IL-6 significantly correlated with the prognosis in low-grade glioma and the mediating effect of immune microenvironment.

To screen immune-related prognostic biomarkers in low-grade glioma (LGG), and reveal the potential regulatory mechanism. The differential expressed genes (DEGs) between alive and dead patients were initially identified, then the key common genes between DEGs and immune-related genes were obtained. Regarding the key DEGs associated with the overall survival (OS), their clinical value was assessed by Kaplan-Meier, RCS, logistic regression, ROC, and decision curve analysis methods. We also assessed the role of immune infiltration on the association between key DEGs and OS. All the analyses were based on the TGCA-LGG data. Finally, we conducted the molecular docking analysis to explore the targeting binding of key DEGs with the therapeutic agents in LGG. Among 146 DEGs, only interleukin-6 (IL-6) was finally screened as an immune-related biomarker. High expression of IL-6 significantly correlated with poor OS time (all P < .05), showing a linear relationship. The combination of IL-6 with IDH1 mutation had the most favorable prediction performance on survival status and they achieved a good clinical net benefit. Next, we found a significant relationship between IL-6 and immune microenvironment score, and the immune microenvironment played a mediating effect on the association of IL-6 with survival (all P < .05). Detailly, IL-6 was positively related to M1 macrophage infiltration abundance and its biomarkers (all P < .05). Finally, we obtained 4 therapeutic agents in LGG targeting IL-6, and their targeting binding relationships were all verified. IL6, as an immune-related biomarker, was associated with the prognosis in LGG, and it can be a therapeutic target in LGG.

Prognostic relevance of radiological findings on early postoperative MRI for 187 consecutive glioblastoma patients receiving standard therapy.

Several prognostic factors are known to influence survival for patients treated with IDH-wildtype glioblastoma, but unknown factors may remain. We aimed to investigate the prognostic implications of early postoperative MRI findings. A total of 187 glioblastoma patients treated with standard therapy were consecutively included. Patients either underwent a biopsy or surgery followed by an early postoperative MRI. Progression-free survival (PFS) and overall survival (OS) were analysed for known prognostic factors and MRI-derived candidate factors: resection status as defined by the response assessment in neuro-oncology (RANO)-working group (no contrast-enhancing residual tumour, non-measurable contrast-enhancing residual tumour, or measurable contrast-enhancing residual tumour) with biopsy as reference, contrast enhancement patterns (no enhancement, thin linear, thick linear, diffuse, nodular), and the presence of distant tumours. In the multivariate analysis, patients with no contrast-enhancing residual tumour or non-measurable contrast-enhancing residual tumour on the early postoperative MRI displayed a significantly improved progression-free survival compared with patients receiving only a biopsy. Only patients with non-measurable contrast-enhancing residual tumour showed improved overall survival in the multivariate analysis. Contrast enhancement patterns were not associated with survival. The presence of distant tumours was significantly associated with both poor progression-free survival and overall survival and should be considered incorporated into prognostic models.

The effect of somatic mutations in mitochondrial DNA on the survival of patients with primary brain tumors.

AIM: To assess the presence of mitochondrial (mt) DNA somatic mutations, determine the relationship between clinicopathological characteristics and mutations, and assess the survival outcomes in Malay patients with primary brain tumors. METHODS: The study enrolled 54 patients with primary brain tumors. DNA extracted from paired tissue and blood samples was subjected to Sanger sequencing to identify alterations in the entire mtDNA. The associations between clinicopathological characteristics and mutations were evaluated. Cox-regression multivariate analysis was conducted to identify factors significantly associated with survival, and Kaplan-Meier analysis was used to compare the survival of patients with and without mutations. RESULTS: Overall, 29.6% of the patients harbored 19 somatic mutations distributed across 15 loci within the mtDNA. Notably, 36.8% of these mutations were not previously documented in MITOMAP. One newly identified mutation caused a frameshift in the ATPase6 gene, resulting in a premature stop codon. Three mutations were classified as deleterious in the MitImpact2 database. Overall, 1097 mtDNA polymorphisms were identified across 331 different locations. Patients with mutations exhibited significantly shorter survival than patients without mutations. CONCLUSIONS: mtDNA mutations negatively affected the survival outcomes of Malaysian patients with primary brain tumors. However, studies with larger samples are needed to confirm the association between mutation burden and survival rates.

The Father of Wisdom: "The Influence of Surgical Experience on Overall Survival in Patients with Malignant Gliomas".

BACKGROUND: The role of surgery in the management of malignant gliomas has been feverishly deliberated after the publication of the first expansive case series, the last two decades reinvigorating the discussion regarding the value of total removal in improving survivability. Despite numerous technologies being implemented to increase the resection rates of malignant gliomas, the role of surgical experience has been largely overlooked. This article aims to discuss the importance of a single surgeon's experience in treating high-grade gliomas over a period of 20 years. MATERIAL AND METHODS: In order to demonstrate the role of surgical experience, we divided the patients operated by a single neurosurgeon into two distinct intervals: between 2000 and 2009 and between 2012 and 2020, respectively. Only cases with subsequent adjuvant radio-chemotherapy were included. For objective reasons, no technologies that could assist the extent of resection (EOR) such as intraoperative MRI (iMRI) or 5-ALA could be used in the country of our study. Gross total resection was the main goal whenever possible, whereas subtotal removal was defined as a clear remnant on contrasted MRI or CT performed 24-48 h postoperatively. Using the Kaplan-Meier method, we analyzed the survival and disease-free interval of our patients according to age, pathology, and degree of resection. RESULTS: In the 20-year interval of our retrospective study, the main author (ISF) operated 1591 cases of gliomas in a total of 1878 surgeries, including recurrences. The number of high-grade glioma (HGG) patients was 909 (57.10%), 495 of which were male (54.5%) and 414 (45.5%) female. The mean age of the HGG population was 51.9 years. The most common type of HGG subtype were glioblastomas with a total number 620 cases (68.2%). Regarding overall survival (OS), average survival at 12 months was better by 1.6%, and 12.1% improved at 18 months and 17.8% longer at 24 months in the 2012-2020 interval. The mean OS in the earlier interval was 11.00 months compared to the second when it reached 13.441 months (CI, 12.642-14.24). CONCLUSION: Surgical treatment represents a critical step in the multimodal treatment of malignant gliomas. According to our results, surgical experience improves not only overall survival in a manner equivalent to adjuvant chemotherapy but also the quality of life. As such, a special qualification in neurooncology may prove necessary in offering these patients a second chance at life.

Artificial neural network identified a 20-gene panel in predicting immunotherapy response and survival benefits after anti-PD1/PD-L1 treatment in glioblastoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising immunotherapy approach, but glioblastoma clinical trials have not yielded satisfactory results. OBJECTIVE: To screen glioblastoma patients who may benefit from immunotherapy. METHODS: Eighty-one patients receiving anti-PD1/PD-L1 treatment from a large-scale clinical trial and 364 patients without immunotherapy from The Cancer Genome Atlas (TCGA) were included. Patients in the ICI-treated cohort were divided into responders and nonresponders according to overall survival (OS), and the most critical responder-relevant features were screened using random forest (RF). We constructed an artificial neural network (ANN) model and verified its predictive value with immunotherapy response and OS. RESULTS: We defined two groups of ICI-treated glioblastoma patients with large differences in survival benefits as nonresponders (OS ≤6 months, n = 18) and responders (OS ≥17 months, n = 8). No differentially mutated genes were observed between responders and nonresponders. We performed RF analysis to select the most critical responder-relevant features and developed an ANN with 20 input variables, five hidden neurons and one output neuron. Receiver operating characteristic analysis and the DeLong test demonstrated that the ANN had the best performance in predicting responders, with an AUC of 0.97. Survival analysis indicated that ANN-predicted responders had significantly better OS rates than nonresponders. CONCLUSION: The 20-gene panel developed by the ANN could be a promising biomarker for predicting immunotherapy response and prognostic benefits in ICI-treated GBM patients and may guide oncologists to accurately select potential responders for the preferential use of ICIs.

Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer.

OBJECTIVES: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. MATERIALS AND METHODS: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. RESULTS: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively. CONCLUSIONS: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

Identification and validation of anoikis-related genes to clarify the prognosis and immune mechanisms of patients with low-grade glioma.

BACKGROUND: Low-grade glioma (LGG) has an extremely poor prognosis, and the mechanism leading to malignant development has not been determined. The aim of our study was to clarify the function and mechanism of anoikis and TIMP1 in the malignant progression of LGG. METHODS: We screened 7 anoikis-related genes from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to construct a prognostic-predicting model. The study assessed the clinical prognosis, pathological characteristics, and immune cell infiltration in both high- and low-risk groups. Additionally, the potential modulatory effects of TIMP1 on proliferation, migration, and anoikis in LGG were investigated both in vivo and in vitro. RESULTS: In this study, we identified seven critical genes, namely, PTGS2, CCND1, TIMP1, PDK4, LGALS3, CDKN1A, and CDKN2A. Kaplan‒Meier (K‒M) curves demonstrated a significant correlation between clinical features and overall survival (OS), and single-cell analysis and mutation examination emphasized the heterogeneity and pivotal role of hub gene expression imbalances in LGG development. Immune cell infiltration and microenvironment analysis further elucidated the relationships between key genes and immune cells. In addition, TIMP1 promoted the malignant progression of LGG in both in vitro and in vivo models. CONCLUSIONS: This study confirmed that TIMP1 promoted the malignant progression of LGG by inhibiting anoikis, providing insights into LGG pathogenesis and potential therapeutic targets.

Diffusion- and Perfusion-Weighted MRI Radiomics for Survival Prediction in Patients with Lower-Grade Gliomas.

PURPOSE: Lower-grade gliomas of histologic grades 2 and 3 follow heterogenous clinical outcomes, which necessitates risk stratification. This study aimed to evaluate whether diffusion-weighted and perfusion-weighted MRI radiomics allow overall survival (OS) prediction in patients with lower-grade gliomas and investigate its prognostic value. MATERIALS AND METHODS: In this retrospective study, radiomic features were extracted from apparent diffusion coefficient, relative cerebral blood volume map, and Ktrans map in patients with pathologically confirmed lower-grade gliomas (January 2012-February 2019). The radiomics risk score (RRS) calculated from selected features constituted a radiomics model. Multivariable Cox regression analysis, including clinical features and RRS, was performed. The models' integrated area under the receiver operating characteristic curves (iAUCs) were compared. The radiomics model combined with clinical features was presented as a nomogram. RESULTS: The study included 129 patients (median age, 44 years; interquartile range, 37-57 years; 63 female): 90 patients for training set and 39 patients for test set. The RRS was an independent risk factor for OS with a hazard ratio of 6.01. The combined clinical and radiomics model achieved superior performance for OS prediction compared to the clinical model in both training (iAUC, 0.82 vs. 0.72, p=0.002) and test sets (0.88 vs. 0.76, p=0.04). The radiomics nomogram combined with clinical features exhibited good agreement between the actual and predicted OS with C-index of 0.83 and 0.87 in the training and test sets, respectively. CONCLUSION: Adding diffusion- and perfusion-weighted MRI radiomics to clinical features improved survival prediction in lower-grade glioma.

Molecular characterization and survival analysis of a cohort of glioblastoma, IDH-wildtype.

Glioblastoma, IDH-wild type, the most common malignant primary central nervous system tumor, represents a formidable challenge in clinical management due to its poor prognosis and limited therapeutic responses. With an evolving understanding of its underlying biology, there is an urgent need to identify prognostic molecular groups that can be subject to targeted therapy. This study established a cohort of 124 sequential glioblastomas from a tertiary hospital and aimed to find correlations between molecular features and survival outcomes. Comprehensive molecular characterization of the cohort revealed prevalent alterations as previously described, such as TERT promoter mutations and involvement of the PI3K-Akt-mTOR, CK4/6-CDKN2A/B-RB1, and p14ARF-MDM2-MDM4-p53 pathways. MGMT promoter methylation is a significant predictor of improved overall survival, aligned with previous data. Conversely, age showed a marginal association with higher mortality. Multivariate analysis to account for the effect of MGMT promoter methylation and age showed that, in contrast to other published series, this cohort demonstrated improved survival for tumors harboring PTEN mutations, and that there was no observed difference for most other molecular alterations, including EGFR amplification, RB1 loss, or the coexistence of EGFR amplification and deletion/exon skipping (EGFRvIII). Despite limitations in sample size, this study contributes data to the molecular landscape of glioblastomas, prompting further investigations to examine these findings more closely in larger cohorts.

Improved outcomes for triple negative breast cancer brain metastases patients after stereotactic radiosurgery and new systemic approaches.

PURPOSE: Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS: We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS: Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS: TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.

Prognosis versus Actual Outcomes in Stereotactic Radiosurgery of Brain Metastases: Reliability of Common Prognostic Parameters and Indices.

This study aims to evaluate the clinical outcome of stereotactic radiosurgery as the sole treatment for brain metastases and to assess prognostic factors influencing survival. A total of 108 consecutive patients with 213 metastases were retrospectively analyzed. Treatment was determined with close-meshed MRI follow-up. Various prognostic factors were assessed, and several prognostic indices were compared regarding their reliability to estimate overall survival. Median overall survival was 15 months; one-year overall survival was 50.5%. Both one- and two-year local controls were 90.9%. The rate of new metastases after SRS was 49.1%. Multivariate analysis of prognostic factors revealed that the presence of extracranial metastases, male sex, lower KPI, and progressive extracranial disease were significant risk factors for decreased survival. Of all evaluated prognostic indices, the Basic Score for Brain Metastases (BSBMs) showed the best correlation with overall survival. A substantial survival advantage was found for female patients after SRS when compared to male patients (18 versus 9 months, p = 0.003). SRS of brain metastasis is a safe and effective treatment option when frequent monitoring for new metastases with MRI is performed. Common prognostic scores lack reliable estimation of survival times. Female sex should be considered as an additional independent positive prognostic factor influencing survival.

Supramaximal resection: retrospective study on IDH-wildtype Glioblastomas based on the new RANO-Resect classification.

BACKGROUND: The prognostic value of the extent of resection in the management of Glioblastoma is a long-debated topic, recently widened by the 2022 RANO-Resect Classification, which advocates for the resection of the non-enhancing disease surrounding the main core of tumors (supramaximal resection, SUPR) to achieve additional survival benefits. We conducted a retrospective analysis to corroborate the role of SUPR by the RANO-Resect Classification in a single center, homogenous cohort of patients. METHODS: Records of patients operated for WHO-2021 Glioblastomas at our institution between 2007 and 2018 were retrospectively reviewed; volumetric data of resected lesions were computed and classified by RANO-Resect criteria. Survival and correlation analyses were conducted excluding patients below near-total resection. RESULTS: 117 patients met the inclusion criteria, encompassing 45 near-total resections (NTR), 31 complete resections (CR), and 41 SUPR. Median progression-free and overall survival were 11 and 15 months for NTR, 13 and 17 months or CR, 20 and 24 months for SUPR, respectively (p < 0.001), with inverse correlation observed between survival and FLAIR residual volume (r -0.28). SUPR was not significantly associated with larger preoperative volumes or higher rates of postoperative deficits, although it was less associated with preoperative neurological deficits (OR 3.37, p = 0.003). The impact of SUPR on OS varied between MGMT unmethylated (HR 0.606, p = 0.044) and methylated (HR 0.273, p = 0.002) patient groups. CONCLUSIONS: Results of the present study support the validity of supramaximal resection by the new RANO-Resect classification, also highlighting a possible surgical difference between tumors with methylated and unmethylated MGMT promoter.

Diagnostic and Prognostic Value of Circulating DNA Fragments in Glioblastoma Multiforme Patients.

Novel blood-circulating molecules, as potential biomarkers for glioblastoma multiforme (GBM) diagnosis and monitoring, are attracting particular attention due to limitations of imaging modalities and invasive tissue biopsy procedures. This study aims to assess the diagnostic and prognostic values of circulating cell-free DNA (cfDNA) in relation to inflammatory status in GBM patients and to determine the concentration and average size of DNA fragments typical of tumour-derived DNA fractions. Preoperative plasma samples from 40 patients (GBM 65.0 ± 11.3 years) and 40 healthy controls (HC 70.4 ± 5.4 years) were compared. The cfDNA concentrations and lengths were measured using the electrophoresis platform, and inflammatory indices (NLR, PLR, LMR, and SII) were calculated from complete blood cell analysis. More fragmented cfDNA and 4-fold higher 50-700 bp cfDNA concentrations were detected in GBM patients than in healthy controls. The average cfDNA size in the GBM group was significantly longer (median 336 bp) than in the HC group (median 271 bp). Optimal threshold values were 1265 pg/µL for 50-700 bp cfDNA (AUC = 0.857) and 290 bp for average cfDNA size (AUC = 0.814). A Kaplan-Meier survival curves analysis also demonstrated a higher mortality risk in the GBM group with a cut-off >303 bp cfDNA. This study is the first to have revealed glioblastoma association with high levels of cfDNA > 1000 pg/µL of 50-700 bp in length, which can be aggravated by immunoinflammatory reactivity.

D-Loop Mutations as Prognostic Markers in Glioblastoma-A Pilot Study.

Glioblastoma, a highly aggressive brain tumor, poses significant treatment challenges. A deeper investigation into its molecular complexity is essential for the identification of novel prognostic biomarkers and therapeutic strategies, potentially improving patient outcomes in terms of survival and quality of life. While nuclear DNA mutations have been extensively studied, the role of mitochondrial DNA (mtDNA) mutations, specifically in the D-loop region, remains poorly understood. This prospective case-control study aimed to assess the prognostic significance of the mtDNA D-loop m.16126T>C variant in glioblastoma patients. Immunohistochemistry and droplet digital PCR (ddPCR) were employed for mutation analysis, complemented by statistical analyses and a literature review. The study cohort comprised 22 glioblastoma patients (mean age 59.36 ± 14.17, 12 (54.55%) females), and 25 controls (59.48 ± 13.22, 12 (80%) females). The D-loop m.16126T>C variant was observed in four (18%) of the glioblastoma samples and was associated with shorter median survival (9.5 vs. 18 months; p = 0.016, log-rank test). This study underscores the importance of investigating mtDNA, especially D-loop variants, in glioblastoma, suggesting its potential as a prognostic biomarker and, therefore, its possible therapeutic targets, warranting further exploration.

Survival Outcome Prediction in Glioblastoma: Insights from MRI Radiomics.

Background: Extracting multiregional radiomic features from multiparametric MRI for predicting pretreatment survival in isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients is a promising approach. Methods: MRI data from 49 IDH wild-type glioblastoma patients pre-treatment were utilized. Diffusion and perfusion maps were generated, and tumor subregions segmented. Radiomic features were extracted for each tissue type and map. Feature selection on 1862 radiomic features identified 25 significant features. The Cox proportional-hazards model with LASSO regularization was used to perform survival analysis. Internal and external validation used a 38-patient training cohort and an 11-patient validation cohort. Statistical significance was set at p < 0.05. Results: Age and six radiomic features (shape and first and second order) from T1W, diffusion, and perfusion maps contributed to the final model. Findings suggest that a small necrotic subregion, inhomogeneous vascularization in the solid non-enhancing subregion, and edema-related tissue damage in the enhancing and edema subregions are linked to poor survival. The model's C-Index was 0.66 (95% C.I. 0.54-0.80). External validation demonstrated good accuracy (AUC > 0.65) at all time points. Conclusions: Radiomics analysis, utilizing segmented perfusion and diffusion maps, provide predictive indicators of survival in IDH wild-type glioblastoma patients, revealing associations with microstructural and vascular heterogeneity in the tumor.

Survival prediction in patients with gynecological cancer irradiated for brain metastases.

BACKGROUND AND PURPOSE: This large population-based, retrospective, single-center study aimed to identify prognostic factors in patients with brain metastases (BM) from gynecological cancers. MATERIAL AND METHODS: One hundred and forty four patients with BM from gynecological cancer treated with radiotherapy (RT) were identified. Primary cancer diagnosis, age, performance status, number of BM, presence of extracranial disease, and type of BM treatment were assessed. Overall survival (OS) was calculated using the Kaplan-Meier method and the Cox proportional hazards regression model was used for multivariable analysis. A prognostic index (PI) was developed based on scores from independent predictors of OS. RESULTS: Median OS for the entire study population was 6.2 months. Forty per cent of patients died within 3 months after start of RT. Primary cancer with the origin in cervix or vulva (p = 0.001),  Eastern Cooperative Oncology Group (ECOG) 3-4 (p < 0.001), and the presence of extracranial disease (p = 0.001) were associated with significantly shorter OS. The developed PI based on these factors, categorized patients into three risk groups with a median OS of 13.5, 4.0, and 2.4 months for the good, intermediate, and poor prognosis group, respectively. INTERPRETATION: Patients with BM from gynecological cancers carry a poor prognosis. We identified prognostic factors and developed a scoring tool to select patients with better or worse prognosis. Patients in the high-risk group have a particular poor prognosis, and omission of RT could be considered.

A multi-omics analysis-based model to predict the prognosis of low-grade gliomas.

Lower-grade gliomas (LGGs) exhibit highly variable clinical behaviors, while classic histology characteristics cannot accurately reflect the authentic biological behaviors, clinical outcomes, and prognosis of LGGs. In this study, we carried out analyses of whole exome sequencing, RNA sequencing and DNA methylation in primary vs. recurrent LGG samples, and also combined the multi-omics data to construct a prognostic prediction model. TCGA-LGG dataset was searched for LGG samples. 523 samples were used for whole exome sequencing analysis, 532 for transcriptional analysis, and 529 for DNA methylation analysis. LASSO regression was used to screen genes with significant association with LGG survival from the frequently mutated genes, differentially expressed genes, and differentially methylated genes, whereby a prediction model for prognosis of LGG was further constructed and validated. The most frequently mutated diver genes in LGGs were IDH1 (77%), TP53 (48%), ATRX (37%), etc. Top significantly up-regulated genes were C6orf15, DAO, MEOX2, etc., and top significantly down-regulated genes were DMBX1, GPR50, HMX2, etc. 2077 genes were more and 299 were less methylated in recurrent vs. primary LGG samples. Thirty-nine genes from the above analysis were included to establish a prediction model of survival, which showed that the high-score group had a very significantly shorter survival than the low-score group in both training and testing sets. ROC analysis showed that AUC was 0.817 for the training set and 0.819 for the testing set. This study will be beneficial to accurately predict the survival of LGGs to identify patients with poor prognosis to take specific treatment as early, which will help improve the treatment outcomes and prognosis of LGG.

Simultaneous boost radiotherapy versus conventional dose radiotherapy for patients with newly diagnosed glioblastoma: a multi-institutional analysis.

We compared survival outcomes of high-dose concomitant boost radiotherapy (HDCBRT) and conventional dose radiotherapy (CRT) for newly diagnosed glioblastoma (GB). Patients treated with intensity-modulated radiation therapy for newly diagnosed GB were included. In HDCBRT, specific targets received 69, 60, and 51 Gy in 30 fractions, while 60 Gy in 30 fractions was administered with a standard radiotherapy method in CRT. Overall survival (OS) and progression-free survival (PFS) were compared using the Log-rank test, followed by multivariate Cox analysis. The inverse probability of treatment weighting (IPTW) method was also applied to each analysis. Among 102 eligible patients, 45 received HDCBRT and 57 received CRT. With a median follow-up of 16 months, the median survival times of OS and PFS were 21 and 9 months, respectively. No significant differences were observed in OS or PFS in the Kaplan-Meier analyses. In the multivariate analysis, HDCBRT correlated with improved OS (hazard ratio, 0.49; 95% confidence interval, 0.27-0.90; P = 0.021), and this result remained consistent after IPTW adjustments (P = 0.028). Conversely, dose suppression due to the proximity of normal tissues and IMRT field correlated with worse OS and PFS (P = 0.008 and 0.049, respectively). A prospective study with a stricter protocol is warranted to validate the efficacy of HDCBRT for GB.

Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study.

INTRODUCTION: There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome. MATERIAL AND METHODS: A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors. RESULTS: There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862). CONCLUSIONS: Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.

Clinical role of NDRG2-based methylation status on survival pattern of glioblastoma.

OBJECTIVES: Gliobalstoma is the most common primary brain tumor in adults with an extensive genetic and transcriptional heterogeneity, still identification of the role of DNA methylation, as one of epigenetic alterations, is emerged. Authors aimed to study the clinical role of N-myc downstream-regulated gene 2 (NDRG2) -based methylation among GBM patients versus benign neurological diseases (BND), investigate its prognostic role and its relation with survival outcomes. METHODS: A total of 78 FFPE specimens were recruited as follows: GBM (n = 58) and BND (n = 20) then analyzed for NDRG2 methylation using Methyl II quantitative PCR system. The sensitivity and specificity of methylation was detected using receiver operating characteristic (ROC) curve and the relation with clinicopathological criteria for GBM and response to treatment were studied. Survival patterns; progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier analyses. RESULTS: Mean methylation NDRG2 level was significantly increased in GBM patients as compared to BND and its sensitivity and specificity were 96.55% and 95%, respectively with area under curve (AUC) equals 0.973. Among the clinical characteristic factors, mean methylation level reported significant difference with ECOG and tumor site. Survival out comes revealed that NDRG2 methylation increased with worse PFS and OS at significant level (long rank test X2 = 13.3, p < .0001; and X2 = 7.1, p = .008, respectively). CONCLUSION: Current findings highlight the importance of studying DNA methylation of NDRG2 as a key factor to understand the role of epigenetic alterations in GBM.