Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2027-2027
Author(s):  
Michael Weller ◽  
Bettina Hentschel ◽  
Matthias Simon ◽  
Manfred Westphal ◽  
Gabriele Schackert ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Molecular Characteristics ◽  
Wild Type ◽  
Who Grade ◽  
Term Survival ◽  
Long Term Survival ◽  
Tp53 Mutations ◽  
Mgmt Promoter

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

scholarly journals Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor

2016 ◽  
Vol 50 (4) ◽  
pp. 394-401 ◽  
Author(s):  
Uros Smrdel ◽  
Mara Popovic ◽  
Matjaz Zwitter ◽  
Emanuela Bostjancic ◽  
Andrej Zupan ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Term Survival ◽  
Long Term Survival ◽  
Survivor Group ◽  
Significant Difference ◽  
Mgmt Promoter ◽  
Term Survivor

Abstract Background In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma. Patients and methods Long-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization). Results Methylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups. Conclusions Molecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored.

scholarly journals Characteristics of glioblastoma long-term survivors

2021 ◽  
Vol 23 (Supplement_4) ◽  
pp. iv15-iv15
Author(s):  
Tamara Ali ◽  
Farouk Olubajo ◽  
Nitika Rathi ◽  
Piyali Pal ◽  
Michael Jenkinson ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Performance Status ◽  
Outcome Data ◽  
Mgmt Promoter Methylation ◽  
Small Subset ◽  
Who Grade ◽  
Number Of Patients ◽  
Mgmt Promoter ◽  
Long Term Survivors

Abstract Aims Glioblastoma (GBM) is the commonest and most aggressive primary malignant brain tumour in adults. A small number of patients survive for &gt;5 years and are referred to as long-term survivors (LTS). This study aimed to quantify and characterise GBM LTS in a single large UK centre. Method A retrospective observational cohort study was performed. Patients diagnosed with GBM in a single UK centre between 2000–2011 (inclusive) who survived &gt;5 years from diagnosis were included. Histopathological samples were re-examined as per the WHO 2016 classification criteria and tested for molecular biomarkers including MGMT promoter methylation, IDH1/2 mutations, 1p19q codeletion and ATRX. Demographic, imaging, treatment and outcome data were collected. Results 1130 patients diagnosed with GBM were identified, 30 of whom survived for &gt;5 years. Twenty-three were re-confirmed as GBM histologically and seven were reclassified as anaplastic oligodendroglioma or anaplastic astroctyoma. Median overall survival for this cohort was 6.2 years. We report a 2% 5-year survival, and a 0.7% 7-year survival. LTS-associated factors were younger age (&lt;65 years old), frontal unilateral tumours, maximal management (surgery and chemoradiotherapy), good post-operative performance status (WHO &lt;2), MGMT promoter methylation and IDH1/2 mutation. Conclusion A small subset of GBM patients survive for &gt;5 years. Most still succumb to the disease, implying 5-year survival is not indicative of a cure. On applying current molecular markers, a quarter of previously diagnosed glioblastoma in this LTS population were revised to be WHO grade III gliomas.

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.

scholarly journals Identification of KRAS G12V associated clonal neoantigens and immune microenvironment in long-term survival of pancreatic adenocarcinoma

2021 ◽  
Author(s):  
Chao Wang ◽  
Min Shi ◽  
Lei Zhang ◽  
Jun Ji ◽  
Ruyan Xie ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Genomic Analysis ◽  
Molecular Characteristics ◽  
Immune Microenvironment ◽  
Term Survival ◽  
Long Term Survival ◽  
Tumor Immune Microenvironment ◽  
Genetic Features ◽  
Multiple Recurrences

Abstract Objective To investigate the molecular characteristics in tumor immune microenvironment that affect long-term survival of patients with pancreatic adenocarcinoma (PAAD). Methods The tumor related genetic features of a female PAAD patient (over 13-year survival) who suffered from multiple recurrences and metastases, and six operations over one decade were investigated deeply. Genomic features and immune microenvironment signatures of her primary lesion as well as six metastatic tumors at different time-points were characterized. Results High-frequency clonal neoantigenic mutations identified in these specimens revealed the significant associations between clonal neoantigens with her prognosis after each surgery. Meanwhile, the TCGA and ICGC databases were employed to analyse the function of KRAS G12V in pancreatic cancer. Conclusions The genomic analysis of clonal neoantigens combined with tumor immune microenvironment could promote the understandings of personalized prognostic evaluation and the stratification of resected PAAD individuals with better outcome.

scholarly journals Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma

2020 ◽  
Vol 22 (8) ◽  
pp. 1162-1172 ◽  
Author(s):  
Antje Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Prognostic Impact ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Mgmt Promoter

Abstract Background O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. Methods This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients &gt;65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. Results In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0–10.0] months for TMZ treatment versus 9.4 [8.1–10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76–1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2–4.1) months vs 4.6 (4.2–5.0) months] did not differ, with HR = 1.02 (0.83–1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9–24.4] mo and 8.5 [6.9–13.3] mo) versus RT (9.6 [6.4–13.7] mo and 4.8 [4.3–6.2] mo, HR 0.44 [0.27–0.70], P &lt; 0.001 for OS and 0.46 [0.29–0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. Conclusion MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2013-2013
Author(s):  
Wolfgang Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Published Data ◽  
Global Methylation ◽  
Methyl Transferase ◽  
Mgmt Promoter

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.

scholarly journals Objective Response to Radiation Therapy and Long-Term Survival of Patients with WHO Grade II Astrocytic Gliomas with Known LOH 1p/19q Status

2007 ◽  
Vol 183 (9) ◽  
pp. 517-522 ◽  
Author(s):  
Ali-Reza Fathi ◽  
Erik Vassella ◽  
Marlene Arnold ◽  
Jürgen Curschmann ◽  
Michael Reinert ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Objective Response ◽  
Who Grade ◽  
Term Survival ◽  
Long Term Survival ◽  
Grade Ii ◽  
Astrocytic Gliomas

scholarly journals The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival

2000 ◽  
Vol 182 (17) ◽  
pp. 4889-4898 ◽  
Author(s):  
Todd P. Primm ◽  
Susan J. Andersen ◽  
Valerie Mizrahi ◽  
David Avarbock ◽  
Harvey Rubin ◽  
...  
Keyword(s):  
Growth Rate ◽  
Mycobacterium Tuberculosis ◽  
Stringent Response ◽  
Wild Type ◽  
Liquid Media ◽  
Term Survival ◽  
Long Term Survival ◽  
Starvation Conditions

ABSTRACT The stringent response utilizes hyperphosphorylated guanine [(p)ppGpp] as a signaling molecule to control bacterial gene expression involved in long-term survival under starvation conditions. In gram-negative bacteria, (p)ppGpp is produced by the activity of the related RelA and SpoT proteins. Mycobacterium tuberculosis contains a single homolog of these proteins (RelMtb) and responds to nutrient starvation by producing (p)ppGpp. A relMtb knockout strain was constructed in a virulent strain of M. tuberculosis, H37Rv, by allelic replacement. The relMtb mutant displayed a significantly slower aerobic growth rate than the wild type in synthetic liquid media, whether rich or minimal. The growth rate of the wild type was equivalent to that of the mutant when citrate or phospholipid was employed as the sole carbon source. These two organisms also showed identical growth rates within a human macrophage-like cell line. These results suggest that the in vivo carbon source does not represent a stressful condition for the bacilli, since it appears to be utilized in a similar RelMtb-independent manner. In vitro growth in liquid media represents a condition that benefits from RelMtb-mediated adaptation. Long-term survival of therelMtb mutant during in vitro starvation or nutrient run out in normal media was significantly impaired compared to that in the wild type. In addition, the mutant was significantly less able to survive extended anerobic incubation than the wild-type virulent organism. Thus, the RelMtb protein is required for long-term survival of pathogenic mycobacteria under starvation conditions.

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