritumoral MRI characteristics of glioblastomas (GBMs) that were in contact with the ventricles (ventricle-contacting tumors) and those that were not (noncontacting tumors). GBMs are heterogeneous tumors with variable survival. Lower survival is suggested for patients with ventricle-contacting tumors than for those with noncontacting tumors. This might be supported by aggressive peritumoral MRI features. However, differences in MRI characteristics of the peritumoral environment between ventricle-contacting and noncontacting GBMs have not yet been investigated. METHODS Patients with newly diagnosed GBM underwent preoperative MRI with contrast-enhanced T1-weighted, FLAIR, diffusion-weighted, and perfusion-weighted sequences. Tumors were categorized into ventricle-contacting or noncontacting based on contrast enhancement. Survival analysis was performed using log-rank for univariate analysis and Cox regression for multivariate analysis. Normalized perfusion (relative cerebral blood volume [rCBV]) and diffusion (apparent diffusion coefficient [ADC]) values were calculated in 2 regions: the peritumoral nonenhancing FLAIR region overlapping the subventricular zone and the remaining peritumoral nonenhancing FLAIR region. RESULTS Overall survival was significantly lower for patients with contacting tumors than for those with noncontacting tumors (434 vs 747 days, p < 0.001). Progression-free survival showed a comparable trend (260 vs 375 days, p = 0.094). Multivariate analysis confirmed a survival difference for both overall survival (HR 3.930, 95% CI 1.740-8.875, p = 0.001) and progression-free survival (HR 2.506, 95% CI 1.254-5.007, p = 0.009). Peritumoral perfusion was higher in contacting than in noncontacting tumors for both FLAIR regions (p = 0.04). There was no difference in peritumoral ADC values between the 2 groups. CONCLUSIONS Patients with ventricle-contacting tumors had poorer outcomes than patients with noncontacting tumors. This disadvantage of ventricle contact might be explained by higher peritumoral perfusion leading to more aggressive behavior.
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Affiliation(s)
- Bart Roelf Jan van Dijken
- 1Department of Radiology (EB44), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Peter Jan van Laar
- 1Department of Radiology (EB44), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Chao Li
- 2Cambridge Brain Tumour Imaging Laboratory, Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, Cambridge, United Kingdom.,3Department of Neurosurgery, Shanghai General Hospital, Shanghai, China
| | - Jiun-Lin Yan
- 2Cambridge Brain Tumour Imaging Laboratory, Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, Cambridge, United Kingdom.,4Department of Neurosurgery, Chang Gung Memorial Hospital, Keelung, Taiwan; and.,5Department of Neurosurgery, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Natalie Rosella Boonzaier
- 2Cambridge Brain Tumour Imaging Laboratory, Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, Cambridge, United Kingdom
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- 2Cambridge Brain Tumour Imaging Laboratory, Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, Cambridge, United Kingdom
| | - Anouk van der Hoorn
- 1Department of Radiology (EB44), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,2Cambridge Brain Tumour Imaging Laboratory, Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, Cambridge, United Kingdom
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14
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Reulen HJ, Suero Molina E, Zeidler R, Gildehaus FJ, Böning G, Gosewisch A, Stummer W. Intracavitary radioimmunotherapy of high-grade gliomas: present status and future developments. Acta Neurochir (Wien) 2019; 161:1109-1124. [PMID: 30980242 DOI: 10.1007/s00701-019-03882-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 03/20/2019] [Indexed: 02/07/2023]
Abstract
There is a distinct need for new and second-line therapies to delay or prevent local tumor regrowth after current standard of care therapy. Intracavitary radioimmunotherapy, in combination with radiotherapy, is discussed in the present review as a therapeutic strategy of high potential. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The available body of literature on intracavitary radioimmunotherapy (iRIT) in glioblastoma and anaplastic astrocytomas is presented. Several past and current phase I and II clinical trials, using mostly an anti-tenascin monoclonal antibody labeled with I-131, have shown median overall survival of 19-25 months in glioblastoma, while adverse events remain low. Tenascin, followed by EGFR and variants, or smaller peptides have been used as targets, and most clinical studies were performed with I-131 or Y-90 as radionuclides while only recently Re-188, I-125, and Bi-213 were applied. The pharmacokinetics of iRIT, as well as the challenges encountered with this therapy, is comprehensively discussed. This promising approach deserves further exploration in future studies by incorporating several innovative modifications.
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Affiliation(s)
| | - Eric Suero Molina
- Department of Neurosurgery, University Hospital of Münster, Münster, Germany.
| | - Reinhard Zeidler
- Helmholtz-Zentrum Munich, German Research Center for Environmental Health, Research Group Gene Vectors, Munich, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU Munich, Munich, Germany
| | | | - Guido Böning
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Astrid Gosewisch
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Walter Stummer
- Department of Neurosurgery, University Hospital of Münster, Münster, Germany
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15
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Krivoshapkin AL, Sergeev GS, Gaytan AS, Kalneus LE, Kurbatov VP, Abdullaev OA, Salim N, Bulanov DV, Simonovich AE. Automated Volumetric Analysis of Postoperative Magnetic Resonance Imaging Predicts Survival in Patients with Glioblastoma. World Neurosurg 2019; 126:e1510-e1517. [PMID: 30910753 DOI: 10.1016/j.wneu.2019.03.142] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 03/13/2019] [Accepted: 03/14/2019] [Indexed: 11/26/2022]
Abstract
BACKGROUND Glioblastomas (GBMs) are primary brain tumors that are very difficult to treat. Magnetic resonance imaging (MRI) is the reference tool for diagnosis, postoperative control, and follow-up of GBM. The MRI tumor contrast enhancement part serves as a target for surgery. However, there are controversial data about the influence of pre- and postoperative tumor volumetric MRI parameters on overall survival (OS). METHODS Data of 57 patients with GBM were analyzed retrospectively. All patients had maximum safe resection and standard adjuvant treatment. All patients underwent 1.5-T MRI with contrast in the first 24 hours postoperatively. The data of pre- and postoperative volumetric parameters were analyzed using the original software. RESULTS Correlation analysis between the postoperative volume of the tumor contrast enhancement part and the patient's OS revealed a significant level (on the Chaddock scale) of inverse correlation. Residual tumor volume associated with OS of >6 months was determined as <2.5 cm3. The mortality risk in the first 6 months after tumor resection is 3.4 times higher when the tumor remnant is >2.5 cm3 (risk ratio, 3.4; P = 0.0002). CONCLUSIONS The volume of MRI contrast-enhancing GBM remnants after surgery, automatically measured by the software, was a significant predictor for early postoperative progression and death.
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Affiliation(s)
- Alexey L Krivoshapkin
- Department of Neurosurgery, Novosibirsk State Medical University, Novosibirsk, Russia.
| | - Gleb S Sergeev
- Neurosurgical Department, European Medical Center, Moscow, Russia
| | - Alekey S Gaytan
- Neurosurgical Department, European Medical Center, Moscow, Russia
| | - Leonid E Kalneus
- Physics Department, Novosibirsk State University, Novosibirsk, Russia
| | | | - Orkhan A Abdullaev
- Department of Neurosurgery, Novosibirsk State Medical University, Novosibirsk, Russia
| | - Nidal Salim
- Radiotherapy Center, European Medical Center, Moscow, Russia
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16
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Yang X, Zhu H, Yang X, Li N, Huang H, Liu T, Guo X, Xu X, Xia L, Deng C, Tian X, Yang Z. Targeting CAIX with [ 64Cu]XYIMSR-06 Small Molecular Radiotracer Enables Noninvasive PET Imaging of Malignant Glioma in U87 MG Tumor Cell Xenograft Mice. Mol Pharm 2019; 16:1532-1540. [PMID: 30803240 DOI: 10.1021/acs.molpharmaceut.8b01210] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Carbonic anhydrase IX (CAIX) plays an important role in glioma cell proliferation, invasion, metastasis, and resistance to radiotherapy and chemotherapy. An effective and noninvasive PET molecular imaging agent targeting CAIX would help its diagnosis and treatment but is not currently available. Recently, a low-molecular-weight (LMW) CAIX targeting agent, [64Cu]XYIMSR-06, was reported to have significantly improved properties for targeting clear cell renal cell carcinoma (ccRCC). We are encouraged to investigate the feasibility of adapting this agent for the diagnosis and treatment of CAIX-overexpressing malignant glioma. In vitro cell uptake and binding affinity assays were used to verify the binding capacity of [64Cu]XYIMSR-06 to U87 MG tumor cells in which CAIX overexpression was confirmed. The U87 MG tumor-bearing mouse (in situ and subcutaneous) model was built, and mice were injected with the radiotracer and/or coinjected with acetazolamide (0.2 g/kg) as a blocking agent for noninvasive micro-PET imaging. Micro-PET imaging was performed at 2, 4, and 8 h postinjection. ROI (region of interest)-based semiquantification was performed in an orthotopic glioma tumor model. Biodistribution throughout each organ was performed at 2, 4, 4 h block, 8, and 24 h postinjection. Hematoxylin and eosin (HE) staining and immunofluorescence or immunohistochemistry (IF/IHC) staining were implemented postimaging to assess the expression of CAIX in tumor organs. In vitro, [64Cu]XYIMSR-06 exhibits greater uptake in glioma cells (high CAIX expression) than in HCT116 cells (low CAIX expression). The binding affinity of [64Cu]XYIMSR-06 to U87 MG cell lines reaches up to 4.22 nM. Both orthotopic and subcutaneous tumors were clearly visualized at 2-8 h postinjection. Biodistribution studies demonstrated a maximum tumor uptake of 3.13% ID/g at 4 h postinjection, and the tumor to brain ratio (T/brain) was 6.51 at 8 h postinjection. The ROI-based T/brain values were 7.03 and 5.46 at 2 and 8 h postinjection, respectively. Histopathological analysis confirmed the overexpression of CAIX in gliomas, and the area of CAIX-positive IF staining is extremely consistent with the morphology on micro-PET imaging. In this study, [64Cu]XYIMSR-06 demonstrated specific accumulation in CAIX-expressing U87 MG glioma tumors, indicating that the radiotracer has the potential for noninvasively monitoring and guiding personalized treatment of malignant glioma and other tumors overexpressing CAIX.
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Affiliation(s)
- Xianteng Yang
- Guizhou University School of Medicine , Guiyang , Guizhou 550025 , China.,Department of Orthopaedics , People's Hospital of Guizhou Province , Guiyang , Guizhou 550002 , China
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
| | - Xing Yang
- Department of Nuclear Medicine , Peking University First Hospital , Beijing 100034 , China
| | - Nan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
| | - Haifeng Huang
- Guizhou University School of Medicine , Guiyang , Guizhou 550025 , China.,Department of Orthopaedics , People's Hospital of Guizhou Province , Guiyang , Guizhou 550002 , China
| | - Teli Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
| | - Xiaoyi Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
| | - Xiaoxia Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
| | - Lei Xia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
| | - Chaoyong Deng
- Guizhou University School of Medicine , Guiyang , Guizhou 550025 , China
| | - Xiaobin Tian
- Guizhou Medical University , Guiyang , Guizhou 550004 , China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine , Peking University Cancer Hospital & Institute , Beijing 100142 , China
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17
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Ventricular-Subventricular Zone Contact by Glioblastoma is Not Associated with Molecular Signatures in Bulk Tumor Data. Sci Rep 2019; 9:1842. [PMID: 30755636 PMCID: PMC6372607 DOI: 10.1038/s41598-018-37734-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 12/10/2018] [Indexed: 01/25/2023] Open
Abstract
Whether patients with glioblastoma that contacts the ventricular-subventricular zone stem cell niche (VSVZ + GBM) have a distinct survival profile from VSVZ - GBM patients independent of other known predictors or molecular profiles is unclear. Using multivariate Cox analysis to adjust survival for widely-accepted predictors, hazard ratios (HRs) for overall (OS) and progression free (PFS) survival between VSVZ + GBM and VSVZ - GBM patients were calculated in 170 single-institution patients and 254 patients included in both The Cancer Genome (TCGA) and Imaging (TCIA) atlases. An adjusted, multivariable analysis revealed that VSVZ contact was independently associated with decreased survival in both datasets. TCGA molecular data analyses revealed that VSVZ contact by GBM was independent of mutational, DNA methylation, gene expression, and protein expression signatures in the bulk tumor. Therefore, while survival of GBM patients is independently stratified by VSVZ contact, with VSVZ + GBM patients displaying a poor prognosis, the VSVZ + GBMs do not possess a distinct molecular signature at the bulk sample level. Focused examination of the interplay between the VSVZ microenvironment and subsets of GBM cells proximal to this region is warranted.
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18
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Feng S, Cai X, Li Y, Jian X, Zhang L, Li B. Tripartite motif-containing 14 (TRIM14) promotes epithelial-mesenchymal transition via ZEB2 in glioblastoma cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:57. [PMID: 30728039 PMCID: PMC6364431 DOI: 10.1186/s13046-019-1070-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 01/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Several members of the tripartite motif-containing (TRIM) protein family have been reported to serve as vital regulators of tumorigenesis. Recent studies have demonstrated an oncogenic role of TRIM 14 in multiple human cancers; however, the importance of this protein in glioblastoma remains to be elucidated. METHODS The expression levels of TRIM14 were analyzed in a series of database and were examined in a variety of glioblastoma cell lines. Two independent TRIM14 shRNA were transfected into LN229 and U251 cells, and the effect of TRIM14 depletion was confirmed. Transwell assay and wound healing assay assay were carried out to assess the effect of TRIM14 depletion on glioblastoma cell invasion and migration. Western blotting was performed to screen the downstream gene of TRIM14. The stability analysis and Ubiquitylation assays and Orthotopic xenograft studies were also performed to investigate the role of TRIM14 and the relationship with downstream gene. Human glioblastoma tissues were obtained and immunohistochemical staining were carried out to confirm the clinical significance of TRIM14. RESULTS In this study, we showed that TRIM14 was upregulated in human glioblastoma specimens and cell lines, and correlated with glioblastoma progression and shorter patient survival times. Functional experiments showed that decreased TRIM14 expression reduced glioblastoma cell invasion and migration. Furthermore, we identified that zinc finger E-box binding homeobox 2 (ZEB2), a transcription factor involved in epithelial-mesenchymal transition, is a downstream target of TRIM14. Further investigation revealed that TRIM14 inactivation significantly facilitated ZEB2 ubiquitination and proteasomal degradation, which led to aggressive invasion and migration. Our findings provide insight into the specific biological role of TRIM14 in tumor invasion. CONCLUSIONS Our findings provide insight into the specific biological role of TRIM14 in tumor invasion, and suggest that targeting the TRIM14/ZEB2 axis might be a novel therapeutic approach for blocking glioblastoma.
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Affiliation(s)
- Shuang Feng
- Department of Encephalopathy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xiaomin Cai
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yangyang Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoguang Jian
- Department of Encephalopathy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Linxin Zhang
- Department of Encephalopathy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Bin Li
- Department of Encephalopathy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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Piper RJ, Senthil KK, Yan JL, Price SJ. Neuroimaging classification of progression patterns in glioblastoma: a systematic review. J Neurooncol 2018; 139:77-88. [PMID: 29603080 DOI: 10.1007/s11060-018-2843-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 03/21/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Our primary objective was to report the current neuroimaging classification systems of spatial patterns of progression in glioblastoma. In addition, we aimed to report the terminology used to describe 'progression' and to assess the compliance with the Response Assessment in Neuro-Oncology (RANO) Criteria. METHODS We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry. RESULTS From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were not based on radiation volumes (Group 1) and 50 studies that used labels that were based on radiation volumes (Group 2). In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to 'progression', of which the most frequent were 'recurrence' (99%) and 'progression' (92%). We identified that 37% (n = 33/90) of the studies published following the release of the RANO classification were adherent compliant with the RANO criteria. CONCLUSIONS Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardization of terminology and classification systems used in studying progression would increase the efficiency of our research in our attempts to more successfully treat glioblastoma.
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Affiliation(s)
- Rory J Piper
- Cambridge Brain Tumour Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Hill's Road, Cambridge, CB2 0QQ, UK.
| | - Keerthi K Senthil
- Cambridge Brain Tumour Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Hill's Road, Cambridge, CB2 0QQ, UK
| | - Jiun-Lin Yan
- Cambridge Brain Tumour Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Hill's Road, Cambridge, CB2 0QQ, UK
| | - Stephen J Price
- Cambridge Brain Tumour Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Hill's Road, Cambridge, CB2 0QQ, UK
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20
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Fiedler L, Kellner M, Gosewisch A, Oos R, Böning G, Lindner S, Albert N, Bartenstein P, Reulen HJ, Zeidler R, Gildehaus F. Evaluation of 177Lu[Lu]-CHX-A″-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII. Nucl Med Biol 2018; 60:55-62. [DOI: 10.1016/j.nucmedbio.2018.02.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 02/05/2018] [Accepted: 02/18/2018] [Indexed: 01/15/2023]
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21
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Leu S, Boulay JL, Thommen S, Bucher HC, Stippich C, Mariani L, Bink A. Preoperative Two-Dimensional Size of Glioblastoma is Associated with Patient Survival. World Neurosurg 2018; 115:e448-e463. [PMID: 29678715 DOI: 10.1016/j.wneu.2018.04.067] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/09/2018] [Accepted: 04/10/2018] [Indexed: 10/17/2022]
Abstract
BACKGROUND Although tumor size affects survival of patients with lower-grade glioma, a prognostic effect on patients with glioblastoma remains to be established. METHODS We performed a retrospective analysis of 61 patients using volumetric data of tumor compartments of 61 patients obtained by preoperative magnetic resonance images using the visual ABC/2 method. Preoperative enhancing, nonenhancing, necrosis, and edema volume, the preoperative tumor area (TA) as a product of the 2 largest tumor diameters perpendicular to each other on axial T1-weighted postcontrast images, as well as postoperative enhancing residual volumes, were measured. Multivariable Cox proportional hazard models were used to associate these parameters with overall survival, adjusting for potential confounders. RESULTS The median preoperative enhancing tumor volume was 18.2 mL (interquartile range, 8.2-41.7 mL); the median remnant tumor volume was 1.3% (interquartile range, 0.0%-42.9%). During follow-up, 59 patients (92%) died; median survival time and median follow-up time were both 404 days. We found a statistically significant multiplicative effect of TA on survival: the hazard ratio (HR) was increased by 1.096 per unit increase of 200 mm2 (95% confidence interval [CI], 1.027-1.170; P < 0.01). The effect of remnant tumor on HR increased multiplicatively by 1.013 (95% CI, 1.001-1.026; P = 0.04) per unit increase of 1 log (day) and 1% in tumor remnant. HR associated with age at surgery increased by 1.503 per 5 years of age (95% CI, 1.243-1.817; P < 0.01). CONCLUSIONS Preoperative TA proved to be the only glioblastoma size parameter that affects patient survival.
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Affiliation(s)
- Severina Leu
- Department of Neurosurgery, University Hospital Basel, University of Basel, Basel, Switzerland; Brain Tumor Biology Laboratory, Department of Neurosurgery, University Hospital Basel, University of Basel, Basel, Switzerland.
| | - Jean-Louis Boulay
- Brain Tumor Biology Laboratory, Department of Neurosurgery, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Sarah Thommen
- Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Heiner C Bucher
- Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Christoph Stippich
- Division of Neuroradiology, Department of Radiology, University Hospital Basel, University of Basel, Basel, Switzerland; Clinic for Neuroradiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Luigi Mariani
- Department of Neurosurgery, University Hospital Basel, University of Basel, Basel, Switzerland; Brain Tumor Biology Laboratory, Department of Neurosurgery, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Andrea Bink
- Division of Neuroradiology, Department of Radiology, University Hospital Basel, University of Basel, Basel, Switzerland; Clinic for Neuroradiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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22
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Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome. J Neurooncol 2018; 139:125-133. [DOI: 10.1007/s11060-018-2850-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 03/25/2018] [Indexed: 10/17/2022]
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23
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Sinnaeve J, Mobley BC, Ihrie RA. Space Invaders: Brain Tumor Exploitation of the Stem Cell Niche. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:29-38. [PMID: 29024634 PMCID: PMC5745521 DOI: 10.1016/j.ajpath.2017.08.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 07/22/2017] [Accepted: 08/17/2017] [Indexed: 12/20/2022]
Abstract
Increasing evidence indicates that the adult neurogenic niche of the ventricular-subventricular zone (V-SVZ), beyond serving as a potential site of origin, affects the outcome of malignant brain cancers. Glioma contact with this niche predicts worse prognosis, suggesting a supportive role for the V-SVZ environment in tumor initiation or progression. In this review, we describe unique components of the V-SVZ that may permit or promote tumor growth within the region. Cell-cell interactions, soluble factors, and extracellular matrix composition are discussed, and the role of the niche in future therapies is explored. The purpose of this review is to highlight niche intrinsic factors that may promote or support malignant cell growth and maintenance, and point out how we might leverage these features to improve patient outcome.
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Affiliation(s)
- Justine Sinnaeve
- Departments of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Bret C Mobley
- Departments of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rebecca A Ihrie
- Departments of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
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24
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Mistry AM. Clinical correlates of subventricular zone-contacting glioblastomas: a meta-analysis. J Neurosurg Sci 2017; 63:581-587. [PMID: 29205011 DOI: 10.23736/s0390-5616.17.04274-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION The clinical and molecular correlates of glioblastomas (GBMs) contacting the subventricular zone (SVZ+ GBM) are unknown. This work aimed to reveal any such correlates that may help explain their increased GBM malignancy. EVIDENCE ACQUISITION A meta-analysis was, therefore, conducted to assess whether tumor's MGMT promoter methylation status, isocitrate dehydrogenase (IDH) mutation status, volume, and extent of resection as well as patients' age at diagnosis and preoperative Karnofsky performance status score (KPS) correlate with SVZ contact by GBM. In addition, available imaging of GBM patients in The Cancer Imaging Archive was assessed for SVZ contact and their corresponding clinical and molecular variables were obtained through The Cancer Genome Atlas (TCGA) database. EVIDENCE SYNTHESIS Twenty-one studies were identified through PubMed and EMBASE database search. This review included 257 patients identified from the TCIA/TCGA database. MGMT promoter methylation status (summary odds ratio [OD], 1.18 [0.84-1.66], P=0.34), IDH mutation status (OD: 0.63 [0.20-1.99], P=0.43), and patients' age of diagnosis (summary mean difference, MD, 0.10 years [-1.85, 2.05], P=0.92) did not associated with SVZ contact of the GBM. However, SVZ+ GBMs were significantly larger than SVZ- GBMs (MD: 17.3 cm3 [8.70-25.8], P<0.0001). SVZ+ GBM patients had lower KPS scores (MD: -3.33 [-5.31-(-1.35)], P=0.001) and were half as likely to receive a gross total resection (OD: 0.50 [0.40-0.64], P<0.00001). CONCLUSIONS Additional, large studies that rigorously control for all the known clinical and molecular prognosticators, especially extent of resection and preoperative KPS scores, are needed to evaluate whether SVZ contact by GBM independently influences survival.
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Affiliation(s)
- Akshitkumar M Mistry
- Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, USA -
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25
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Volumetric quantification of glioblastoma: experiences with different measurement techniques and impact on survival. J Neurooncol 2017; 135:391-402. [DOI: 10.1007/s11060-017-2587-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 07/25/2017] [Indexed: 11/27/2022]
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26
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Mistry AM, Dewan MC, White-Dzuro GA, Brinson PR, Weaver KD, Thompson RC, Ihrie RA, Chambless LB. Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum. J Neurooncol 2017; 132:341-349. [PMID: 28074322 PMCID: PMC5771712 DOI: 10.1007/s11060-017-2374-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 01/03/2017] [Indexed: 12/19/2022]
Abstract
The clinical effect of radiographic contact of glioblastoma (GBM) with neurogenic zones (NZ)-the ventricular-subventricular (VSVZ) and subgranular (SGZ) zones-and the corpus callosum (CC) remains unclear and, in the case of the SGZ, unexplored. We investigated (1) if GBM contact with a NZ correlates with decreased survival; (2) if so, whether this effect is associated with a specific NZ; and (3) if radiographic contact with or invasion of the CC by GBM is associated with decreased survival. We retrospectively identified 207 adult patients who underwent cytoreductive surgery for GBM followed by chemotherapy and/or radiation. Age, preoperative Karnofsky performance status score (KPS), and extent of resection were recorded. Preoperative MRIs were blindly analyzed to calculate tumor volume and assess its contact with VSVZ, SGZ, CC, and cortex. Overall (OS) and progression free (PFS) survivals were calculated and analyzed with multivariate Cox analyses. Among the 207 patients, 111 had GBM contacting VSVZ (VSVZ+GBMs), 23 had SGZ+GBMs, 52 had CC+GBMs, and 164 had cortex+GBMs. VSVZ+, SGZ+, and CC+ GBMs were significantly larger in size relative to their respective non-contacting controls. Multivariate Cox survival analyses revealed GBM contact with the VSVZ, but not SGZ, CC, or cortex, as an independent predictor of lower OS, PFS, and early recurrence. We hypothesize that the VSVZ niche has unique properties that contribute to GBM pathobiology in adults.
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Affiliation(s)
- Akshitkumar M Mistry
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA.
| | - Michael C Dewan
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA
| | | | - Philip R Brinson
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA
| | - Kyle D Weaver
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA
| | - Reid C Thompson
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA
| | - Rebecca A Ihrie
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA
| | - Lola B Chambless
- Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA
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27
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Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis. J Neurooncol 2016; 131:125-133. [PMID: 27644688 DOI: 10.1007/s11060-016-2278-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 09/03/2016] [Indexed: 02/07/2023]
Abstract
The ventricular-subventricular zone (V-SVZ), which lies in the walls of the lateral ventricles (LV), is the largest neurogenic niche within the adult brain. Whether radiographic contact with the LV influences survival in glioblastoma (GBM) patients remains unclear. We assimilated and analyzed published data comparing survival in GBM patients with (LV+GBM) and without (LV-GBM) radiographic LV contact. PubMed, EMBASE, and Cochrane electronic databases were searched. Fifteen studies with survival data on LV+GBM and LV-GBM patients were identified. Their Kaplan-Meier survival curves were digitized and pooled for generation of median overall (OS) and progression free (PFS) survivals and log-rank hazard ratios (HRs). The log-rank and reported multivariate HRs after accounting for the common predictors of GBM survival were analyzed separately by meta-analyses. The calculated median survivals (months) from pooled data were 12.95 and 16.58 (OS), and 4.54 and 6.25 (PFS) for LV+GBMs and LV-GBMs, respectively, with an overall log-rank HRs of 1.335 [1.204-1.513] (OS) and 1.387 [1.225-1.602] (PFS). Meta-analysis of log-rank HRs resulted in summary HRs of 1.58 [1.35-1.85] (OS, 10 studies) and 1.41 [1.22-1.64] (PFS, 5 studies). Meta-analysis of multivariate HRs resulted in summary HRs of 1.35 [1.14-1.58] (OS, 6 studies) and 1.64 [0.88-3.05] (PFS, 3 studies). Patients with GBM contacting the LV have lower survival. This effect may be independent of the common predictors of GBM survival, suggesting a clinical influence of V-SVZ contact on GBM biology.
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28
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Gandhi P, Khare R, Niraj K, Garg N, Sorte SK, Gulwani H. Unique case of oligoastrocytoma with recurrence and grade progression: Exhibiting differential expression of high mobility group-A1 and human telomerase reverse transcriptase. World J Clin Cases 2016; 4:296-301. [PMID: 27672647 PMCID: PMC5018629 DOI: 10.12998/wjcc.v4.i9.296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 05/29/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Mixed gliomas, primarily oligoastrocytomas, account for about 5%-10% of all gliomas. Distinguishing oligoastrocytoma based on histological features alone has limitations in predicting the exact biological behavior, necessitating ancillary markers for greater specificity. In this case report, human telomerase reverse transcriptase (hTERT) and high mobility group-A1 (HMGA1); markers of proliferation and stemness, have been quantitatively analyzed in formalin-fixed paraffin-embedded tissue samples of a 34 years old patient with oligoastrocytoma. Customized florescence-based immunohistochemistry protocol with enhanced sensitivity and specificity is used in the study. The patient presented with a history of generalized seizures and his magnetic resonance imaging scans revealed infiltrative ill-defined mass lesion with calcified foci within the left frontal white matter, suggestive of glioma. He was surgically treated at our center for four consecutive clinical events. Histopathologically, the tumor was identified as oligoastrocytoma-grade II followed by two recurrence events and final progression to grade III. Overall survival of the patient without adjuvant therapy was more than 9 years. Glial fibrillary acidic protein, p53, Ki-67, nuclear atypia index, pre-operative neutrophil-lymphocyte ratio, are the other parameters assessed. Findings suggest that hTERT and HMGA1 are linked to tumor recurrence and progression. Established markers can assist in defining precise histopathological grade in conjuction with conventional markers in clinical setup.
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29
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SCHWARM FRANKP, UHLE FLORIAN, SCHÄNZER ANNE, ACKER TILL, STEIN MARCO, REINGES MARCUSH, WEISCHER CORNELIA, WEIGAND MARCUSA, UHL EBERHARD, KOLODZIEJ MALGORZATAA. High-mobility group AT-hook protein 2 expression and its prognostic significance in MGMT methylated and unmethylated glioblastoma. Int J Oncol 2016; 48:1485-92. [DOI: 10.3892/ijo.2016.3397] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 12/29/2015] [Indexed: 11/05/2022] Open
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30
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Is a modification of the radiotherapeutic target volume necessary after resection of glioblastomas with opening of the ventricles? J Neurooncol 2016; 127:581-7. [PMID: 26830090 DOI: 10.1007/s11060-016-2068-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 01/22/2016] [Indexed: 10/22/2022]
Abstract
Extensive surgical resection of centrally localized, newly diagnosed glioblastoma can lead to opening ventricles and therefore carries a potential risk of spreading tumor cells into the cebrospinal fluid. However, whether ventricle opening consequently implies a greater frequency of distant tumor recurrence after radiation therapy-and, therefore, reduced survival-remains unknown. Therefore, is an adaption of target volumes in radiation therapy necessary to account for a potential tumor cell spread into the ventricle system? The present study assessed the resection statuses of 311 primary-glioblastoma patients who underwent radiation therapy. Overall, in 78 cases (25.1 %) the ventricle system was opened during surgical resection. This study assessed the connection between ventricle opening and progression-free survival, overall survival, and distant and multifocal recurrence. OS rates of patients that underwent gross total resection were superior to patients with subtotal resection (p = 0.002). PFS (p = 0.53) and OS (p = 0.18) did not differ due to ventricle opening during surgical resection. However, in a subsample of STR cases increased survival was observed when the ventricle system was opened (16.8 vs. 14.3 months; p = 0.03). The occurrence of distant (p = 0.75) and contralateral recurrence (p = 0.87) was not influenced by ventricle opening. Newly diagnosed glioblastoma patients whose ventricle systems were opened during microsurgical resection did not experience decreased survival or show increased likelihoods of distant and contralateral progressions following radiation therapy. In short, patients profit from surgical resections that are as extensive as reasonably possible, even if this entails ventricle opening. Thus, additional inclusion of the ventricles in the radiation therapy target volume after ventricle opening does not seem to be indicated.
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31
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Lobo MR, Kukino A, Tran H, Schabel MC, Springer CS, Gillespie GY, Grafe MR, Woltjer RL, Pike MM. Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma. PLoS One 2015; 10:e0144488. [PMID: 26645398 PMCID: PMC4672903 DOI: 10.1371/journal.pone.0144488] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 11/19/2015] [Indexed: 12/20/2022] Open
Abstract
Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the combination of cediranib with a proteasome inhibitor substantially increases the anti-angiogenic efficacy produced from either agent alone, and synergistically slows glioma tumor growth and extends survival, suggesting a promising treatment which warrants further investigation.
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Affiliation(s)
- Merryl R. Lobo
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Ayaka Kukino
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Huong Tran
- Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Matthias C. Schabel
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Charles S. Springer
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America
| | - G. Yancey Gillespie
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Marjorie R. Grafe
- Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Randall L. Woltjer
- Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Martin M. Pike
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America
- * E-mail:
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32
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Henker C, Kriesen T, Fürst K, Goody D, Glass Ä, Pützer BM, Piek J. Effect of 10 different polymorphisms on preoperative volumetric characteristics of glioblastoma multiforme. J Neurooncol 2015; 126:585-92. [PMID: 26603163 DOI: 10.1007/s11060-015-2005-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 11/19/2015] [Indexed: 01/09/2023]
Abstract
There is a distinct diversity between the appearance of every glioblastoma multiforme (GBM) on pretreatment magnetic resonance imaging (MRI) with a potential impact on clinical outcome and survival of the patients. The object of this study was to determine the impact of 10 different single nucleotide polymorphisms (SNPs) on various volumetric parameters in patients harboring a GBM. We prospectively analyzed 20 steroid-naïve adult patients who had been treated for newly diagnosed GBM. The volumetry was performed using MRI with the help of a semiautomated quantitative software measuring contrast enhancing tumor volume including necrosis, central necrosis alone and peritumoral edema (PTE). We calculated ratios between the tumor volume and edema (ETR), respectively necrosis (NTR). SNP analysis was done using genomic DNA extracted from peripheral blood genotyped via PCR and sequencing. There was a strong correlation between tumor volume and PTE (p < 0.001), necrosis (p < 0.001) and NTR (p = 0.003). Age and sex had no influence on volumetric data. The Aquaporin 4-31G > A SNP had a significant influence on the ETR (p = 0.042) by decreasing the measured edema compared with the tumor volume. The Interleukin 8-251A > T SNP was significantly correlated with an increased tumor (p = 0.048), PTE (p = 0.033) and necrosis volume (p = 0.028). We found two SNPs with a distinct impact on pretreatment tumor characteristics, presenting a potential explanation for the individual diversity of GBM appearance on MRI and influence on survival.
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Affiliation(s)
- Christian Henker
- Department of Neurosurgery, University Hospital Rostock, Schillingallee 35, 18057, Rostock, Germany.
| | - Thomas Kriesen
- Department of Neurosurgery, University Hospital Rostock, Schillingallee 35, 18057, Rostock, Germany
| | - Katharina Fürst
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Schillingallee 69, 18057, Rostock, Germany
| | - Deborah Goody
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Schillingallee 69, 18057, Rostock, Germany
| | - Änne Glass
- Institute for Biostatistics and Informatics in Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany
| | - Brigitte M Pützer
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Schillingallee 69, 18057, Rostock, Germany
| | - Jürgen Piek
- Department of Neurosurgery, University Hospital Rostock, Schillingallee 35, 18057, Rostock, Germany
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