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.

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.

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.

Potential value of expression of receptor accessory protein 4 for evaluating the prognosis of lower-grade glioma patients.

BACKGROUND: REEP4 is involved in the regulation of the biological process of mitosis. Lower grade glioma (LGG), as a malignant tumor, is accompanied by abnormalities in mitosis, but there have been no reports of REEP4 so far. METHODS: We collected transcriptome data, DNA methylation data and the clinical characteristics of thousands of patients with LGG. Various big data analysis methods and molecular biology experiments were employed to reveal the impact of REEP4 on the pathological process of LGG. RESULTS: It was found that the expression of REEP4 was significantly elevated and negatively regulated by its methylation site. Therefore, both the high expression of REEP4 and low methylation state of cg16311504 showed that the patients are correlated with lower patient survival rate. In addition, high REEP4 expression participates in the regulation of various cancer-related cellular signaling pathways, such as the cell cycle, MAPK signaling pathway, NOD-like receptor signaling pathway, etc. More importantly, the level of immune cell infiltration significantly increased in the high expression group of REEP4 in the LGG tumor microenvironment and REEP4 has a high positive correlation with PD-L1 and other immune checkpoints. CONCLUSIONS: In brief, this study is the first to introduce REEP4 in malignant tumors, which can be used as an independent risk factor that participates in the malignant process of LGG. More importantly, REEP4 has the potential to become a new star in the field of anti-tumor treatment.

Editorial comment: Radiogenomics of glioblastoma: shifting the focus from tumor cells to immune microenvironment.

KEY POINTS: • The ICI score derived from gene expression profile of immune cells infiltrating GBM correlates with overall survival and is an effective prognostic biomarker.• In this study, the authors developed a radiomics-based machine learning model able to identify gene expression profiles of GBM intratumoral stromal and immune cells and predict the ICI score on the preoperative MRI scans with high accuracy.• Radiogenomics could potentially be applied in primary brain tumors to noninvasively assess the specific tumor immune characteristics, predict patients' prognosis and identify those patients with higher probability to respond to immunotherapy.

Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases.

PURPOSE: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. EXPERIMENTAL DESIGN: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. RESULTS: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1-resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months, with 42% (7/17) remaining on treatment at data cutoff. CONCLUSIONS: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8.

Glioblastomas de larga supervivencia: un análisis sistemático de la literatura a propósito de un caso / Long-term survival of glioblastoma: A systematic analysis of literature about a case

Introducción: A pesar de las modificaciones introducidas en el tratamiento de los glioblastomas a partir del 2005, los pacientes supervivientes de más de 10 años se han mantenido constantes, siendo dicha cifra muy pobre e inferior al 1% en la mayoría de los estudios.Material y métodos: Se realiza un análisis sistemático de la literatura identificando los factores que pueden influir en los pacientes de larga supervivencia. Se identifica un caso en nuestro medio de más de 20 años de supervivencia realizándose un análisis actual del bloque de parafina que se conservaba del paciente.Resultados: La variable que más se asocia a la larga supervivencia en todos los análisis multivariantes es la edad, aunque, cuando se analiza las características genéticas y moleculares de los tumores, parecen existir otras variables como la metilación del promotor MGMT que juegan un papel muy importante. El análisis anatomo-patológico actual de la muestra comprueba la certeza del diagnóstico en nuestro paciente de muy larga supervivencia.Conclusiones: Múltiples variables son encontradas que influencian la larga supervivencia en distintas series, si bien los estudios analizados son muy heterogéneos resultando muy difícil la comparación entre ellos. La mayoría de los estudios referenciados pertenecen a bases de datos nacionales de distintos países que engloban a cientos de pacientes. Sería interesante fomentar el uso de una única base de datos en España que permita, entre otros, el análisis de estos pacientes de larga supervivencia afectos de glioblastoma (AU)

Introduction: In spite of the changes for the treatment of glioblastoma since 2005, we haven’t seen differences between long-survival patients of more than 10 years showing a value minor than 1%.Material and method: We realize a systematic analysis and identify important factors for long survivor patients. We also show an own case with more of 20 years of survival. We make a new pathological study of the old paraffin block of this patient.Results: The most important variable associated with long-survival between all multivariant studies is the age. When we try to find genetic and molecular alterations in glioblastoma associated with prolongated survival, the MGMT promoter methylation play the most important role. We find a correct diagnosis in the current analysis of our patient's sample with very long survival.Conclusions: Multiple variables are found that affect long survival of glioblastoma series but analyzed studies are very heterogeneous and it is very difficult comparation between them. Most articles we review are obtained from databases of different countries with hundreds of patients. It would be very interesting to promote the use of a single database in Spain that allows us to study these long-term glioblastoma survivors (AU)

Prediction of Cancer-Specific Survival of Brainstem Glioma in Children Based on Risk Stratification Model.

Objective: To develop and authenticate a risk stratification framework and nomogram for ascertaining cancer-specific survival (CSS) among the pediatric brainstem gliomas. Methods: For patients less than 12 years, according to Surveillance, Epidemiology, and End Results (SEER), information from 1998 to 2016 is found in their databases. The survival outcomes, treatments, and demographic clinicopathologic conditions are scrutinized per the database validation, and training cohorts are divided and validated using multivariate Cox regression analysis. A nomogram was designed, and predominantly, the risk stratification conceptualization engaged selected tenets according to the multivariate analysis. The model's authenticity was substantiated through C-index measure and calibration curves. Results: There are 806 pediatric concerns of histologically concluded brainstem glioma in the research. According to multivariate analysis, age, grade, radiotherapy, and race (with P value < 0.05) depicted independent prognostic variations of the pediatric gliomas. The nomogram's C-index was approximately 0.75 and an accompanied predictive capability for CSS. Conclusion: The nomogram constructed in this glioma's context is the primary predictor of using risk stratification. A combination of nomograms with the risk stratification mechanism assists clinicians in monitoring high-risk individuals and engage targeted accessory treatment.

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

PURPOSE: Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN: A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. RESULTS: Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS: These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.

Value of C-11 methionine PET/CT in patients with intracranial germinoma.

PURPOSE: The purpose of this study was to investigate the value of C-11 methionine (MET) positron emission tomography (PET)/computed tomography (CT) in patients with intracranial germinoma (IG). MATERIAL AND METHODS: We conducted a retrospective analysis of 21 consecutive patients with pathologically confirmed IGs and eight patients with intracranial non-germinomas (INGs) located in a similar region. Clinical characteristics, imaging findings, and tumor markers such as α-fetoprotein (AFP) and ß-human chorionic gonadotropin (HCG) were used as clinical variables. Maximum standardized uptake value (SUVmax), tumor-to-normal tissue (T/N) ratio, and visual scoring of tumor were used as MET PET parameters. RESULTS: All IGs were well visualized on MET PET with a three-grade visual scoring system. In addition, SUVmax of IGs was higher than that of INGs (P = 0.005). Pre-treatment (Pre-Tx) T/N ratio was significantly correlated with pre-Tx serum HCG (P = 0.031). Moreover, MET PET parameters showed significant associations with tumor location, sex, KRAS variant, and symptoms. CONCLUSION: MET PET/CT could be a useful diagnostic tool in patients suspected of having IGs. In addition, the MET avidity of tumor is a potential surrogate biomarker of HCG, which has been used as a diagnostic marker for IGs. Tumor MET parameters also had significant differences according to tumor locations, sex, symptoms, and KRAS mutation. However, MET avidity of tumors had no significant prognostic value.

Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features, and Somatostatin Analogs Resistance.

Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12-15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-ß), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.

Pineal Region Gliomas: A Systematic Review of Clinical Features and Treatment Outcomes.

BACKGROUND/AIM: To review the current literature on pineal region gliomas, summarizing the clinical characteristics and treatment outcomes. MATERIALS AND METHODS: PubMed, Scopus, and Cochrane databases were used to identify relevant articles. Comprehensive clinical characteristic review and survival analysis were conducted. RESULTS: Twelve studies describing 81 patients were included. The median age was 39 years (male=54.3%). Fifty patients (61.7%) had obstructive hydrocephalus requiring cerebrospinal fluid diversion with either ventriculoperitoneal shunt (VPS) (40.0%) or endoscopic third ventriculostomy (ETV) (24.0%). Patients who underwent VPS had significant survival benefits compared to ETV (p<0.05). All patients in our review underwent surgery, and gross-total resection (≥98%) was achieved in 34.6%. The supracerebellar infratentorial approach was the most employed surgical approach (62.3%). Chemotherapy was administered in 32.1% of cases, and radiotherapy in 40.7%. The median overall survival (OS) was 12 months, and the overall one-year survival rate was 60%. CONCLUSION: This study could not establish a correlation between the extent of tumor resection and positive treatment outcomes. However, among cases with hydrocephalus, patients who underwent VPS placement had better survival as compared to ETV.

Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study.

PURPOSE: Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication-competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies. PATIENTS AND METHODS: Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients. RESULTS: Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell-related genes was highest in the patient with the longest survival after G207 inoculation. CONCLUSIONS: Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.

A Risk Score Signature Consisting of Six Immune Genes Predicts Overall Survival in Patients with Lower-Grade Gliomas.

BACKGROUND: Lower-grade gliomas (LGGs) are less aggressive with a long overall survival (OS) time span. Because of individualized genomic features, a prognostic system incorporating molecular signatures can more accurately predict OS. METHODS: Differential expression analysis between LGGs and normal tissues was performed using the Gene Expression Omnibus (GEO) datasets (GSE4290 and GSE12657). Immune-related differentially expressed genes (ImmPort-DEGs) were analyzed for functional enrichment. The least absolute shrinkage and selection operator (LASSO) analysis was performed to develop an immune risk score signature (IRSS). We extracted information from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) to establish and validate the model. The relationship of model gene sets with immune infiltration was analyzed based on gene set variation analysis (GSVA) scores. Patients were divided into low- and high-risk groups based on the median score. The time-dependent receiver-operating characteristic (ROC) curve and the Kaplan-Meier curve were used to evaluate the model. Then, a precise prognostic nomogram was established, and its efficacy was verified. RESULTS: A total of 18 related immune genes were identified, building a 6-gene IRSS (BMP2, F2R, FGF13, PCSK1, PRKCB, and PTGER3). DEGs were enriched in T cell and NK cell regulatory pathways. Immune infiltration analysis confirmed that the gene signature correlated with a decrease in innate immune cells. In terms of model evaluation, ROC curves at 1, 3, and 5 years showed moderate predictive ability of IRSS (AUC = 0.930, 0.797, and 0.728). The Cox regression analysis revealed that IRSS was an independent prognostic factor, and the nomogram model had good predictive ability (C - index = 0.828). Meanwhile, the predictive power of IRSS was also confirmed in the training cohort. The Kaplan-Meier results showed that the prognosis of the high-risk group was significantly worse in all cohorts. CONCLUSION: IRSS may serve as a novel survival prediction tool in the classification of LGG patients.

Effects of ESCO2 or its methylation on the prognosis, clinical characteristics, immune microenvironment, and pathogenesis of low-grade glioma.

The establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) has an important regulatory effect on cell proliferation and division, which is closely related to the malignant process of glioma cells. Therefore, this study attempts to provide a target for biologically targeted therapy for low-grade glioma (LGG) by demonstrating the regulatory effect of ESCO2 during the pathological process of LGG. First, the 1064 samples of LGG transcriptomic data and corresponding clinicopathological information obtained from various databases were included in the study. Second, the chi-squared test showed that the expression of ESCO2 was associated with the malignant characteristics of LGG (recurrence and grade), and Kaplan Meier and multivariate analysis suggested that ESCO2 was an independent risk factor, resulting in a significant reduction in the overall duration of survival of patients. Third, co-expression analysis showed that the level of mRNA expression of ESCO2 was negatively regulated by multiple methylation sites (cg04108328, cg12564175, and cg26534677), and the hypermethylation status of cg12564175 could prolong the overall survival of patients. Fourth, the Tumor Immune Estimation Resource (TIMER) database shows that ESCO2 can have a positive regulatory relationship with six different immune cells, such as CD8 + T cells and macrophages, and a positive expression relationship with PD-1 and PD-L1. Finally, Gene Set Enrichment Analysis (GSEA) showed that ESCO2 may play a carcinogenic role by affecting cell replication and DNA repair. In summary, this study confirmed the carcinogenic effect of ESCO2 on LGG for the first time. It is speculated that both the mRNA of ESCO2 and its methylation site (cg12564175) can be useful biological targets for molecular targeted therapy of LGG.

Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival.

Pleomorphic xanthoastrocytoma (PXA) in its classic manifestation exhibits distinct morphological features and is assigned to CNS WHO grade 2 or grade 3. Distinction from glioblastoma variants and lower grade glial and glioneuronal tumors is a common diagnostic challenge. We compared a morphologically defined set of PXA (histPXA) with an independent set, defined by DNA methylation analysis (mcPXA). HistPXA encompassed 144 tumors all subjected to DNA methylation array analysis. Sixty-two histPXA matched to the methylation class mcPXA. These were combined with the cases that showed the mcPXA signature but had received a histopathological diagnosis other than PXA. This cohort constituted a set of 220 mcPXA. Molecular and clinical parameters were analyzed in these groups. Morphological parameters were analyzed in a subset of tumors with FFPE tissue available. HistPXA revealed considerable heterogeneity in regard to methylation classes, with methylation classes glioblastoma and ganglioglioma being the most frequent mismatches. Similarly, the mcPXA cohort contained tumors of diverse histological diagnoses, with glioblastoma constituting the most frequent mismatch. Subsequent analyses demonstrated the presence of canonical pTERT mutations to be associated with unfavorable prognosis among mcPXA. Based on these data, we consider the tumor type PXA to be histologically more varied than previously assumed. Histological approach to diagnosis will predominantly identify cases with the established archetypical morphology. DNA methylation analysis includes additional tumors in the tumor class PXA that share similar DNA methylation profile but lack the typical morphology of a PXA. DNA methylation analysis also assist in separating other tumor types with morphologic overlap to PXA. Our data suggest the presence of canonical pTERT mutations as a robust indicator for poor prognosis in methylation class PXA.

Bioinformatics analysis of C3 in brain low-grade gliomas as potential therapeutic target and promoting immune cell infiltration.

Low-grade gliomas is the malignant nervous tumor with distinct biological and clinical characteristics. Despite advances in diagnostic and therapeutic methods, how to significantly elongate the survival of low-grade gliomas is still challengeable. Complement 3, as the critical component in the innate immune system, plays an essential role in local immune response and participating into regulation of the epithelial-mesenchymal transition and tumor microenvironment. In this study, we systematically determined the expression levels and immunological roles of C3 in low-grade gliomas using various public databases. Then, we further identified the impact of C3 expression on immune cell infiltration compared to normal tissue, indicating the effect of cellular microenvironment on overall survival of LGG patients. We obtained clinical characteristics, transcriptome, and survival of C3 in LGG from the TCGA, GEPIA2.0, and cBioportal databases. Two differentially expressed genes (DEGs) were obtained, DEGs compared to normal tissue (DEG_G1) and DEGs between C3 high expression and C3 low expression in LGG patients (DEG_G2). By performing the GO analysis and protein-protein interaction (PPI) network of DEG_G1, we have identified the top-ranked 10 hub genes, which are highly associated with regulation of cell cycle. The gene set enrichment analysis demonstrated that overexpression of C3 in LGG patient is positively correlated with regulation of cell cycle. The relative PPI analysis and GSEA of DEG_G2 were performed and analysis results indicated that higher expression of C3 in the LGG can activate immune-related pathways. Finally, immune cell infiltration analysis of C3 in the LGG patients was employed and clearly indicated that higher neutrophil infiltration can worsen the survival of the LGG patients with higher expression of C3. These results were confirmed by the Human Protein Atlas database, in which expression level of C3 protein in gliomas patients always higher. This investigation implied that C3 can be as diagnostic biomarker and potential targets of precise therapy for the LGG patients.

Managing Central Nervous System Spread of Lung Cancer: The State of the Art.

Brain metastases (BrM) are common in both non-small-cell lung cancer and small-cell lung cancer. Substantial progress in BrM management has occurred in the past decade related to advances in both radiation and medical oncology. Recent and ongoing radiation trials have focused on increasing the candidacy for focal therapy of BrM with stereotactic radiosurgery; reducing the toxicity and improving patient selection for whole brain radiotherapy; and, in small-cell lung cancer, evaluating brain magnetic resonance imaging surveillance without prophylactic cranial irradiation, hippocampal avoidance in prophylactic cranial irradiation and whole brain radiotherapy, and the role of upfront stereotactic radiosurgery for BrM. In medical oncology, the development of multiple tyrosine kinase inhibitors with encouraging CNS activity and emerging data on the CNS activity of immune checkpoint inhibitors in some patients have opened the door to novel systemic and multidisciplinary treatment strategies for the management of BrM. Future research will focus on more robust characterizations of the CNS activity of targeted therapy and immunotherapies, as well as optimal integration and patient selection for multidisciplinary strategies involving CNS-active drugs, radiation therapy, and CNS surveillance.

Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity.

Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma's hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.