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

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.

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Feng ◽  
Jinping Zhou ◽  
Lin Zhao ◽  
Xinpeng Wang ◽  
Danyu Ma ◽  
...  

Glioma is a relatively low aggressive brain tumor. Although the median survival time of patients for lower-grade glioma (LGG) was longer than that of patients for glioblastoma, the overall survival was still short. Therefore, it is urgent to find out more effective molecular prognostic markers. The role of the Fam20 kinase family in different tumors was an emerging research field. However, the biological function of Fam20C and its prognostic value in brain tumors have rarely been reported. This study aimed to evaluate the value of Fam20C as a potential prognostic marker for LGG. A total of 761 LGG samples (our cohort, TCGA and CGGA) were included to investigate the expression and role of Fam20C in LGG. We found that Fam20C was drastically overexpressed in LGG and was positively associated with its clinical progression. Kaplan-Meier analysis and a Cox regression model were employed to evaluate its prognostic value, and Fam20C was found as an independent risk factor in LGG patients. Gene set enrichment analysis also revealed the potential signaling pathways associated with Fam20C gene expression in LGG; these pathways were mainly enriched in extracellular matrix receptor interactions, cell adhesion, cell apoptosis, NOTCH signaling, cell cycle, etc. In summary, our findings provide insights for understanding the potential role of Fam20C and its application as a new prognostic biomarker for LGG.


2018 ◽  
Vol 130 (1) ◽  
pp. 56-66 ◽  
Author(s):  
Michael Karsy ◽  
Jian Guan ◽  
L. Eric Huang

OBJECTIVEGliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.METHODSGenomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.RESULTSA total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.CONCLUSIONSThese results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.


2020 ◽  
Vol 14 (12) ◽  
pp. 1127-1137
Author(s):  
Tong-Tong Zhang ◽  
Yi-Qing Zhu ◽  
Hong-Qing Cai ◽  
Jun-Wen Zheng ◽  
Jia-Jie Hao ◽  
...  

Aim: This study aimed to develop an effective risk predictor for patients with stage II and III colorectal cancer (CRC). Materials & methods: The prognostic value of p-mTOR (Ser2448) levels was analyzed using Kaplan–Meier survival analysis and Cox regression analysis. Results: The levels of p-mTOR were increased in CRC specimens and significantly correlated with poor prognosis in patients with stage II and III CRC. Notably, the p-mTOR level was an independent poor prognostic factor for disease-free survival and overall survival in stage II CRC. Conclusion: Aberrant mTOR activation was significantly associated with the risk of recurrence or death in patients with stage II and III CRC, thus this activated proteins that may serve as a potential biomarker for high-risk CRC.


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.


2021 ◽  
Author(s):  
jun wang ◽  
huawei li ◽  
ran xu ◽  
tong lu ◽  
jiaying zhao ◽  
...  

Abstract ObjectiveThe purpose of this paper is to predict the following items. preoperative baseline monocyte-to-lymphocyte ratio (MLR)、neutrophil-to-lymphocyte ratio (NLR) Platura-to-lymphocyte ratio (PLR) and dimeric fibrin fragment D (D-dimer) associated with clinical outcome in patients with Early Lung Cancer (LC).MethodsWe performed a retrospective analysis of 376 patients with LC. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier, and univariate and multivariate Cox regression analyses were performed to identify prognostic factors. Finally, multivariate Cox regression analysis was used to evaluate the influence of favorable factors on patients’ OS and PFS combined with the basic clinical characteristics of the patient ResultsAmong the variables screened by univariate Cox regression, MLR < 0.22, NLR < 1.99, PLR < 130.55 and D-Dimer < 70.5 (ng/ml) were significantly associated with both better OS and PFS. In multivariate Cox regression analysis, it was determined that MLR and D-Dimer had a better independent correlation with OS (p = 0.009, p = 0.05, respectively), while MLR was only better independently associated with PFS (P = 0.005). Furthermore, according to the number of favorable factors, patients with none of these factors had a significantly worse prognosis than patients with at least one of these factors.ConclusionBaseline characteristics of low MLR, low NLR, low PLR and low D-dimer were associated with better outcomes.


2020 ◽  
Author(s):  
Rui Wang ◽  
Zian Feng ◽  
Jie Hu ◽  
Xiaodong He ◽  
Zuojun Shen

Abstract Background: N6-methyladenosine (m6A) RNA modification is the most abundant modification method in mRNA, and it plays an important role in the occurrence and development of many cancers. However, data on the role of m6A RNA methylation regulators in lung adenocarcinoma (LUAD) are still lacking. This paper mainly discusses the role of m6A RNA methylation regulators in LUAD, to identify novel prognostic biomarkers.Methods: The gene expression data of 19 m6A methylation regulator in LUAD patients and its relevant clinical parameters were extracted from The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm were performed to construct a risk signature and evaluated its prognostic prediction efficiency by using the receiver operating characteristic (ROC) curve. The risk score of each patient was calculated according to the risk signature, and LUAD patients were divided into high-risk group and low-risk group. Kaplan-Meier survival analysis and Cox regression analysis were used to identify the independent prognostic significance of risk signature. Finally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore the differential signaling pathways and cellular processes between the two groups.Results: The expression of 15 m6A RNA methylation regulators in LUAD tissues was significantly different than that in normal tissues. YTHDF3, YTHDF2, KIAA1429, HNRNPA2B1, RBM15, METTL3, HNRNPC, YTHDF1, IGF2BP2, IGF2BP3, IGF2BP1 were significantly up-regulated in LUAD, and the expressions of FTO, ZC3H13, WTAP, and METL14 were significantly down-regulated. We selected IGF2BP1, HNRNPC, and HNRNPA2B1 to construct the risk signature. ROC curve indicated the area under the curve (AUC) was 0.659, which means the risk signature had a good prediction efficiency. The results of Kaplan-Meier survival analysis and Cox regression analysis showed that the risk score can be used as an independent prognostic factor for LUAD.Conclusions: The m6A RNA methylation regulators IGF2BP1, HNRNPC, and HNRNPA2B1 have a significant correlation with the clinicopathological characteristics of LUAD, which may be a promising prognostic feature and clinical treatment target.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2043-2043 ◽  
Author(s):  
Giuseppe Lombardi ◽  
Luisa Bellu ◽  
Franco Berti ◽  
Patrizia Farina ◽  
Sara Galuppo ◽  
...  

2043 Background: the optimal management of EP with GBM remains controversial. The role of RT with TMZ for EP is unclear, and EP are often treated with RT alone, TMZ alone or palliative approaches. We describe our experience of combining RT with concurrent TMZ for treatment of EP with GBM Methods: medical records of patients ≥65 years old with newly GBM, histologically confirmed at Veneto Institute of Oncology – Padua, and treated with RT plus TMZ, were reviewed. Concomitant TMZ was 75mg/m2/die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Median progression-free survival(PFS) and overall survival(OS) were estimated with Kaplan-Meier method. Toxicity was scored according to CTCAE 4.0 Results: we analyzed 60 patients(PTS), 34 males and 26 females; the average age was 70 (range 65-82); ECOG PS was 0-1 in 35 PTS and 2 in 25 PTS; complete surgery was performed in 35 PTS, partial surgery in 25 PTS. 40 and 20 PTS received RT within 6 or more weeks (range 7-9) from surgery. MGMT and IDH1 were analyzed in 43 PTS: MGMT methylated in 20 PTS (46%), all PTS had wild-type IDH1. 34 PTS were treated with RT 40Gy in 15 fractions, 26 PTS with RT 60Gy in 30 fractions with no significant difference in ECOG PS, MGMT and type of surgery between the two subgroups. For all PTS, PFS and OS were 9.5 and 12.7 ms, respectively. OS was 13.7 and 12.4 ms (p=0.9) in PTS receiving RT within 6 or more weeks from surgery, respectively. 13% of PTS showed grade 3-4 haematological toxicity, 12% grade 3-4 asthenia, 3% nausea/vomiting. MGMT methylated and complete surgery was associated with a longer survival. PFS was 9 vs 10 months (p=0.4) and OS was 11.7 vs 13.7 ms (p=0.1), for PTS treated with 40Gy and 60Gy, respectively. Regarding toxicity: grade 3-4 haematological toxicity was 9% vs 23%, severe asthenia was 9% vs 15%, nausea/vomiting was 3% vs 4% of PTS receiving RT 40Gy and 60Gy, respectively. Conclusions: RT plus TMZ is effective and safe in EP with GBM and good ECOG PS. PFS and OS was not statistically different between PTS receiving RT 40Gy or 60Gy, although we showed a trend for longer OS with RT 60Gy; in contrast, severe toxicity was higher in PTS with RT 60Gy. OS was similar between PTS receiving RT within 6 or more weeks (7-9ws) from surgery.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15795-e15795 ◽  
Author(s):  
Andrea Wang-Gillam ◽  
Li-Tzong Chen ◽  
Chung-Pin Li ◽  
Gyorgy Bodoky ◽  
Andrew Dean ◽  
...  

e15795 Background: Increased NLR and PLR have been associated with poor survival in several malignancies. Here we report the association of NLR and PLR with overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 trial (NCT01494506), which evaluated nal-IRI+5-FU/LV for the treatment of mPDAC patients (pts) after disease progression following gemcitabine-based therapy. Methods: Pts missing baseline NLR/PLR data were excluded. Medians reflect Kaplan-Meier estimates; hazard ratios (HRs) reflect Cox regression analysis. P values in this exploratory analysis are descriptive. Results: Of 116 evaluable pts in the nal-IRI+5-FU/LV arm, 82 (71%) had NLR ≤5 and 44 (38%) had PLR ≤150 (data cutoff: Nov 16, 2015). Of 105 evaluable pts in the 5-FU/LV control arm, 73 (70%) had NLR ≤5 and 36 (34%) had PLR ≤150. In pts with baseline NLR ≤5 or PLR ≤150, median OS and PFS were significantly longer in the nal-IRI+5-FU/LV treatment arm vs the 5-FU/LV control arm (Table). In pts with baseline NLR >5 or PLR >150, median OS and PFS were numerically longer in the treatment vs control arm, but differences were less compelling (95% CIs for HRs included 1). Conclusions: Median OS and PFS were improved with nal-IRI+5-FU/LV vs 5-FU/LV in pts with baseline NLR ≤5 or PLR ≤150. This exploratory analysis extends the prognostic significance of NLR and PLR to the post-gemcitabine setting. Clinical trial information: NCT01494506. [Table: see text]


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3973-3973
Author(s):  
Annemiek Broyl ◽  
Rowan Kuiper ◽  
Mark van Duin ◽  
Bronno van der Holt ◽  
Laila el Jarari ◽  
...  

Abstract Abstract 3973 Introduction: Cereblon (CRBN) expression has been described to be essential for the activity of Thalidomide and Lenalidomide. This suggests that presence and possibly increased level of CRBN expression would be associated with better outcome in Thalidomide/Lenalidomide treated patients. The aim of this study was to evaluate CRBN expression in relation to outcome in patients receiving Thalidomide maintenance. Patients and methods: The HOVON-65/GMMG-HD4 trial is a multi-center, phase III trial, comparing Bortezomib in induction and post-intensification vs. conventional chemotherapy and daily Thalidomide 50 mg for 2 years post-intensification in newly diagnosed MM patients. This trial demonstrated that Bortezomib during induction and maintenance improved CR and achieved superior PFS and OS (Sonneveld et al., JCO, July 16, 2012). Gene expression profiling was performed at the start of the trial by Affymetrix U133 Plus 2.0 GeneChip, and was available for 96 patients which started Thalidomide maintenance. CRBN expression levels were based on a combined value of probe sets 218142_s_at and 222533_at. CRBN expression was validated using real-time PCR. All survival analyses were performed in SPSS, with survival time taken from the start of maintenance. Results: In patients receiving Thalidomide maintenance, increased CRBN expression was significantly associated with longer progression free survival (p=0.005, hazard ratio = 0.7) and longer overall survival (p=0.04, hazard ratio= 0.7). Using Kaplan-Meier analysis for visualization and using the median expression to define high and low expression, a significant separation was found for PFS (Log rank p=0.009) but not for OS (Log rank p=0.13). No association was observed between CRBN expression and PFS/OS after Bortezomib maintenance (PFS, p=0.4, hazard ratio=1.1; OS, p=0.7, hazard ratio=1.1). Multivariate Cox regression analysis was performed using the covariates ISS, CRBN and high-risk cytogenetics, defined as having del(17p) and/or 1q gain and/or t(4;14). Higher CRBN levels remained significantly related to longer PFS (hazard ratio 0.7, p=0.03), but not OS (hazard ratio of 0.8, p=0.3). High-risk cytogenetics and ISS were both significant in both PFS and OS multivariate models, with hazard ratios of 2.8 and 3.6, for high-risk cytogenetics and 2.5 and 5.5, for ISS stage 3, respectively (p=0.0004, p=0.003, high-risk cytogenetics and p=0.01 and p=0.005, ISS stage 3, respectively). Conclusion: These data suggest use of CRBN as a biomarker for thalidomide outcome, but further analysis in other Thalidomide trials is required to validate this finding. Disclosures: Lokhorst: Genmab: Consultancy. Sonneveld:Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; celgene: Honoraria, Research Funding.


2018 ◽  
Vol 128 (4) ◽  
pp. 1076-1083 ◽  
Author(s):  
Ali A. Alattar ◽  
Michael G. Brandel ◽  
Brian R. Hirshman ◽  
Xuezhi Dong ◽  
Kate T. Carroll ◽  
...  

OBJECTIVEThe available evidence suggests that the clinical benefits of extended resection are limited for chemosensitive tumors, such as primary CNS lymphoma. Oligodendroglioma is generally believed to be more sensitive to chemotherapy than astrocytoma of comparable grades. In this study the authors compare the survival benefit of gross-total resection (GTR) in patients with oligodendroglioma relative to patients with astrocytoma.METHODSUsing the Surveillance, Epidemiology, and End Results (SEER) Program (1999–2010) database, the authors identified 2378 patients with WHO Grade II oligodendroglioma (O2 group) and 1028 patients with WHO Grade III oligodendroglioma (O3 group). Resection was defined as GTR, subtotal resection, biopsy only, or no resection. Kaplan-Meier and multivariate Cox regression survival analyses were used to assess survival with respect to extent of resection.RESULTSCox multivariate analysis revealed that the hazard of dying from O2 and O3 was comparable between patients who underwent biopsy only and GTR (O2: hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.73–1.53; O3: HR 1.18, 95% CI 0.80–1.72). A comprehensive search of the published literature identified 8 articles without compelling evidence that GTR is associated with improved overall survival in patients with oligodendroglioma.CONCLUSIONSThis SEER-based analysis and review of the literature suggest that GTR is not associated with improved survival in patients with oligodendroglioma. This finding contrasts with the documented association between GTR and overall survival in anaplastic astrocytoma and glioblastoma. The authors suggest that this difference may reflect the sensitivity of oligodendroglioma to chemotherapy as compared with astrocytomas.


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