316 Extent of Resection and MGMT Promotor Methylation Status are Independent Risk Factors in IDH1_R132H Wild-type Primary Glioblastomas

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 268-268
Author(s):  
Florian Gessler ◽  
Anne Braczynski ◽  
Stephanie Tritt ◽  
Peter Baumgarten ◽  
Patrick Harter ◽  
...  

Abstract INTRODUCTION Previous pivotal studies on the influence of extent of resection (EOR) in primary glioblastoma (GBM) have failed to incorporate molecular tumor markers, so the impact of extensive surgical approaches in the light of MGMT methylation and/or IDH mutation status is unclear. METHODS We retrospectively analyzed our prospectively collected database of patients undergoing surgery for newly diagnosed GBM WHO °IV and included only IDH1_R132H wild-type patients. All patients had volumetric assessment of EOR and received adjuvant treatment according to local tumor board recommendation and patient preference. We hypothesized that gross total resection was associated with better outcome. This analysis was approved by our local ethics committee. RESULTS >175 patients (median age: 60 years) were included. Median overall survival (OS) was 18.0 months. MGMT promotor methylation was present in 80 patients (45.7%). Complete removal of contrast-enhancing tissue (CRET) was achieved in 104 patients (59.4%). In Cox regression analysis, both MGMT-promoter methylation (HR 1.55; 95% CI, 1.01-2.19; P = 0.013) and CRET (HR 1.48; 95% CI, 1.06-2.07; P = 0.020) were significantly associated with favorable progression-free survival (PFS). Further, both MGMT promotor methylation (HR 2.13; 95% CI, 1.45-3.12; P = 0.0001) and CRET (HR 1.81; 95% CI, 1.24-2.63; P = 0.002) were independently associated with longer OS. No benefit was seen for resections <99%. Of other risk factors analyzed, only age (>60 vs. <= 60 years) was significantly associated with PFS (HR 1.60; 95% CI, 1.14-2.24; P = 0.006) and OS (HR 2.19; 95% CI, 1.51-3.19; P < 0.0001). No significant outcome differences were observed between non-MGMT methylated patients undergoing CRET, and non-CRET, MGMT methylated patients (PFS: P = 0.726; OS: P = 0.477). CONCLUSION Both CRET and MGMT promotor methylation are independent prognostic factors for improved OS and PFS. Our study incorporates molecular markers and our data highlight the importance of aggressive surgical approaches. If achieved, CRET might compensate for the biological disadvantage of lacking MGMT promotor methylation.

Neurosurgery ◽  
2017 ◽  
Vol 82 (6) ◽  
pp. 808-814 ◽  
Author(s):  
Toral Patel ◽  
Evan D Bander ◽  
Rachael A Venn ◽  
Tiffany Powell ◽  
Gustav Young-Min Cederquist ◽  
...  

Abstract BACKGROUND Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (WHO) grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. OBJECTIVE To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan–Meier method. RESULTS Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {CI} 0.000-0.074] and HR = 0.001 [95% CI 0.00-0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17-4.13] and HR = 2.99 [95% CI 0.15-61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wtLGGs, but the impact on IDH1 mtLGGs requires further study.


Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 293-294 ◽  
Author(s):  
Toral R Patel ◽  
Evan D Bander ◽  
Rachael A Venn ◽  
Tiffany L Powell Avila ◽  
Gustav Y Cederquist ◽  
...  

Abstract INTRODUCTION Accumulating evidence suggests that maximizing extent of resection (EOR) improves outcomes for patients with WHO grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. To answer this question, we evaluated a cohort of patients with surgically-resection WHO grade II gliomas and known IDH1 mutation status, to assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS). METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing surgical resection at a single institution. EOR was assessed with quantitative three-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan-Meier method. RESULTS >52 (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median pre-operative tumor volume was 37.4 cm3 (range: 0.9-190.2 cm3). Median EOR was 57.6% (range: 0.08% 99.3%). Median follow-up was 44.4 months. Malignant progression was identified in 31 patients and 17 patients died. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, Cox regression analysis stratified by IDH status demonstrated that a greater EOR independently prolonged MPFS and OS for wtIDH patients (HR = 0.002 [95% CI 0.000 - 0.074] and HR = 0.001 [95% CI 0.00 - 0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17 - 4.13] and HR = 2.99 [95% CI 0.15 - 61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wild-type LGGs. However, the impact of EOR on IDH1 mutant LGGs is less significant and requires further study.


Neurosurgery ◽  
2021 ◽  
Author(s):  
Peng Wang ◽  
Chen Luo ◽  
Peng-jie Hong ◽  
Wen-ting Rui ◽  
Shuai Wu

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.


2009 ◽  
Vol 31 (6) ◽  
pp. 487-500
Author(s):  
Gayatri Sharma ◽  
Sameer Mirza ◽  
Yi-Hsin Yang ◽  
Rajinder Parshad ◽  
Priya Hazrah ◽  
...  

Background: Methylation-mediated suppression of detoxification, DNA repair and tumor suppressor genes has been implicated in cancer development. This study was designed to investigate the impact of concurrent methylation of multiple genes in breast tumors on disease prognosis.Methods: Methylation specific PCR was carried out to analyze the methylation status of seven genes in archived breast tissues and determine the effect of aberrant methylation of multiple genes on disease prognosis and patients’ survival.Results: Promoter hypermethylation was observed in PRB 67%, ERα 64%, RASSF1A 63%, p16INK4A 51%, PRBβ2 22%, GSTP1 25% and BRCA1 27% of the breast cancers, respectively. Concurrent methylation of BRCA1, ERα, GSTP1 and RARβ2, was observed in a large proportion of breast cancers analyzed, suggesting that these genes do not appear to be methylated alone. Patients with high methylation indices had poor prognosis (p < 0.001, Hazards ratio = 14.58). Cox regression analysis showed RARβ2 promoter methylation to be an independent important determinant of breast cancer prognosis.Conclusions: Our results suggest that methylation of multiple genes plays an important role in prognosis of breast cancer. Our study not only describes the association of methylation mediated silencing of multiple genes with the severity of disease, but also drives to speculate the molecular crosstalk between genes or genetic pathways regulated by them individually.


Gerontology ◽  
2017 ◽  
Vol 64 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Krystyna Krzemień-Wolska ◽  
Andrzej Tomasik ◽  
Celina Wojciechowska ◽  
Karolina Barańska-Pawełczak ◽  
Ewa Nowalany-Kozielska ◽  
...  

Background: The controversy over electrotherapy for patients aged >80 years occurs already at the stage of qualification for this treatment type and concerns optimal device selection, the implantation strategy, and the overall benefit from pacemaker therapy. The group also has a considerable number of cardiovascular risk factors, and the data from the literature on the impact of the pacing mode on the remote prognosis of this group are ambiguous. Objective: Assessment of the risk factors for death among patients with implanted pacemakers >80 years of age in a 4-year follow-up. Methods: The study group consisted of 140 consecutive patients (79 women) aged 84.48 ± 3.65 years with single- or dual-chamber pacemakers implanted >80 years of age because of symptomatic bradycardia. In univariate and multivariate Cox regression analyses, demographic, echocardiographic, and laboratory parameters, pharmacotherapy, and factors related to the implanted device - i.e., indications, pacemaker type, and the implantation position of the tip of the right ventricular lead - were included. The endpoint was death for any reason in a 4-year follow-up. Results: During follow-up, 68 patients (48.6%) died. Although atrial fibrillation with a slow ventricular response constituted 20% of the indications for implantation, 60.8% of the patients received a single-chamber system (VVI/VVIR). In the whole group, the multivariate Cox regression analysis showed both a favourable prognostic significance of DDD pacing system implantation (HR = 0.507; 95% CI: 0.294-0.876) and coexisting hypertension (HR = 0.520; 95% CI: 0.299-0.902). The risk factors were fasting glycaemia (HR = 1.180; 95% CI: 1.038-1.342) and, potentially, female sex (HR = 1.672; 95% CI: 0.988-2.830; p = 0.056). In the female subgroup a more favourable prognosis was related to the use of angiotensin-converting enzyme inhibitors (HR = 0.435; 95% CI: 0.202-0.933) and DDD pacemaker implantation (HR = 0.381; 95% CI: 0.180-0.806). In the male subgroup a more favourable prognosis was related to concerned patients with coexisting hypertension (HR = 0.349; 95% CI: 0.079-0.689). Conclusions: DDD mode pacing seems to serve as a factor which decreases mortality among patients aged >80 years in long-term follow-up. The potentially poorer prognosis for the female patients in this group may result from a combination of the dominant VVI pacing mode, potential propagation of atrial fibrillation, a low proportion of antithrombotic therapy, and sex-related predispositions to thromboembolic complications.


2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi143-vi143
Author(s):  
Toru Umehara ◽  
Hideyuki Arita ◽  
Ema Yoshioka ◽  
Tomoko Shofuda ◽  
Manabu Kinoshita ◽  
...  

Abstract INTRODUCTION Recent studies have reported that NFKBIA deletion (dNFKBIA) was potentially associated with worse prognosis in glioblastoma (GBM) patients. However, no consensus has been reached to its universal prognostic value. Here, we investigated the survival impact of dNFKBIA using two primary IDH wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). Additionally, prognostic impact of a combination of NFKBIA copy number and MGMT methylation status was evaluated. METHOD The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The survival impact of dNFKBIA and/or unmethylated MGMT (uMGMT) were analyzed for 212 KNBTG cases and 265 TCGA cases. The hazard ratio (HR) and p-value were computed using Cox regression analysis. RESULTS dNFKBIA was less frequently observed in KNBTG (47 cases, 22.2%) than in TCGA (84 cases, 31.7%). dNFKBIA was associated with unfavorable prognosis in KNBTG (HR 1.52, p = 0.031), while this was not validated in TCGA (HR 1.14, p=0.406). uMGMT was a common adverse prognostic factor in KNBGT (HR 1.72, p = 0.001) and TCGA (HR 1.50, p = 0.008) cohort. When stratified by NFKBIA status, uMGMT was also associated with shorter survival in NFKBIA deleted cases both in KNBTG (HR 1.87, p = 0.002) and TCGA (HR 1.59, p = 0.014). On the other hand, MGMT status was not significantly associated with prognosis in NFKBIA intact cases in either KNBTG (HR 1.45, p = 0.279) or TCGA (HR 1.55, p = 0.131). DISCUSSION Although the prognostic value of dNFKBIA in IDH wild-type GBM patients was not validated in TCGA cohort, our results indicated that the prognostication based on MGMT methylation was potentially interacted by NFKBIA status.


2022 ◽  
Vol 8 ◽  
Author(s):  
Hongqiang Zhang ◽  
Wending Huang ◽  
Qi Feng ◽  
Wei Sun ◽  
Wangjun Yan ◽  
...  

Objective: To investigate risk factors of local recurrence of synovial sarcoma and the impact of local recurrence on survival.Methods: We retrospectively reviewed clinical data of patients with II to IIIB (AJCC8) synovial sarcoma who underwent surgery at our center between March 2005 and December 2016. Data relating clinicopathological factors, treatment and prognosis were collected. The impact of local recurrence on overall survival (OS), local recurrence-free survival (LRFS), and distant relapse-free survival (DRFS) were analyzed. The prognostic factors associated with local recurrence were also analyzed using Kaplan-Meier Curves and Cox regression analysis.Results: A total of 171 patients were included in this analysis. After a median follow-up of 48 months, 66 patients (38.6%) experienced local recurrence. The 5-year OS, LRFS, and DRFS rates of patients with local recurrence were 37.6, 6.1, and 24.1%, respectively. Multivariate analysis showed that larger initial tumors, multiple recurrences, positive resection margins, marginal resection, and lack of adjuvant therapy were associated with higher local recurrence.Conclusion: Local recurrence of synovial sarcoma is associated with distant metastasis and poor survival. Chemoradiation improves the prognosis of patients with local recurrence, in particular those for which recurrence occurs shortly after initial treatment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Chunmei Zhu ◽  
Shuyuan Zhang ◽  
Di Liu ◽  
Qingqing Wang ◽  
Ningning Yang ◽  
...  

Background: DNA methylation played essential roles in regulating gene expression. The impact of DNA methylation status on the occurrence and development of cancers has been well demonstrated. However, little is known about its prognostic role in breast cancer (BC).Materials: The Illumina Human Methylation450 array (450k array) data of BC was downloaded from the UCSC xena database. Transcriptomic data of BC was downloaded from the Cancer Genome Atlas (TCGA) database. Firstly, we used univariate and multivariate Cox regression analysis to screen out independent prognostic CpGs, and then we identified methylation-associated prognosis subgroups by consensus clustering. Next, a methylation prognostic model was developed using multivariate Cox analysis and was validated with the Illumina Human Methylation27 array (27k array) dataset of BC. We then screened out differentially expressed genes (DEGs) between methylation high-risk and low-risk groups and constructed a methylation-based gene prognostic signature. Further, we validated the gene signature with three subgroups of the TCGA-BRCA dataset and an external dataset GSE146558 from the Gene Expression Omnibus (GEO) database.Results: We established a methylation prognostic signature and a methylation-based gene prognostic signature, and there was a close positive correlation between them. The gene prognostic signature involved six genes: IRF2, KCNJ11, ZDHHC9, LRP11, PCMT1, and TMEM70. We verified their expression in mRNA and protein levels in BC. Both methylation and methylation-based gene prognostic signatures showed good prognostic stratification ability. The AUC values of 3-years, 5-years overall survival (OS) were 0.737, 0.744 in the methylation signature and 0.725, 0.715 in the gene signature, respectively. In the validation groups, high-risk patients were confirmed to have poorer OS. The AUC values of 3 years were 0.757, 0.735, 0.733 in the three subgroups of TCGA dataset and 0.635 in GSE146558 dataset.Conclusion: This study revealed the DNA methylation landscape and established promising methylation and methylation-based gene prognostic signatures that could serve as potential prognostic biomarkers and therapeutic targets.


2021 ◽  
pp. 152660282199672
Author(s):  
Giovanni Tinelli ◽  
Marie Bonnet ◽  
Adrien Hertault ◽  
Simona Sica ◽  
Gian Luca Di Tanna ◽  
...  

Purpose: Evaluate the impact of hybrid operating room (HOR) guidance on the long-term clinical outcomes following fenestrated and branched endovascular repair (F-BEVAR) for complex aortic aneurysms. Materials and Methods: Prospectively collected registry data were retrospectively analyzed to compare the procedural, short- and long-term outcomes of consecutive F-BEVAR performed from January 2010 to December 2014 under standard mobile C-arm versus hybrid room guidance in a high-volume aortic center. Results: A total of 262 consecutive patients, including 133 patients treated with a mobile C-arm equipped operating room and 129 with a HOR guidance, were enrolled in this study. Patient radiation exposure and contrast media volume were significantly reduced in the HOR group. Short-term clinical outcomes were improved despite higher case complexity in the HOR group, with no statistical significance. At a median follow-up of 63.3 months (Q1 33.4, Q3 75.9) in the C-arm group, and 44.9 months (Q1 25.1, Q3 53.5, p=0.53) in the HOR group, there was no statistically significant difference in terms of target vessel occlusion and limb occlusion. When the endograft involved 3 or more fenestrations and/or branches (complex F-BEVAR), graft instability (36% vs 25%, p=0.035), reintervention on target vessels (20% vs 11%, p=0.019) and total reintervention rates (24% vs 15%, p=0.032) were significantly reduced in the HOR group. The multivariable Cox regression analysis did not show statistically significant differences for long-term death and aortic-related death between the 2 groups. Conclusion: Our study suggests that better long-term clinical outcomes could be observed when performing complex F-BEVAR in the latest generation HOR.


2021 ◽  
Vol 20 ◽  
pp. 153303382110279
Author(s):  
Qinping Guo ◽  
Yinquan Wang ◽  
Jie An ◽  
Siben Wang ◽  
Xiushan Dong ◽  
...  

Background: The aim of our study was to develop a nomogram model to predict overall survival (OS) and cancer-specific survival (CSS) in patients with gastric signet ring cell carcinoma (GSRC). Methods: GSRC patients from 2004 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database and randomly assigned to the training and validation sets. Multivariate Cox regression analyses screened for OS and CSS independent risk factors and nomograms were constructed. Results: A total of 7,149 eligible GSRC patients were identified, including 4,766 in the training set and 2,383 in the validation set. Multivariate Cox regression analysis showed that gender, marital status, race, AJCC stage, TNM stage, surgery and chemotherapy were independent risk factors for both OS and CSS. Based on the results of the multivariate Cox regression analysis, prognostic nomograms were constructed for OS and CSS. In the training set, the C-index was 0.754 (95% CI = 0.746-0.762) for the OS nomogram and 0.762 (95% CI: 0.753-0.771) for the CSS nomogram. In the internal validation, the C-index for the OS nomogram was 0.758 (95% CI: 0.746-0.770), while the C-index for the CSS nomogram was 0.762 (95% CI: 0.749-0.775). Compared with TNM stage and SEER stage, the nomogram had better predictive ability. In addition, the calibration curves also showed good consistency between the predicted and actual 3-year and 5-year OS and CSS. Conclusion: The nomogram can effectively predict OS and CSS in patients with GSRC, which may help clinicians to personalize prognostic assessments and clinical decisions.


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