scholarly journals Risk of Venous Thromboembolism in Grade II-IV Gliomas as a Function of Molecular Subtype

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011414
Author(s):  
Maria Diaz ◽  
Jasmin Jo ◽  
Mark Smolkin ◽  
Sarah Jane Ratcliffe ◽  
David Schiff
Keyword(s):  
Venous Thromboembolism ◽  
Promoter Methylation ◽  
Cumulative Incidence ◽  
Molecular Subtype ◽  
Methylation Status ◽  
World Health ◽  
Molecular Testing ◽  
Lower Grade ◽  
Idh Mutation ◽  
Grade Ii

Objective:To determine the incidence of venous thromboembolism (VTE) in lower-grade gliomas (LGG, World Health Organization (WHO) grades II-III) and to stratify the risk of VTE by molecular subtype in gliomas grade II-IV, we performed a retrospective review of a large cohort of glioma patients.Methods:We performed a retrospective analysis of a cohort of 635 adult glioma patients with molecular testing seen at the University of Virginia with a diagnosis of glioma established from January 2005 to August 2017. Estimates of cumulative incidence of VTE were calculated with death as competing risk; significance was determined using the Fine and Gray model.Results:Of 256 LGG patients, 81 were isocitrate dehydrogenase (IDH) wild-type; 113 IDH mutant, 1p/19q codeleted; and 62 IDH mutant, 1p/19q intact. With a median follow-up of 17.9 months, the overall cumulative incidence of VTE was 8.2% for grade II (147 patients), 9.2% for grade III (109 patients), and 30.5% for grade IV (334 patients). In grade II-IV patients, absence of an IDH mutation was associated with a three-fold increase in VTE risk when compared to IDH-mutant patients (HR=3.06, 95% CI=2.03-4.64). In GBM patients, there was no difference in VTE incidence according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.Conclusion:Patients with LGG have a higher VTE risk compared to the general population, which is decreased, but not eliminated, in the presence of an IDH mutation. MGMT promoter methylation in GBM does not affect the incidence of VTE.

scholarly journals P14.23 Risk of venous thromboembolism (VTE) in grade II-IV gliomas as a function of molecular subtype

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii71-iii72
Author(s):  
M Diaz ◽  
J Jo ◽  
D Schiff
Keyword(s):  
Molecular Subtype ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Molecular Testing ◽  
Lower Grade ◽  
Idh Mutation ◽  
Mgmt Methylation ◽  
Who Grade ◽  
Grade Ii ◽  
Grade Iii

Abstract BACKGROUND VTE affects up to 30% of patients with glioblastoma (GBM, WHO grade IV), but little is known about its incidence in lower-grade gliomas (LGG, WHO grade II-III). It has been suggested that isocitrate dehydrogenase (IDH) mutation status dramatically decreases the incidence of VTE in glioma patients, through a combination of F3 promoter hypermethylation leading to lower expression of the procoagulant protein tissue factor, and an increased production of D-2-hydroxyglutarate, which has anticoagulant properties (Unruh et al, 2016). Our objective was to determine the incidence of VTE in LGG and stratify VTE risk by molecular subtype in gliomas grade II-IV. MATERIAL AND METHODS We performed a retrospective analysis of 590 glioma patients with molecular testing seen at our institution (UVa) from January 2005 to August 2017. We divided LGG patients into 3 groups: IDH-wildtype (IDHwt); IDH-mutant (IDHmt), 1p/19q-codeleted; and IDHmt, 1p/19q-intact. GBM patients were divided according to MGMT methylation status. Estimates of cumulative incidence of VTE were calculated with death as competing risk, and significance testing was determined using the Fine and Gray model. RESULTS Of 256 LGG patients (147 grade II and 109 grade III), 81 were IDHwt, 113 IDHmt and 1p/19q-codeleted, and 62 IDHmt and 1p/19q-intact. There were 334 GBM patients, with MGMT methylation status available in 263 (98 (37%) methylated and 165 (63%) unmethylated). With a median follow-up of 545 days, the overall incidence of VTE was 8.2% for grade II, 9.2% for grade III and 30.5% for grade IV. The 6-, 12- and 24-month VTE incidence was 4.1%, 4.8% and 5.4% respectively for grade II, 4.6%, 7.3% and 9.2% for grade III and 23.1%, 26.6% and 29% for grade IV. In LGG patients, VTE incidence was slightly higher in IDHwt tumors (11.1%) vs IDHmt, 1p/19q-codeleted (8.8%) and IDHmt, 1p/19q-intact tumors (4.8%). However, this difference was not statistically significant (IDHwt vs IDHmt, 1p/19q-codeleted, sub-distribution hazard ratio (SHR)=1.67, 95% CI=0.59–4.72; IDHwt vs IDHmt, 1p/19q-intact, SHR=1.87, 95% CI=0.54–6.53). In GBM patients, there was no difference in the VTE incidence according to MGMT methylation status (SHR=0.99, 95% CI=0.64–1.54). CONCLUSION In our cohort, the risk of VTE in GBM patients was consistent with historical data; patients with LGG also had a higher VTE risk compared to the general population. In contrast to other retrospective studies in which the incidence of VTE for grade II-IV IDHmt gliomas was 0% (Unruh et al, 2016; Nazari et al, 2018), our data suggest that VTEs do occur in IDHmt LGG patients, although at a lower rate than in IDHwt. MGMT methylation does not seem to influence the incidence of VTE. VTE risk stratification in GBM patients based on IDH mutation is forthcoming.

Malignant transformation-related genes in meningiomas: allelic loss on 1p36 and methylation status of p73 and RASSF1A

2007 ◽  
Vol 107 (2) ◽  
pp. 398-404 ◽  
Author(s):  
Yukimi Nakane ◽  
Atsushi Natsume ◽  
Toshihiko Wakabayashi ◽  
Sachie Oi ◽  
Motokazu Ito ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Genetic Alterations ◽  
Allelic Loss ◽  
Lower Grade ◽  
Who Grade ◽  
Genetic Fingerprint ◽  
I 11 ◽  
Grade Ii

Object Analysis of meningiomas supports the suggestion that loss of heterozygosity (LOH) of chromosome arm 1p plays an important role in malignancy. The aim of this study was to identify genes related to meningioma progression from the benign state to the atypical and anaplastic states by examining 1p LOH and the promoter methylation of RASSF1A and p73. Methods The authors studied 40 surgical specimens (22 WHO Grade I, 11 Grade II, and seven Grade III) obtained in 37 patients with meningioma. The LOH at 1p36 was analyzed using microsatellite markers, and promoter methylation of p73 and RASSF1A was analyzed using methylation-specific polymerase chain reaction. Results No 1p LOH was detected in the Grade I tumors, whereas it was detected in more than 80% of the Grade II and III tumors. Methylation of the p73 promoter was observed in 81.8 and 71.4% of the Grade II and III tumors, respectively, but it was not observed in any of the Grade I tumors; methylation of the RASSF1A promoter was observed in 18.2, 63.6, and 42.9% of the Grade I, II, and III tumors, respectively. Interestingly, 1p LOH and p73 promoter hyper-methylation were detected in the malignantly transformed tumors but not in the lower-grade primary ones. Conclusions Based on the hypothesis that meningiomas cumulatively acquire genetic alterations and thus progress from the benign to the atypical and anaplastic states, genetic alterations in the methylation status of p73 or RASSF1A along with 1p LOH may result in the malignant transformation of a meningioma. This type of genetic fingerprint may play both diagnostic and therapeutic roles.

scholarly journals IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas

2018 ◽  
Vol 20 (11) ◽  
pp. 1505-1516 ◽  
Author(s):  
Lei Zhang ◽  
Liqun He ◽  
Roberta Lugano ◽  
Kenney Roodakker ◽  
Michael Bergqvist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Lower Grade ◽  
Idh Mutation ◽  
Wild Type ◽  
Who Grade ◽  
Mutation Status ◽  
Grade Ii ◽  
Grade Ii Glioma

Abstract Background Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype. Methods Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro. Results Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro. Conclusion IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

scholarly journals An independently validated survival nomogram for lower-grade glioma

2019 ◽  
Vol 22 (5) ◽  
pp. 665-674 ◽  
Author(s):  
Haley Gittleman ◽  
Andrew E Sloan ◽  
Jill S Barnholtz-Sloan
Keyword(s):  
Health Care ◽  
Brain Tumor ◽  
Health Care Providers ◽  
Molecular Subtype ◽  
Lower Grade ◽  
Newly Diagnosed ◽  
Care Providers ◽  
Lower Grade Glioma ◽  
Grade Ii ◽  
Online Software

Abstract Background Gliomas are the most common primary malignant brain tumor. Diffuse low-grade and intermediate-grade gliomas, which together compose the lower-grade gliomas (LGGs; World Health Organization [WHO] grades II and III), present a therapeutic challenge to physicians due to the heterogeneity of their clinical behavior. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a survival nomogram for patients with newly diagnosed LGG. Methods Data were obtained for newly diagnosed LGG patients from The Cancer Genome Atlas (TCGA) and the Ohio Brain Tumor Study (OBTS) with the following variables: tumor grade (II or III), age at diagnosis, sex, Karnofsky performance status (KPS), and molecular subtype (IDH mutant with 1p/19q codeletion [IDHmut-codel], IDH mutant without 1p/19q codeletion, and IDH wild-type). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using TCGA data and independently validated using the OBTS data. Models were internally validated using 10-fold cross-validation and externally validated with calibration curves. Results A final nomogram was validated for newly diagnosed LGG. Factors that increased the probability of survival included grade II tumor, younger age at diagnosis, having a high KPS, and the IDHmut-codel molecular subtype. Conclusions A nomogram that calculates individualized survival probabilities for patients with newly diagnosed LGG could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software for implementing this nomogram is provided: https://hgittleman.shinyapps.io/LGG_Nomogram_H_Gittleman/. Key Points 1. A survival nomogram for lower-grade glioma patients has been developed and externally validated. 2. Free online software for implementing this nomogram is provided allowing for ease of use by practicing health care providers.

scholarly journals NI-02 THE ASSOCIATION BETWEEN 11C-METHIONINE UPTAKE, IDH GENE MUTATION, AND MGMT PROMOTER METHYLATION IN PATIENTS WITH GRADE II AND III GLIOMAS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii25-ii26
Author(s):  
Yoshiko Okita ◽  
Tomoko Shofuda ◽  
Daisuek Kanematsu ◽  
Ema Yoshioka ◽  
Yoshinori Kodama ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Emission Tomography ◽  
Idh Mutation ◽  
Reliable Prediction ◽  
Positron Emission ◽  
Mgmt Promoter ◽  
Methionine Uptake ◽  
Grade Ii

Abstract AIM We evaluated the association between 11C-methionine positron emission tomography (11C-methionine PET) findings, isocitrate dehydrogenase (IDH) gene mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with grade II and III gliomas. MATERIALS AND METHODS Data were collected from 40 patients with grade II and III gliomas who underwent both magnetic resonance imaging (MRI) and 11C-methionine positron emission tomography (PET) as part of their pre-surgical examination. We examined IDH mutation through DNA sequencing, and MGMT promoter methylation through quantitative methylation-specific polymerase chain reaction (PCR). RESULTS A threshold of MGMT promoter methylation of 1.0% was significantly associated with tumor/normal tissue (T/N) ratio. The T/N ratio in samples with MGMT promoter methylation ≥1.0% was higher than that in samples with MGMT promoter methylation <1.0%, and the difference was statistically significant (p = 0.011). Reliable prediction of MGMT promoter methylation (<1.0% vs ≥1.0%) was possible using the T/N ratio under the receiver operator characteristic (ROC) curve with a sensitivity and specificity of 75% each (cut-off value = 1.6) (p = 0.0226, AUC = 0.76172). Conversely, the T/N ratio had no association with IDH mutation (p = 0.6). The ROC curve revealed no reliable prediction of IDH mutation using the T/N ratio (p = 0.606, AUC = 0.60577). CONCLUSION 11C-methionine PET parameters can predict MGMT promoter methylation but not IDH mutation status. 11C-methionine uptake may have limited potential to reflect DNA methylation processes in grade II and III gliomas.

Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis

2010 ◽  
Vol 120 (6) ◽  
pp. 719-729 ◽  
Author(s):  
Philippe Metellus ◽  
Bema Coulibaly ◽  
Carole Colin ◽  
Andre Maues de Paula ◽  
Alexandre Vasiljevic ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Idh Mutation ◽  
Who Grade ◽  
Dismal Prognosis ◽  
Grade Ii ◽  
Who Grade Ii Gliomas

scholarly journals Intracranial solitary fibrous tumors/hemangiopericytomas: first report of malignant progression

2018 ◽  
Vol 128 (6) ◽  
pp. 1719-1724 ◽  
Author(s):  
Caroline Apra ◽  
Karima Mokhtari ◽  
Philippe Cornu ◽  
Matthieu Peyre ◽  
Michel Kalamarides
Keyword(s):  
Case Series ◽  
Malignant Progression ◽  
World Health ◽  
Low Grade ◽  
Lower Grade ◽  
First Report ◽  
Solitary Fibrous Tumors ◽  
Initial Surgery ◽  
Grade Ii ◽  
Grade Iii

OBJECTIVEMeningeal solitary fibrous tumors/hemangiopericytomas (MSFTs/HPCs) are rare intracranial tumors resembling meningiomas. Their classification was redefined in 2016 by the World Health Organization (WHO) as benign Grade I fibrohyaline type, intermediate Grade II hypercellular type, and malignant highly mitotic Grade III. This grouping is based on common histological features and identification of a common NAB2-STAT6 fusion.METHODSThe authors retrospectively identified 49 cases of MSFT/HPC. Clinical data were obtained from the medical records, and all cases were analyzed according to this new 2016 WHO grading classification in order to identify malignant transformations.RESULTSRecurrent surgery was performed in 18 (37%) of 49 patients. Malignant progression was identified in 5 (28%) of these 18 cases, with 3 Grade I and 2 Grade II tumors progressing to Grade III, 3–13 years after the initial surgery. Of 31 Grade III tumors treated in this case series, 16% (5/31) were proved to be malignant progressions from lower-grade tumors.CONCLUSIONSLow-grade MSFTs/HPCs can transform into higher grades as shown in this first report of such progression. This is a decisive argument in favor of a common identity for MSFT and meningeal HPC. High-grade MSFTs/HPCs tend to recur more often and be associated with reduced overall survival. Malignant progression could be one mechanism explaining some recurrences or metastases, and justifying long-term follow-up, even for patients with Grade I tumors.

scholarly journals Prognostic and Predictive Impact of MGMT Promoter Methylation Status in High Risk Grade 2 Glioma

2021 ◽  
Author(s):  
Waqar Haque ◽  
Caitlyn Teh ◽  
E. Brian Butler ◽  
Bin S. Teh
Keyword(s):  
Overall Survival ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cox Proportional Hazards ◽  
Adjuvant Radiation ◽  
Prognostic Impact ◽  
Mgmt Methylation ◽  
Predictive Values ◽  
Grade Ii ◽  
Grade Ii Glioma

Abstract BackgroundMGMT promoter methylation has been associated with favorable prognosis and survival outcomes in patients with glioblastoma and grade 3 glioma. However, the effects of promoter methylation of MGMT in patients with grade 2 gliomas have not been established. The purpose of the current study is to evaluate the prognostic impact and predictive values of MGMT methylation in patients with grade 2 glioma.MethodsThe National Cancer Database (NCDB) was queried (2004-2016) for patients with newly diagnosed grade 2 glioma. Demographics and clinical characteristics of these patients were examined. Statistics included Kaplan-Meier overall survival (OS) analysis alongside Cox proportional hazards modeling.ResultsA total of 11,223 patients met the selection criteria; 1,252 patients (11%) had MGMT testing. Of the patients who had MGMT testing, 58.5% were MGMT methylated (mMGMT), and 43.5% were MGMT unmethylated (uMGMT). mMGMT patients had greater median overall survival (77.3 months) than both uMGMT patients (42.6 months) and patients with no MGMT status reported (61.9 months (p<0.001 for both). mMGMT was also associated with improved OS, when compared to patients with uMGMT, for patients receiving adjuvant chemoradiation or adjuvant radiation therapy.ConclusionsThis is the largest study to date demonstrating both the prognostic and predictive impact of MGMT methylation on patients with grade II glioma. The current results show that mMGMT is a prognostic factor and possibly a predictive biomarker for grade II glioma patients. MGMT methylation status can be used to determine and stratify patients by risk levels, and thus select patients for treatment intensification.

scholarly journals Predictors of early, recurrent, and intractable seizures in low-grade glioma

2020 ◽  
Author(s):  
Jasmin Jo ◽  
Kathryn Nevel ◽  
Ryan Sutyla ◽  
Mark Smolkin ◽  
M Beatriz Lopes ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
World Health ◽  
Rank Test ◽  
Molecular Testing ◽  
Low Grade ◽  
Idh Mutation ◽  
Who Grade ◽  
Intractable Seizures ◽  
Significant Difference ◽  
Male Sex

Abstract Background Seizures are common among patients with low-grade glioma (LGG) and can significantly affect morbidity. We sought to determine the association between the clinical and molecular factors with seizure incidence and refractoriness in LGG patients. Methods We conducted a retrospective review at the University of Virginia in patients with LGG (World Health Organization, WHO Grade II) evaluated between 2002 and 2015. Descriptive statistics were calculated for variables of interest, and the Kaplan-Meier method was used to estimate survival curves, which were compared with the log-rank test. Results A total of 291 patients were included; 254 had molecular testing performed for presence of an isocitrate dehydrogenase (IDH) mutation and/or 1p/19q codeletion. Sixty-eight percent of patients developed seizures prior to LGG diagnosis; 41% of all patients had intractable seizures. Using WHO 2016 integrated classification, there was no significant difference in seizure frequency during preoperative and postoperative periods or in developing intractable seizures, though a trend toward increased preoperative seizure incidence among patients with the IDH mutation was identified (P = .09). Male sex was significantly associated with higher seizure incidence during preoperative (P &lt; .001) and postoperative periods (P &lt; .001); men were also more likely to develop intractable seizures (P = .01). Conclusions Seizures are common among patients with LGG. Differences in preoperative or postoperative and intractable seizure rates by WHO 2016 classification were not detected. Our data showed a trend toward higher seizure incidence preoperatively in patients with IDH-mutant LGG. We describe a unique association between male sex and seizure incidence and intractability that warrants further study.

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