Correlation between Promoter Hypermethylation of the O6-Methylguanine-Deoxyribonucleic Acid Methyltransferase Gene and Prognosis in Patients with High-grade Astrocytic Tumors Treated with Surgery, Radiotherapy, and 1-(4-Amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea-based Chemotherapy

Neurosurgery ◽  
2004 ◽  
Vol 54 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Takanori Kamiryo ◽  
Kenji Tada ◽  
Shoji Shiraishi ◽  
Naoki Shinojima ◽  
Masato Kochi ◽  
...  
Keyword(s):  
Survival Time ◽  
Deoxyribonucleic Acid ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Cox Proportional Hazards Model ◽  
Karnofsky Performance Scale ◽  
Relative Role ◽  
High Grade ◽  
Astrocytic Tumors ◽  
Mgmt Promoter

Abstract OBJECTIVE O 6-Methylguanine-deoxyribonucleic acid methyltransferase (MGMT) is a deoxyribonucleic acid repair protein associated with the chemoresistance of chloroethylnitrosoureas. We investigated whether MGMT promoter hypermethylation is associated with prognosis in patients with high-grade astrocytic tumors treated uniformly with surgery, radiotherapy, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-based chemotherapy. METHODS Using the methylation-specific polymerase chain reaction, we assayed promoter hypermethylation of the MGMT gene in tumor deoxyribonucleic acid from 116 adult patients with supratentorial high-grade astrocytic tumors (42 anaplastic astrocytomas [AAs] and 74 glioblastomas multiforme [GBMs]). The Cox proportional hazards model was used in forward stepwise regression to assess the relative role of prognostic factors (i.e., age at surgery, sex, Karnofsky Performance Scale score, extent of surgical resection, methylation status of the MGMT promoter, and association between MGMT promoter methylation and survival). RESULTS MGMT promoter hypermethylation was confirmed in 19 (45.2%) of 42 AA patients and 33 (44.6%) of 74 GBM patients. It was significantly associated with both longer overall and progression-free survival time in AA but not GBM patients. CONCLUSION Our results demonstrate that MGMT promoter hypermethylation is associated with longer survival time in patients with AA who were treated with surgery, radiotherapy, and ACNU-based chemotherapy but not in patients with GBM.

P04.22 Tumor treating fields in high-grade glioma patients: A retrospective single-center study

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii23-ii23
Author(s):  
R Lucaciu ◽  
B Suchorska ◽  
M Wettig ◽  
S Jung ◽  
M Scholz
Keyword(s):  
Promoter Methylation ◽  
Daily Life ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Therapeutic Modality ◽  
High Grade ◽  
Newly Diagnosed ◽  
Non Invasive ◽  
Tumor Treating Fields ◽  
Mgmt Promoter

Abstract BACKGROUND Tumor-treating fields (TTFields) are a modern anti-mitotic, non-invasive therapy for the treatment of patients with recurrent and newly diagnosed glioblastoma multiforme (GBM). In Europe, Optune® recieved in 2015 the CE certification. TTFields are a low-intensity (1–3 V/cm) approved therapeutic modality using a non-invasive application of intermediate frequency (200 kHz) alternating electric fields through four transducer arrays directly applied to the skin. The EF-14 study has shown that the addition of TTFields to temozolomide chemotherapy in patients with newly diagnosed GBM significantly improved overall survival (OS) and progression-free survival (PFS) without additional adverse events, apart from mild to moderate skin irritations (Stupp et al., JAMA 2017). MATERIAL We retrospectively analyzed data from TTFields-treated patients (2015–2020) that were treated at our department. Patient characteristics such as MGMT promoter methylation status, age, and diagnosis, as well as treatment duration and TTFields therapy usage, were evaluated for this study. RESULTS 29 patients were treated with TTFields therapy between 2015 and 2020 at our hospital. Most patients received TTFields as primary treatment together with temozolomide maintenance therapy. In detail, 48% of patients were diagnosed with newly diagnosed GBM, 41% received TTFields therapy after tumor recurrence and 10% were diagnosed with other high-grade gliomas. In summary, patients could integrate TTFields therapy into their daily life and showed high adherence to the therapy.Particularly, one of our patients (with MGMT-promoter methylation positive) receives TTFields therapy now for almost 1229 days (approx. 41 months) and is still on therapy. Additionally, this patient shows a high usage rate of 86% indicating well integration of the therapy into daily life. CONCLUSION Taken together, our data provided the outcomes of using TTFields together with chemotherapy in the treatment of recurrent and newly diagnosed GBM in our department. Therapy with TTFields has been showing to provide significant clinical benefit for GBM patients.

scholarly journals Diagnosis and management of multiple high-grade gliomas: a retrospective study

2019 ◽  
Author(s):  
Yang Gao ◽  
Hui Zheng ◽  
Liangdong Li ◽  
Changshuai Zhou ◽  
Xin Chen ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Survival Time ◽  
Dna Methyltransferase ◽  
Therapeutic Strategies ◽  
Karnofsky Performance Scale ◽  
Subtotal Resection ◽  
Surgical Removal ◽  
High Grade ◽  
Survival Group ◽  
High Grade Gliomas

Abstract Background: Multiple high-grade gliomas (M-HGG) are uncommon lesions in the central nervous system. The management is controversial and the prognosis remains unfavorable. The aim of this study is to identify the characteristics of M-HGG and explore more appropriate therapeutic strategies for patients. Methods: A retrospective study was performed on 15 patients who were treated with M-HGG between August 2016 and March 2018 in our hospital. Clinical data including age, sex, Karnofsky Performance Scale (KPS) scores, number and location of lesions, surgical approach, pathology, adjuvant therapy (radio or chemotherapy) and prognosis were collected. Results: The most frequent position of tumors was temporal lobe, followed by frontal and occipital lobe. Patients who underwent surgical removal (gross total resection or subtotal resection) showed longer survival time than that in biopsy group (p < 0.05). The index of Ki-67 was higher (36.11 ± 1.8 vs 22.33 ± 2.1, p < 0.05) and the KPS score was lower (60.00 ± 2.7 vs 82.86 ± 2.9, p < 0.05) in death group than that in survival group. Two patients presented with different pathological grades: GBM (WHO IV), anaplastic astrocytoma (WHO III). Four patients presenting with methylation of genes of O-6-methylguanine DNA methyltransferase (MGMT) were still alive. No IDH1 mutation was detected in all cases. Eight patients died during follow-up, and the average survival period was 11.2 months. The survival time of living patients was more than 15.9 months. Conclusions: Surgical removal of dominant tumors of M-GBM is recommended, and stereotactic biopsy can achieve pathologic diagnosis if surgical removal is inaccessible. Comprehensive analysis of the clinical features and molecular pathology of multiple gliomas is helpful to find more effective diagnostic and therapeutic strategies.

“Long extended” temozolomide in a selected population  with  not radically resected high-grade gliomas.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12510-e12510
Author(s):  
Gian Paolo Spinelli ◽  
Giuseppe Lo Russo ◽  
Evelina Miele ◽  
Antonio Maria Alberti ◽  
Martina Strudel ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Haematological Toxicity ◽  
Mgmt Promoter Methylation ◽  
Response To Treatment ◽  
High Grade ◽  
Number Of Patients ◽  
Mgmt Promoter ◽  
High Grade Gliomas ◽  
Ecog Ps

e12510 Background: Despite the important progress in the treatment of solid tumors, high grade gliomas (HGGs) remain neoplasm with poor prognosis, especially when are not radically resected. Here we report the results of a selected population treated with standard schedule of Radiotherapy (RT) + Temozolomide (TMZ) followed by TMZ until progression. Methods: From January 2008 to January 2010, 14 newly diagnosed HGG patients, with median age of 50.6 years (range 27-75 yrs), were enrolled at Oncology Unit of S. Maria Goretti Hospital in Latina (University of Rome “Sapienza”). All patients were not radically resected and with ECOG PS=O. Furthermore patients were selected according to O6 Methyl-Guanine-DNA-Methyl Transferase (MGMT) promoter methylation status. Only methylated patients were included in our study. After surgery, patients received standard treatment with TMZ (75 mg/m2) concomitant with RT (60 Gy total dose). After a break of six weeks, Magnetic Resonance Imaging (MRI) was performed and all patients with stable or responsive disease received TMZ (150mg/200mg/m2/d x 5dq 28d) until progression. The response to treatment was evaluated according to RANO criteria Results: In our study the results showed one year overall survival (OS) and progression free survival (PFS) rates of 85,7% and 71,4% respectively. Moreover we observed two years OS rate of 70% and two years PFS rate of 10%. A total of 108 cycles of adjuvant TMZ were administered with average number of 9 per patient (range 1-16). The most frequent side effects observed were haematological toxicity and fatigue. Thrombocytopenia (G2-G3) was observed in 42% of patients, neutropenia (G2-G3), fatigue (G2-G3) and nausea (G2-G3) in 30%, 32% and 25% of patients respectively. Conclusions: Despite the small number of patients, our experience suggests a manageable safety profile and a good efficacy of TMZ until progression in a selected population of patients (HGGs not radically resected, with a good ECOG PS). These data also confirms the literature knowledge, underlining the prognostic positive impact of MGMT promoter methylation in patients with HGG.

scholarly journals ATIM-47. NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi12-vi12 ◽  
Author(s):  
Michael Weller ◽  
David Reardon ◽  
Alba Brandes ◽  
John Sampson ◽  
Paul Mulholland ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Methylation Status ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
Cox Proportional Hazards Model ◽  
Mgmt Methylation ◽  
Open Label ◽  
Mgmt Promoter

Abstract BACKGROUND Current therapies for recurrent glioblastoma provide limited survival benefit. In the open-label, phase 3 CheckMate 143 study (NCT02017717), although the primary endpoint was not met, the median overall survival (mOS) was comparable between nivolumab (anti–PD-1) and bevacizumab in the overall population of patients with glioblastoma at first recurrence after temozolomide chemoradiotherapy (Reardon et al, WFNOS 2017). Exploratory subgroup analyses were conducted to evaluate the association of O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline with mOS. METHODS Prespecified patient subgroups included MGMT promoter status (methylated vs unmethylated) and baseline corticosteroid use (yes [within 5 days of first dose] vs no). FINDINGS: Methylation status was available for 102/184 (55%) nivolumab-treated and 109/185 (59%) bevacizumab-treated patients. Using a multivariable Cox proportional hazards model analysis, no baseline corticosteroid use (HR, 0.59 [95% CI, 0.36–0.95]) and methylated MGMT status (HR, 0.47 [95% CI, 0.29–0.78]) were each associated with longer mOS among nivolumab-treated patients. Among patients with methylated MGMT and no baseline corticosteroid use, mOS was 17.0 months with nivolumab (n=31) and 10.1 months with bevacizumab (n=22; HR, 0.58 [95% CI, 0.30–1.11]). In patients with methylated tumors and baseline corticosteroids, mOS was 7.7 months with nivolumab (n=12) and 13.5 months with bevacizumab (n=17). Among patients with unmethylated tumors and no baseline corticosteroids, mOS was 8.3 months with nivolumab (n=30) and 10.3 months with bevacizumab (n=29). In patients with unmethylated tumors and baseline corticosteroids, mOS was 5.6 months with nivolumab (n=28) and 8.3 months with bevacizumab (n=28). CONCLUSION A trend toward longer mOS with nivolumab was observed in a subgroup of patients with methylated MGMT and no baseline corticosteroid use. These findings suggest that MGMT methylation status and corticosteroid use at baseline could be used to identify patients who may benefit from nivolumab and thus warrant further study.

scholarly journals The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma

Medicina ◽  
2019 ◽  
Vol 55 (2) ◽  
pp. 34
Author(s):  
Nikola Jovanović ◽  
Tatjana Mitrović ◽  
Vladimir J. Cvetković ◽  
Svetlana Tošić ◽  
Jelena Vitorović ◽  
...  
Keyword(s):  
Overall Survival ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Primary Glioblastoma ◽  
Mgmt Promoter ◽  
The Impact

Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter as a key prognostic factor in primary glioblastoma. The aim of our study was to screen Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Materials and methods: A cohort of 30 Serbian primary glioblastoma patients treated with radiation therapy and chemotherapy were analyzed for MGMT promoter methylation and correlated with clinical data. Results: MGMT methylation status was determined in 25 out of 30 primary glioblastomas by methylation-specific PCR (MSP). MGMT promoter hypermethylation was detected in 12 out of 25 patients (48%). The level of MGMT promoter methylation did not correlate with patients’ gender (p = 0.409), age (p = 0.536), and OS (p = 0.394). Treatment with TMZ significantly prolonged the median survival of a patient (from 5 to 15 months; p < 0.001). Conclusions: Due to a small cohort of primary GBM patients, our study is not sufficient for definitive conclusions regarding the prognostic value of MGMT methylation for the Serbian population. Our preliminary data suggest a lack of association between MGMT promoter methylation and overall survival and a significant correlation of TMZ treatment with overall survival. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma.

scholarly journals Prospective Biomarker Study in Newly Diagnosed Glioblastoma: Cyto-C Clinical Trial

2021 ◽  
Author(s):  
Corinne E Griguer ◽  
Claudia R Oliva ◽  
Christopher S Coffey ◽  
Merit E Cudkowicz ◽  
Robin A Conwit ◽  
...  
Keyword(s):  
Survival Time ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Abstract Background Glioblastoma (GBM) has a 5-year survival rate of 3–5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome c oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival time (OS), and the secondary end point was progression-free survival time (PFS). Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a sub-group of GBM patients with improved long term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Analysis of MGMT promoter methylation status in high grade glioma patients with long term and conventional survival times: A retrospective study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2084-2084 ◽  
Author(s):  
M. Preusser ◽  
M. Hassler ◽  
K. Elandt ◽  
E. Gelpi ◽  
J. Hainfellner ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Tumor Tissue ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
High Grade ◽  
Survival Times ◽  
Significant Difference ◽  
Mgmt Promoter ◽  
Methylated Mgmt Promoter

2084 Background: Response to alkylating chemotherapy in patients with high grade gliomas (HGG) has been found correlated to epigenetic silencing of the DNA repair gene MGMT (O6-methylguanine-DNA methyltransferase) in the tumor tissue. Patients with HGG expressing a methylated MGMT promoter benefited from alkylating chemotherapy in terms of a prolonged survival as compared to patients with unmethylated MGMT promoter. Methods: Our study cohort comprised 47 patients with HGG, all treated with concomitant chemotherapy and radiotherapy in our institution. 23/47 patients (8 women, 15 men, aged 22.4–64.5 years, median 36.3) survived longer than 36 months (range of survival times 36–137 months, in median 46.9 months) and were defined as long term survivors (LS). 24/47 patients (5 women and 19 men, aged 18.3–73.3 years, median 47.7) with early tumor relapse who survived in median for 23.5 months were defined as HGG patients with conventional survival (CS). In all cases, we extracted DNA from formalin-fixed and paraffin-embedded tumor tissue samples. The methylation status of the MGMT promoter was determined by bisulfide modification of the DNA and methylation-specific polymerase-chain- reaction (MSP). MSP results were rated by 4 independent observers. Results: There was high interobserver agreement at interpretation of MSP results (range of kappa values: 0.71–0.87). Among LS, we found MGMT promoter methylation in 13/24 (81.5%) patients and an unmethylated MGMT promoter in 3 patients, whereas the MSP results were not interpretable in 7 patients of this patient subgroup. Among CS, we found promoter methylation in 16 patients (66.6%), unmethylated promoter in 6 patients and uninterpretable results in one patient. There was no statistically significant difference in MGMT promoter methylation rate between LS and CS. Conclusions: The proportion of gliomas with methylated MGMT promoter in this series is unexpectedly high, particularly for CS patients. Potential explanations for this finding are methodological differences due to the use of paraffin-embedded tumors instead of frozen tumor material as in most published series and a potential random accumulation of MGMT positive tumors in the patients with CS survival. No significant financial relationships to disclose.

Proliferation-dominant high-grade astrocytoma: survival benefit associated with extensive resection of FLAIR abnormality region

2020 ◽  
Vol 132 (4) ◽  
pp. 998-1005 ◽  
Author(s):  
Haihui Jiang ◽  
Yong Cui ◽  
Xiang Liu ◽  
Xiaohui Ren ◽  
Mingxiao Li ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Characteristic Curve ◽  
Extent Of Resection ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
High Grade ◽  
Extensive Resection ◽  
High Grade Astrocytoma

OBJECTIVEThe aim of this study was to investigate the relationship between extent of resection (EOR) and survival in terms of clinical, molecular, and radiological factors in high-grade astrocytoma (HGA).METHODSClinical and radiological data from 585 cases of molecularly defined HGA were reviewed. In each case, the EOR was evaluated twice: once according to contrast-enhanced T1-weighted images (CE-T1WI) and once according to fluid attenuated inversion recovery (FLAIR) images. The ratio of the volume of the region of abnormality in CE-T1WI to that in FLAIR images (VFLAIR/VCE-T1WI) was calculated and a receiver operating characteristic curve was used to determine the optimal cutoff value for that ratio. Univariate and multivariate analyses were performed to identify the prognostic value of each factor.RESULTSBoth the EOR evaluated from CE-T1WI and the EOR evaluated from FLAIR could divide the whole cohort into 4 subgroups with different survival outcomes (p < 0.001). Cases were stratified into 2 subtypes based on VFLAIR/VCE-T1WIwith a cutoff of 10: a proliferation-dominant subtype and a diffusion-dominant subtype. Kaplan-Meier analysis showed a significant survival advantage for the proliferation-dominant subtype (p < 0.0001). The prognostic implication has been further confirmed in the Cox proportional hazards model (HR 1.105, 95% CI 1.078–1.134, p < 0.0001). The survival of patients with proliferation-dominant HGA was significantly prolonged in association with extensive resection of the FLAIR abnormality region beyond contrast-enhancing tumor (p = 0.03), while no survival benefit was observed in association with the extensive resection in the diffusion-dominant subtype (p=0.86).CONCLUSIONSVFLAIR/VCE-T1WIis an important classifier that could divide the HGA into 2 subtypes with distinct invasive features. Patients with proliferation-dominant HGA can benefit from extensive resection of the FLAIR abnormality region, which provides the theoretical basis for a personalized resection strategy.

Sign in / Sign up

Export Citation Format

Share Document