scholarly journals Prognostic effects of O6-Methylguanine DNA methyltransferase promoter hypermethylation in high-grade glioma patients with carmustine wafer implants

2017 ◽  
Vol 50 (2) ◽  
pp. 45
Author(s):  
Kuo-Chen Wei ◽  
Mao-Yu Chen ◽  
Ping-Ching Pai ◽  
ShihMing Jung ◽  
Chi-Cheng Chuang ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
High Grade Glioma ◽  
Promoter Hypermethylation ◽  
High Grade ◽  
Methylguanine Dna Methyltransferase ◽  
Carmustine Wafer

scholarly journals MODL-15. THE COMBINATION TREATMENT OF PARP INHIBITOR AND TMZ, OR DAG WILL BE PROMISING TREATMENT IN SF8628

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii414-iii414
Author(s):  
Shigeo Ohba ◽  
Yuichi Hirose
Keyword(s):  
Combination Treatment ◽  
Dna Methyltransferase ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Adenosine Diphosphate ◽  
Promoter Hypermethylation ◽  
Methylguanine Dna Methyltransferase ◽  
Dna Crosslinks ◽  
Promising Treatment ◽  
Base Excision

Abstract Diffuse midline glioma, H3 K27M-mutant (DMG) is a newly defined entity. The prognosis of DMG is poor. Because surgical resection is often incomplete for DMG, radiotherapy and chemotherapy are important. Temozolomide (TMZ) is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). It has been reported that most of DMG lacked MGMT promoter hypermethylation, which is thought to contribute to less effectiveness of TMZ to DMG. The purpose of the study is to explore the way to inhibit the proliferation of DMG. A DMG cell line, SF8628, was used for the experiments. SF8628 had the expression of MGMT and was revealed to be resistant to TMZ. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of SF8628. As expected, PARP inhibitor enhanced TMZ-induced cytotoxicity in SF8628. Dianhydrogalactiol (DAG) is a bifunctional DNA-targeting agent forming N7-alkylguanine and inter-strand DNA crosslinks. DAG reduced the clonogenicity of SF8628. Moreover, inhibition of homologous recombination enhanced the DAG-induced cytotoxicity in SF8629. The combination treatment of PARP inhibitor and TMZ, or DAG were revealed to be promising treatments in SF8628.

scholarly journals Determining optimal clinical target volume margins in high-grade glioma based on microscopic tumor extension and magnetic resonance imaging

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shulun Nie ◽  
Yufang Zhu ◽  
Jia Yang ◽  
Tao Xin ◽  
Song Xue ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Goodness Of Fit ◽  
Clinical Target Volume ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
High Grade Glioma ◽  
Target Volume ◽  
Tumor Location ◽  
High Grade ◽  
Clinical Trial Registry

Abstract Introduction In this study, we performed a consecutive macropathologic analysis to assess microscopic extension (ME) in high-grade glioma (HGG) to determine appropriate clinical target volume (CTV) margins for radiotherapy. Materials and methods The study included HGG patients with tumors located in non-functional areas, and supratotal resection was performed. The ME distance from the edge of the tumor to the microscopic tumor cells surrounding brain tissue was measured. Associations between the extent of ME and clinicopathological characteristics were evaluated by multivariate linear regression (MVLR) analysis. An ME predictive model was developed based on the MVLR model. Results Between June 2017 and July 2019, 652 pathologic slides obtained from 30 HGG patients were analyzed. The mean ME distance was 1.70 cm (range, 0.63 to 2.87 cm). The MVLR analysis identified that pathologic grade, subventricular zone (SVZ) contact and O6-methylguanine-DNA methyltransferase (MGMT) methylation, isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion status were independent variables predicting ME (all P < 0.05). A multivariable prediction model was developed as follows: YME = 0.672 + 0.513XGrade + 0.380XSVZ + 0.439XMGMT + 0.320XIDH + 0.333X1p/19q. The R-square value of goodness of fit was 0.780. The receiver operating characteristic curve proved that the area under the curve was 0.964 (P < 0.001). Conclusion ME was heterogeneously distributed across different grades of gliomas according to the tumor location and molecular marker status, which indicated that CTV delineation should be individualized. The model could predict the ME of HGG, which may help clinicians determine the CTV for individual patients. Trial registration The trial was registered with Chinese Clinical Trial Registry (ChiCTR2100046106). Registered 4 May 2021-Retrospectively registered.

scholarly journals MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

2020 ◽  
Author(s):  
Barbara Oldrini ◽  
Nuria Vaquero-Siguero ◽  
Quanhua Mu ◽  
Paula Kroon ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Chemotherapy Resistance ◽  
Glioma Cells ◽  
Promoter Hypermethylation ◽  
Dna Adduct ◽  
Genomic Rearrangements ◽  
Low Grade ◽  
Methylguanine Dna Methyltransferase

AbstractTemozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

scholarly journals Survival benefits of hypofractionated radiotherapy combined with temozolomide or temozolomide plus bevacizumab in elderly patients with glioblastoma aged ≥ 75 years

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Makoto Ohno ◽  
Yasuji Miyakita ◽  
Masamichi Takahashi ◽  
Hiroshi Igaki ◽  
Yuko Matsushita ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Dna Methyltransferase ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Promoter Hypermethylation ◽  
Hypofractionated Radiotherapy ◽  
Methylguanine Dna Methyltransferase ◽  
Grade 3

Abstract Background and purpose The purpose of this study was to evaluate the outcomes of elderly patients (aged ≥75 years) with newly diagnosed glioblastoma (GBM), who were treated with hypofractionated radiotherapy comprising 45 Gy in 15 fractions combined with temozolomide (TMZ) or TMZ and bevacizumab (TMZ/Bev). Materials and methods Between October 2007 and August 2018, 30 patients with GBM aged ≥75 years were treated with hypofractionated radiotherapy consisting of 45 Gy in 15 fractions. Twenty patients received TMZ and 10 received TMZ/Bev as upfront chemotherapy. O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed by pyrosequencing. The cutoff value of the mean level of methylation at the 16 CpG sites was 16%. Results Median overall survival (OS) and progression-free survival (PFS) were 12.9 months and 9.9 months, respectively. The 1-year OS and PFS rates were 64.7 and 34.7%, respectively. Median OS and PFS did not differ significantly between patients with MGMT promoter hypermethylation (N = 11) and those with hypomethylation (N = 16) (17.4 vs. 11.8 months, p = 0.32; and 13.1 vs. 7.3 months, p = 0.11, respectively). The median OS and PFS were not significantly different between TMZ (N = 20) and TMZ/Bev (N = 10) chemotherapy (median OS: TMZ 12.9 months vs. TMZ/Bev 14.6 months, p = 0.93, median PFS: TMZ 8.5 months vs TMZ/Bev 10.0 months, p = 0.64, respectively). The median time until Karnofsky performance status (KPS) score decreasing below 60 points was 7.9 months. The best radiological responses included 11 patients with a partial response (36.7%). Grade 3/4 toxicities included leukopenia in 15 patients (50%), anorexia in 4 (13.3%), and hyponatremia during concomitant chemotherapy in 3 (10%). Conclusion Our hypofractionated radiotherapy regimen combined with TMZ or TMZ/Bev showed benefits in terms of OS, PFS, and KPS maintenance with acceptable toxicities in elderly patients with GBM aged ≥75 years.

MGMT (06-methylguanine-DNA methyltransferase) promoter hypermethylation in the context of colorectal cancer.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e14654-e14654
Author(s):  
Elisabeth Luporsi-Gely ◽  
Amandine Cadènes ◽  
Myriam Bronner ◽  
Hélène de Romémont ◽  
Dominique Saint Dizier ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methyltransferase ◽  
Promoter Hypermethylation ◽  
Methylguanine Dna Methyltransferase

High-Grade Glioma Treated With Surgery; Carmustine Wafer; Postoperative Radiation; and Procarbazine, Lomustine, and Vincristine Chemotherapy

2005 ◽  
Vol 15 (3) ◽  
pp. 167-171 ◽  
Author(s):  
Renato LaRocca ◽  
Shawn Glisson ◽  
Jeffrey Hargis ◽  
David Petruska ◽  
Wayne Villanueva ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
High Grade ◽  
Postoperative Radiation ◽  
Carmustine Wafer

scholarly journals Mutually Exclusive Promoter Hypermethylation Patterns of hMLH1 and O6-Methylguanine DNA Methyltransferase in Colorectal Cancer

2006 ◽  
Vol 8 (1) ◽  
pp. 68-75 ◽  
Author(s):  
Edward J. Fox ◽  
Dermot T. Leahy ◽  
Robert Geraghty ◽  
Hugh E. Mulcahy ◽  
David Fennelly ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methyltransferase ◽  
Promoter Hypermethylation ◽  
Methylguanine Dna Methyltransferase
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