NI-13 Prediction of outcome at the time of discontinuing TMZ-adjuvant therapy in IDH-mutant lower grade glioma using 11C-methinine PET

Abstract Purpose: This study aimed to clarify whether positron emission tomography with 11C-methyl-L-methionine (11C-met PET) can predict consequential outcomes at the time of discontinuing temozolomide (TMZ)-adjuvant chemotherapy in patients with residual isocitrate dehydrogenase gene (IDH)-mutant lower-grade glioma.Methods: In 30 patients showing residual lesions of IDH-mutant lower grade glioma (16 with diffuse astrocytoma and 14 with anaplastic astrocytoma), we performed 11C-met PET, and calculated the tumor-to-normal brain tissue ratio of standardized uptake values (SUVT/N) at the time of discontinuing TMZ-adjuvant chemotherapy. We determined cutoff values to predict tumor relapse using the receiver operating characteristic curve for various prognostic factors including age, Karnofsky performance scale, number of courses of therapy, residual tumor size, and SUVT/N. The promotor methylation status of O6-methylguanine-DNA methyl-transferase gene (MGMT) was assessed using methylation-specific polymerase chain reaction. Progression-free survival (PFS) was compared between groups divided by cutoff values. Uni- and multivariate analyses were conducted using log-rank testing and Cox regression analysis, respectively.Results: Univariate analysis identified MGMT methylation status (p = 0.04) and an SUVT/N of 1.27 (p = 0.02) as predictors of PFS after TMZ discontinuation. In multivariate analysis, both unmethylated MGMT and SUVT/N ≥ 1.27 remained as strong predictors of unfavorable outcome. Conclusion: The present study suggested that 11C-met PET allows prediction of outcomes comparable to MGMT promotor methylation status at the time of discontinuing TMZ-adjuvant chemotherapy in patients with residual IDH-mutant lower-grade glioma.

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Fractal analysis of 11C-methionine PET in patients with newly diagnosed glioma

EJNMMI Physics ◽

10.1186/s40658-021-00418-y ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Yukito Maeda ◽

Yuka Yamamoto ◽

Takashi Norikane ◽

Katsuya Mitamura ◽

Tetsuhiro Hatakeyama ◽

...

Keyword(s):

Fractal Dimension ◽

Fractal Analysis ◽

Anaplastic Astrocytoma ◽

Idh1 Mutation ◽

Lower Grade ◽

Diffuse Astrocytoma ◽

Newly Diagnosed ◽

Mutation Status ◽

Lower Grade Glioma ◽

Met Pet

Abstract Background The present study tested the possible utility of fractal analysis from l-[methyl-11C]-methionine (MET) uptake in patients with newly diagnosed gliomas for differentiating glioma, especially in relation to isocitrate dehydrogenase 1 (IDH1) mutation status, and as compared with the conventional standardized uptake value (SUV) parameters. Methods Investigations of MET PET/CT were performed retrospectively in 47 patients with newly diagnosed glioma. Tumors were divided into three groups: lower grade glioma (IDH1-mutant diffuse astrocytoma and IDH1-mutant anaplastic astrocytoma), higher grade glioma (IDH1-wildtype diffuse astrocytoma and IDH1-wildtype anaplastic astrocytoma), and glioblastoma. The fractal dimension for tumor, maximum SUV (SUVmax) for tumor (T) and mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) and total lesion MET uptake (TLMU) were also measured. Results There were significant differences in SUVmax (p = 0.006) and T/N ratio (p = 0.02) between lower grade glioma and glioblastoma. There were no significant differences among any of the three groups in MTV or TLMU. Significant differences were obtained in the fractal dimension between lower grade glioma and higher grade glioma (p = 0.006) and glioblastoma (p < 0.001). Conclusions The results of this preliminary study in a small patient population suggest that the fractal dimension using MET PET in patients with newly diagnosed gliomas is useful for differentiating glioma, especially in relation to IDH1 mutation status, which has not been possible with SUV parameters.

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NI-19 Use of 11C-methionine PET for decision of discontinuation of adjuvant chemotherapy with temozolomide

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa143.062 ◽

2020 ◽

Vol 2 (Supplement_3) ◽

pp. ii14-ii14

Author(s):

Takaaki Beppu ◽

Yuichi Sato ◽

Toshiaki Sasaki ◽

Kazunori Terasaki ◽

Kuniaki Ogasawara

Keyword(s):

Adjuvant Chemotherapy ◽

Small Sample Size ◽

Standardized Uptake Value ◽

Progression Free Survival ◽

Residual Tumor ◽

Small Sample ◽

Tumor Type ◽

Diffuse Astrocytoma ◽

Significant Difference ◽

Met Pet

Abstract Background: The aim was to clarify whether positron emission tomography with 11C-methyl-L-methionine (met-PET) is useful to decide on discontinuation of TMZ-adjuvant therapy in patients with residual diffuse astrocytic tumor. Methods: Subjects were 44 patients with residual tumor comprising 17 with IDH1-mutant diffuse astrocytoma (DA), 13 with IDH1-mutant anaplastic astrocytoma (AA), and 14 with IDH1-wild glioblastoma (GB). All patients received TMZ-adjuvant chemotherapy (median, 12 courses), and whether to discontinue or continue TMZ-adjuvant chemotherapy was decided on the basis of the tumor-to-normal ratio in standardized uptake value from met-PET (T/N); patients with T/N < 1.6 immediately discontinued TMZ, and patients with T/N > 1.6 were either to continued or discontinued TMZ. Progression-free survival (PFS) was compared between patients with T/N > 1.6 and T/N < 1.6 in each tumor type. Median observation period was 434 days after met-PET scanning. Results: The number of patient who underwent recurrence was 10 in DA, 7 in AA, and 11 in GB. All patients showing T/N > 1.6 underwent tumor recurrence. PFS was significantly longer in patients with T/N < 1.6 than T/N > 1.6 in DA and AA (p < 0.01 in both types), but was no significant difference between 2 groups in GB (p = 0.06). Sixteen of 17 patients (94%) in DA and AA showed recurrence from residual tumor, whereas 4 of 11 patients (36%) in GB showed recurrent tumor at remote regions which were different from residual tumor. Conclusions: The present study suggested that met-PET is beneficial to decide to discontinue adjuvant chemotherapy with TMZ in patients with residual tumors of DA and AA, but not useful for patients with GB. Reasons for unsuccessful results in GB might have been small sample size, failure of establishing the cut off value in T/N, recurrences at remote regions where not be assessed by met-PET.

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The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽

10.1093/neuros/nyab052 ◽

2021 ◽

Author(s):

Peng Wang ◽

Chen Luo ◽

Peng-jie Hong ◽

Wen-ting Rui ◽

Shuai Wu

Keyword(s):

Cox Regression ◽

Progression Free Survival ◽

Extent Of Resection ◽

Lower Grade ◽

Wild Type ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Lower Grade Glioma ◽

Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

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Identification and Validation of an Energy Metabolism-Related lncRNA-mRNA Signature for Lower-Grade Glioma

BioMed Research International ◽

10.1155/2020/3708231 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Jingwei Zhao ◽

Le Wang ◽

Bo Wei

Keyword(s):

Energy Metabolism ◽

Risk Score ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Coexpression Network ◽

Normal Brain ◽

Lower Grade ◽

Prognostic Signature ◽

Lower Grade Glioma ◽

Genome Atlas

Energy metabolic processes play important roles for tumor malignancy, indicating that related protein-coding genes and regulatory upstream genes (such as long noncoding RNAs (lncRNAs)) may represent potential biomarkers for prognostic prediction. This study will develop a new energy metabolism-related lncRNA-mRNA prognostic signature for lower-grade glioma (LGG) patients. A GSE4290 dataset obtained from Gene Expression Omnibus was used for screening the differentially expressed genes (DEGs) and lncRNAs (DELs). The Cancer Genome Atlas (TCGA) dataset was used as the prognosis training set, while the Chinese Glioma Genome Atlas (CGGA) was for the validation set. Energy metabolism-related genes were collected from the Molecular Signatures Database (MsigDB), and a coexpression network was established between energy metabolism-related DEGs and DELs to identify energy metabolism-related DELs. Least absolute shrinkage and selection operator (LASSO) analysis was performed to filter the prognostic signature which underwent survival analysis and nomogram construction. A total of 1613 DEGs and 37 DELs were identified between LGG and normal brain tissues. One hundred and ten DEGs were overlapped with energy metabolism-related genes. Twenty-seven DELs could coexpress with 67 metabolism-related DEGs. LASSO regression analysis showed that 9 genes in the coexpression network were the optimal signature and used to construct the risk score. Kaplan-Meier curve analysis showed that patients with a high risk score had significantly worse OS than those with a low risk score (TCGA: HR=3.192, 95%CI=2.182‐4.670; CGGA: HR=1.922, 95%CI=1.431‐2.583). The predictive accuracy of the risk score was also high according to the AUC of the ROC curve (TCGA: 0.827; CGGA: 0.806). Multivariate Cox regression analyses revealed age, IDH1 mutation, and risk score as independent prognostic factors, and thus, a prognostic nomogram was established based on these three variables. The excellent prognostic performance of the nomogram was confirmed by calibration and discrimination analyses. In conclusion, our findings provided a new biomarker for the stratification of LGG patients with poor prognosis.

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NI-06 MOLECULAR DIAGNOSIS, 11C-METHIONINE UPTAKE AND PROGNOSIS IN GRADE 2 AND 3 GLIOMAS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.119 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii26-ii26

Author(s):

Kaoru Tamura ◽

Yaeko Furuhashi ◽

Motoki Inaji ◽

Daisuke Kobayashi ◽

Takahiro Ogishima ◽

...

Keyword(s):

Who Classification ◽

Genetic Alterations ◽

Normal Brain ◽

Lower Grade ◽

Who Grade ◽

Oligodendroglial Tumors ◽

Integrated Diagnosis ◽

Lower Grade Glioma ◽

Methionine Uptake ◽

Grade 3

Abstract OBJECT The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified 103 consecutive lower grade gliomas using the revised 2016 WHO classification and examined for 11C-methionine uptake and prognosis. METHODS 103 consecutive lower grade glioma patients (Grade 2 in 41 patients, Grade 3 in 62 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. RESULT In the integrated diagnosis, 11 astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The concordance rate with 1p19q co-deletion and ATRX retention was 94.7%. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were 1.83 in Grade 2 and 2.83 in grade 3, which were significantly higher than those in astrocytic tumors with “IDH-mutant” (G2: 1.38, G3:1.62). Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. CONCLUSIONS The results indicated that lower grade glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

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MPC-2 Clinical course and prognosis of lower-grade glioma, IDH wildtype and pTERT mutant

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab159.058 ◽

2021 ◽

Vol 3 (Supplement_6) ◽

pp. vi16-vi16

Author(s):

Yoshinobu Takahashi ◽

Hayato Takeuchi ◽

Seisuke Tanigawa ◽

Takanari Okamoto ◽

Naoya Hashimoto

Keyword(s):

Median Survival ◽

Lower Grade ◽

Diffuse Astrocytoma ◽

Who Grade ◽

Female Ratio ◽

Astrocytic Glioma ◽

Tert Promoter ◽

Lower Grade Glioma ◽

Idh Mutations ◽

Astrocytic Gliomas

Abstract Background and Purpose: In the cIMPACT-Now update 3, it was proposed that grade 2 astrocytic gliomas without IDH-mutations and grade 3 astrocytic gliomas with TERT promoter mutations should be designated as diffuse IDH wildtype astrocytic glioma with molecular features of WHO grade IV glioblastoma. Therefore, we investigated whether this group of tumors actually corresponds to grade IV prognostically in cases that we encountered ourselves. Cases and Methods: Among the 65 patients having primary astrocytic glioma who were operated in our hospital from January 2016 to March 2021, the prognostic values of seven patients with lower-grade glioma, IDH wildtype, and pTERT mutant were investigated. Results: Among the seven patients, the median age was 59 years (50–66 years). Four of them had anaplastic astrocytoma, two had diffuse astrocytoma, and no tumor lesion could be identified upon histological examination for one patient. The male-to-female ratio was 1:6. MGMT methylation was observed in two patients (29%). The median survival was 20 months, with a significantly worse prognosis when compared with lower-grade glioma without the TERT promoter mutation (13 patients: median survival 40 months), but a better prognosis when compared with glioblastoma (45 patients: median survival 13 months) (Log-rank p = 0.0051). Conclusion: Although EGFR amplification, combined whole chromosome 7 gain, and whole chromosome 10 loss were not examined, the prognostic value of lower-grade glioma, IDH wildtype, and pTERT mutant was not as poor as that of glioblastoma. Further investigation is required to confirm whether these groups of tumors should be treated in the same way as grade IV glioblastoma.

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MOMC-3. Hypermethylation and overexpression of HOX genes are poor prognosticators in Lower-Grade Glioma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.013 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii4-ii4

Author(s):

Yasin Mamatjan ◽

Mathew Voisin ◽

Farshad Nassiri ◽

Fabio Moraes ◽

Severa Bunda ◽

...

Keyword(s):

Hox Genes ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

P Value ◽

Low Grade ◽

Lower Grade ◽

Cox Regression Analysis ◽

Hox Gene ◽

Lower Grade Glioma ◽

Diffuse Gliomas

Abstract Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value < 0.0001). The CpG-based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value < 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.

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Adjuvant Chemotherapy is Indicated in Patients with Lower Grade Glioma

Clinical Oncology ◽

10.1016/j.clon.2016.11.006 ◽

2017 ◽

Vol 29 (3) ◽

pp. 141-142 ◽

Cited By ~ 3

Author(s):

N. Brown ◽

T. Carter ◽

P. Mulholland

Keyword(s):

Adjuvant Chemotherapy ◽

Lower Grade ◽

Lower Grade Glioma

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Screening and Identification of Key Biomarkers in Lower Grade Glioma via Bioinformatical Analysis

Applied Bionics and Biomechanics ◽

10.1155/2022/6959237 ◽

2022 ◽

Vol 2022 ◽

pp. 1-12

Author(s):

Fangzhou Guo ◽

Jun Yan ◽

Guoyuan Ling ◽

Hainan Chen ◽

Qianrong Huang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Kegg Pathway ◽

Killer Cell ◽

Gene Clustering ◽

Normal Brain ◽

Lower Grade ◽

Central Nervous System Tumor ◽

Tissue Samples ◽

Lower Grade Glioma ◽

Core Genes

Lower-grade glioma (LGG) is a common type of central nervous system tumor. Due to its complicated pathogenesis, the choice and timing of adjuvant therapy after tumor treatment are controversial. This study explored and identified potential therapeutic targets for lower-grade. The bioinformatics method was employed to identify potential biomarkers and LGG molecular mechanisms. Firstly, we selected and downloaded GSE15824, GSE50161, and GSE86574 from the GEO database, which included 40 LGG tissue and 28 normal brain tissue samples. GEO and VENN software identified of 206 codifference expressed genes (DEGs). Secondly, we applied the DAVID online software to investigate the DEG biological function and KEGG pathway enrichment, as well as to build the protein interaction visualization network through Cytoscape and STRING website. Then, the MCODE plug is used in the analysis of 22 core genes. Thirdly, the 22 core genes were analyzed with UNCLA software, of which 18 genes were associated with a worse prognosis. Fourthly, GEPIA was used to analyze the 18 selected genes, and 14 genes were found to be a significantly different expression between LGGs and normal brain tumor samples. Fifthly, hierarchical gene clustering was used to examine the 14 important gene expression differences in different histologies, as well as analysis of the KEGG pathway. Five of these genes were shown to be abundant in the natural killer cell-mediated cytokines (NKCC) and phagosome pathways. The five key genes that may be affected by the immune microenvironment play a crucial role in LGG development.

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The Solute Carrier Family 7 Genes Are Potential Diagnostic and Prognostic Biomarkers in Lower Grade Glioma

10.21203/rs.3.rs-198130/v1 ◽

2021 ◽

Author(s):

Wentao Liu ◽

Yu Ji ◽

Rijun Ren ◽

Gentang Zhang

Keyword(s):

Gene Expression ◽

Amino Acid ◽

The Cancer Genome Atlas ◽

Normal Brain ◽

Lower Grade ◽

Lower Grade Glioma ◽

Family Gene ◽

Solute Carrier ◽

Genome Atlas ◽

Brain Tissues

Abstract Background: The solute carrier (SLC) 7 family genes are a group of cationic amino acid/glycoprotein transporters and of importance to the maintenance of amino acid nutrition and survival of tumour cells. This study was to investigate the diagnostic values of SLC7 family genes and their associations with overall survival (OS) and relapse-free survival (RFS) in Lower grade glioma (LGG). Methods: SLC7 family gene expression and clinical data were retrieved from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas database. The expression difference of SLC7 family genes was compared between 523 LGG and 1141 normal brain tissues. The associations between gene expression, clinicopathologic factors, patients’ OS and RFS were analysed by various statistical methods in the two datasets. Results: As compared to normal brain tissues, SLC7A10 expression was significantly down-regulated, while SLC7A5, SLC7A7 expression was significantly up-regulated in LGG tissues. Multivariate analysis and validation analysis confirmed that increased SLC7A7 expression was associated with increased mortality (P≤0.001, Odd ratio [OR]:2.66, 95% Confidence interval [CI]: 1.56–4.6). While, increased SLC7A4 and SLC7A14 expression was associated with reduced mortality (P=0.02, OR:0.38, 95% CI: 0.16–0.81; P≤0.001, OR:0.38, 95% CI: 0.21–0.67; respectively). Increased SLC7A11 expression was associated with decreased RFS (P=0.01, OR:0.61, 95% CI: 0.43–0.88). Conclusion: SLC7A5, SLC7A7, SLC7A10 might serve as diagnostic biomarkers in LGG. High SLC7A4, SLC7A7 and SLC7A14 expression is significantly associated with OS. SLC7 family gene expression represents a potentially diagnostic and prognostic biomarker to predict survival in LGG.

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