scholarly journals Pre-operative Neurocognitive Function Was More Susceptible to Decline in Isocitrate Dehydrogenase Wild-Type Subgroups of Lower-Grade Glioma Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhe Zhang ◽  
Zeping Jin ◽  
Xiaojie Yang ◽  
Liang Zhang ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Working Memory ◽  
Isocitrate Dehydrogenase ◽  
Neurocognitive Function ◽  
World Health ◽  
Lower Grade ◽  
Wild Type ◽  
Molecular Subgroups ◽  
Lower Grade Glioma ◽  
Grade Ii ◽  
Grade Iii

Background: Neuropsychological deficits frequently occur in diffuse lower-grade glioma (DLGG) patients, but their relationship with molecular subgroups based on the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) is unclear.Methods: All patients enrolled for this study were divided into different subgroups according to the molecular-integrated 2016 CNS WHO and morphology-centric 2007 CNS WHO to compare their neurocognitive function (NCF) dysfunction. Univariate and multivariate analyses were used to assess the independent factors for NCF decline. The performance of NCF changes for discrimination of IDH and 1p19q status was evaluated by receiver operating characteristic (ROC).Results: There was no significant difference in the clinical characteristics among the molecular and morphologic subgroups. In the molecular subgroups, significant differences in NCF alterations were found in terms of attention function, working memory and executive function in grade II glioma patients; in addition to these changes in NCF, memory function and abstract thinking were also significantly different in grade III glioma patients. The pairwise comparison further confirmed that patients with astrocytoma (A)/anaplastic astrocytoma (AA) with isocitrate dehydrogenase wild-type (IDHwt) glioma were more susceptible to severe cognitive decline in terms of the NCF performance described above. For the morphologic subgroups, only working memory was significantly different in grade III glioma patients. The distribution proportion was significantly different among each subgroup of DLGG (grade II, P = 0.001; grade III, P = 0.002). The proportion of extensive NCF decline (≥5 tests) was 4, 12, and 50% in the IDH mutant oligodendroglioma (IDHm-O), IDHm-A, and IDHwt-A subgroups, and this proportion was 33, 60, and 93% in the IDHm-AO, IDHm-AA, and IDHwt-AA subgroups, respectively. In multivariate regression analysis, molecular types were independent factors for NCF alterations after adjusted the factors of tumor and demographics (p < 0.05). ROC curves suggested combined NCF tests model showed an advantage in the differentiation of IDH status.Conclusions: NCF alteration is closely related to molecular-integrated subgroups with varying degrees and frequencies in DLGG. Patients with IDHwt gliomas are more susceptible to suffer from severe and extensive NCF decline than other subgroups.

scholarly journals Huge heterogeneity in survival in a subset of adult patients with resected, wild-type isocitrate dehydrogenase status, WHO grade II astrocytomas

2019 ◽  
Vol 130 (4) ◽  
pp. 1289-1298 ◽  
Author(s):  
Gaëtan Poulen ◽  
Catherine Gozé ◽  
Valérie Rigau ◽  
Hugues Duffau
Keyword(s):  
Radiation Therapy ◽  
Malignant Transformation ◽  
Isocitrate Dehydrogenase ◽  
Adult Patients ◽  
World Health ◽  
Wild Type ◽  
Who Grade ◽  
Grade Ii ◽  
The Individual

OBJECTIVEWorld Health Organization grade II gliomas are infiltrating tumors that inexorably progress to a higher grade of malignancy. However, the time to malignant transformation is quite unpredictable at the individual patient level. A wild-type isocitrate dehydrogenase (IDH-wt) molecular profile has been reported as a poor prognostic factor, with more rapid progression and a shorter survival compared with IDH-mutant tumors. Here, the oncological outcomes of a series of adult patients with IDH-wt, diffuse, WHO grade II astrocytomas (AII) who underwent resection without early adjuvant therapy were investigated.METHODSA retrospective review of patients extracted from a prospective database who underwent resection between 2007 and 2013 for histopathologically confirmed, IDH-wt, non–1p19q codeleted AII was performed. All patients had a minimum follow-up period of 2 years. Information regarding clinical, radiographic, and surgical results and survival were collected and analyzed.RESULTSThirty-one consecutive patients (18 men and 13 women, median age 39.6 years) were included in this study. The preoperative median tumor volume was 54 cm3 (range 3.5–180 cm3). The median growth rate, measured as the velocity of diametric expansion, was 2.45 mm/year. The median residual volume after surgery was 4.2 cm3 (range 0–30 cm3) with a median volumetric extent of resection of 93.97% (8 patients had a total or supratotal resection). No patient experienced permanent neurological deficits after surgery, and all patients resumed a normal life. No immediate postoperative chemotherapy or radiation therapy was given. The median clinical follow-up duration from diagnosis was 74 months (range 27–157 months). In this follow-up period, 18 patients received delayed chemotherapy and/or radiotherapy for tumor progression. Five patients (16%) died at a median time from radiological diagnosis of 3.5 years (range 2.6–4.5 years). Survival from diagnosis was 77.27% at 5 years. None of the 21 patients with a long-term follow-up greater than 5 years have died. There were no significant differences between the clinical, radiological, or molecular characteristics of the survivors relative to the patients who died.CONCLUSIONSHuge heterogeneity in the survival data for a subset of 31 patients with resected IDH-wt AII tumors was observed. These findings suggest that IDH mutation status alone is not sufficient to predict risk of malignant transformation and survival at the individual level. Therefore, the therapeutic management of AII tumors, in particular the decision to administer early adjuvant chemotherapy and/or radiation therapy following surgery, should not solely rely on routine molecular markers.

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.

Frequent Diagnostic Under-Grading in Isocitrate Dehydrogenase Wild-Type Gliomas due to Small Pathological Tissue Samples

Neurosurgery ◽  
2018 ◽  
Vol 85 (5) ◽  
pp. 689-694 ◽  
Author(s):  
Marielena Gutt-Will ◽  
Michael Murek ◽  
Christa Schwarz ◽  
Ekkehard Hewer ◽  
Sonja Vulcu ◽  
...  
Keyword(s):  
Sample Size ◽  
Isocitrate Dehydrogenase ◽  
Permutation Test ◽  
World Health ◽  
Wild Type ◽  
Sample Sizes ◽  
Who Grade ◽  
Tissue Samples ◽  
Significant Difference ◽  
Grade Ii

Abstract BACKGROUND In contrast to isocitrate dehydrogenase (IDH) mutation analysis, which is homogenous within a given tumor, diagnostic errors in histological analysis following the 2016 World Health Organization (WHO) classification could be due to small samples because of histological heterogeneity. OBJECTIVE To assess whether the sample size sent to histopathology influences the tumor grading in IDH wild-type gliomas. METHODS Histologically diagnosed WHO grade, sample volume, and preoperative tumor volume data of 111 patients aged who received resection of IDHwt gliomas between January 2007 and December 2015 at our hospital were evaluated. The differences between absolute and relative pathological sample sizes stratified by WHO grade were conducted using One-Way-Permutation-Test. RESULTS With a mean sample size of 10.9 cc, 83.8% of patients were histologically diagnosed as WHO grade IV, while 16.2% of patients with a mean sample size of 2.62 cc were diagnosed as WHO grade II/III. One-Way-Permutation-Test showed a significant difference between absolute tissue samples stratified by WHO grade (P = .0374). The distribution of preoperative tumor volumes with WHO grade IV vs WHO grade II/III showed no significant difference (P = .8587). Of all tumors with a sample size >10 cc 100% were pathologically diagnosed as WHO grade IV and those with sample size >5 cc 93.5% were diagnosed as WHO grade IV. CONCLUSION Small sample sizes are associated with a higher risk of under-estimating malignancy in histological grading in IDHwt gliomas. This study suggests a standard minimum sample size (>5cc) in every resection. Modalities of adjuvant treatment for IDHwt, WHO grade II/III gliomas need to reflect a prognosis that is only marginally better than of a glioblastoma.

Prognostic role of mitochondrial pyruvate carrier in isocitrate dehydrogenase–mutant glioma

2018 ◽  
Vol 130 (1) ◽  
pp. 56-66 ◽  
Author(s):  
Michael Karsy ◽  
Jian Guan ◽  
L. Eric Huang
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Krebs Cycle ◽  
Lower Grade ◽  
Z Score ◽  
Wild Type ◽  
Data Set ◽  
Kaplan Meier ◽  
Mitochondrial Pyruvate Carrier ◽  
Lower Grade Glioma

OBJECTIVEGliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.METHODSGenomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.RESULTSA total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.CONCLUSIONSThese results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.

scholarly journals MPC-13 The evaluation of the shift of trend in lower grade glioma diagnoses based on each era`s criteria

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi17-vi18
Author(s):  
Eriel Sandika Pareira ◽  
Makoto Shibuya ◽  
Kentaro Ohara ◽  
Yu Nakagawa ◽  
Tokunori Kanazawa ◽  
...  
Keyword(s):  
Molecular Characteristics ◽  
Lower Grade ◽  
Comparative Genome Hybridization ◽  
Diffuse Glioma ◽  
Idh Mutation ◽  
Morphological Criteria ◽  
Lower Grade Glioma ◽  
Sanger Sequence ◽  
Grade Ii ◽  
Grade Iii

Abstract It is found that molecular characteristics in lower grade gliomas (LrGGs) such as codeletion of 1p/19q and IDH mutation was found to be more accurate to predict the patient`s clinical outcome compared to morphological diagnoses alone. Since the revision WHO2016 classification of LrGGs, molecular characteristics were implemented as diagnostic standard for LrGGs diagnoses. In the other hand, morphological diagnostic standard before WHO2016 classification era was determined by different considerations and therapeutic strategies. The malignancy grades were also majorly determined by morphological diagnoses only. This study re-evaluated 20 years of LrGG cases in single institution based on WHO2007 morphological criteria and compared them to the original institutional diagnoses from each era. The study samples were originally grade II-III diffuse glioma-diagnosed cases resected from 1990 to 2016. Biopsy cases were excluded. IDH mutation was analyzed by Sanger sequence and 1p/19 codeletion status was analyzed by Comparative Genome Hybridization (CGH). As the result 93 cases were collected and based on original diagnoses, more than 50% cases are astrocytomas. Compared to re-assessment by morphological diagnoses (WHO 2007), case numbers of astrocytoma diagnoses are decreased whereas oligodendroglioma and oligoastrocytoma case numbers are increased. But, based on WHO2016 criteria, the case number of astrocytomas is again found to be increased. From comparison between original institutional diagnoses and re-assessment results, it is found that there is a shift of trend from astrocytoma to oligodendroglioma and from grade II to grade III. Comparison between morphological diagnoses (WHO2007) and molecular (WHO2016) found that astrocytoma diagnoses remain unchanged meanwhile 45% of oligodendroglioma diagnoses were shifted into astrocytomas. There is a probability that there are high frequency of morphologically diagnosed oligodendroglioma tumors which are having molecular characteristics of astrocytoma. There is a trend that diagnosed grade II LrGGs are actually grade III based on re-assessment diagnosis.

scholarly journals P04.13 Prognostic role of single stranded DNA binding protein 2 in IDH wild type lower grade glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii31-iii31
Author(s):  
Y Chai ◽  
W Liu ◽  
L Hu ◽  
Y Zhang ◽  
P Liang
Keyword(s):  
Prognostic Factors ◽  
Dna Binding ◽  
Cox Regression ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
World Health ◽  
Lower Grade ◽  
Wild Type ◽  
Single Stranded Dna ◽  
Lower Grade Glioma

Abstract Comprehensive and integrative characterizations of genomic analysis including somatic alterations and molecular subtypes of glioma have been established. However, diffuse gliomas (World Health Organization grades II and III, hereafter referred to collectively as lower-grade gliomas,LGG) consist of highly variable clinical behaviors, leading to emerging studies to identify prognostic factors. Through comparative analyses of 516 cases of primary LGG patients from The Cancer Genome Atlas (TCGA) dataset, we reported that the expression level and methylation level of SSBP2 (encoding single stranded DNA-binding protein 2) gene vary among LGG patients and SSBP2 expression or gene body methylation can be served as prognostic biomarkers for LGG survival. Cox regression results confirmed that SSBP2 as an independent predictor of survival in LGG, with a cox coefficient of 0.534 indicating a worse prognosis. Furthermore, lower-grade glioma was statistically ranked first among 21 different cancer types according to the FDR correction. We further investigated the combination of SSBP2 with other known genetic prognostic factors(IDH mutation and 1p19q co-deletion) of LGG. By matching gene expression profile of LGG patients, IDH-mutant gliomas had decreased expression of SSBP2 compared with IDH-wildtype gliomas and 1p19q intact gliomas had increased expression of SSBP2 compared with 1p19q codeletion gliomas. Moreover, we found that the combination of IDH or 1p19q status with SSBP2 identified LGG subsets with significantly diverse survival effects. Patients with low SSBP2 expression had significantly better 5-, 10-, and 15-year OS in IDH wild type, but not in the cohorts of IDH mutant. Our findings offer an explanation for the specificity of SSBP2 effect on survival rate in IDH wild type LGG patients.

What's New in Grade II and Grade III Gliomas?

2018 ◽  
Vol 38 (01) ◽  
pp. 041-049
Author(s):  
Wolfgang Wick ◽  
Julie Miller
Keyword(s):  
World Health ◽  
Metabolic Enzyme ◽  
Disease Entity ◽  
Wild Type ◽  
Preclinical Models ◽  
Isocitrate Dehydrogenase 1 ◽  
Molecular Features ◽  
Grade Ii ◽  
Health Organization ◽  
Grade Iii

AbstractThe majority of World Health Organization grade II and grade III gliomas harbor heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1), and tumors with an IDH wild-type status show molecular features of a glioblastoma and simply may constitute a separate disease entity. This discovery has led to a profound shift in the way that gliomas are classified and, consequently, how treatment decisions are made. We will review the current understanding of IDH-mutant gliomagenesis and the preclinical models being used to investigate the underlying biology of these tumors and to explore new therapeutic options for these patients. We further summarize the results of recent pivotal trials addressing treatment of grade II and grade III gliomas and highlight promising IDH-mutant-specific therapies on the horizon.

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

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