Factor In Glioblastoma Patients Research Articles

The prognostic importance of glioblastoma size and shape.

Extent of resection, MGMT promoter methylation status, age, functional level, and residual tumor volume are established prognostic factors for overall survival in glioblastoma patients. Preoperative tumor volume has also been investigated, but the results have been inconclusive. We hypothesized that the surface area and the shape were more representative of the tumor's infiltrative capacities, and thus, the purpose of this study was to assess the prognostic value of tumor size and shape in patients with glioblastoma. In total, 271 patients with primary, unifocal glioblastoma were included from two centers in Norway and Sweden, respectively. All tumors were automatically segmented on preoperative MRI scans and manually validated. Tumor volume was used as a measurement of size, whereas sphericity index and area-to-volume ratio defined the shape complexity of the tumor. Contact surface area of the tumor was considered a measurement of both size and shape. Multivariable Cox proportional hazards models were used to assess the prognostic value of the respective tumor measurements, with previously established prognostic factors as covariates. There were no associations between preoperative tumor volume and overall survival. Contact surface area (HR = 1.013, p = 0.002) and sphericity index (HR = 2.223, p = 0.001) were both significant independent prognostic factors for survival in the multivariable Cox models. Contact surface area was also associated with MGMT promoter methylation (p = 0.039) and extent of resection (p = 0.017). Tumor shape complexity appears to be an independent prognostic factor in glioblastoma patients and may also be associated with MGMT promoter methylation status and extent of surgical resection.

CTNI-04. DECODING GLIOBLASTOMA SURVIVAL: UNRAVELING THE PROGNOSTIC POTENTIAL OF OLFACTORY FUNCTION IN A PROSPECTIVE OBSERVATIONAL STUDY

Abstract BACKGROUND Olfactory impairment is a common neurologic deficit among glioblastoma patients.We have previously shown that glioblastoma patients with reduced smell sensitivity had lower overall survival rates compared to those with normal olfactory function.A notable limitation in that study was the unequal distribution of prognostic factors between the two groups,and the absence of continuous olfactory assessments during treatment to investigate if therapy-associated neurotoxicity could be a contributing factor to diminished olfactory acuity.In this trial olfactory function will be evaluated in glioblastoma patients as a prognostic marker with regard to overall survival,neurocognition and quality of life. METHODS This prospective,multicenter study is set to recruit 64 glioblastoma patients alongside 64 healthy controls.Stratification of participants is based on prognostically relevant variables such as resection status,MGMT-promoter-methylation-status,radiographic involvement of olfactory brain areas,olfactory function,age,and Karnofsky performance status scale.We utilize Sniffin´ Sticks to evaluate olfactory function through identification and threshold tests,and this assessment is carried out longitudinally throughout the therapy starting from tumor diagnosis.Infiltration of the olfactory nerves or olfactory brain are scrutinized using a high-resolution coronal T2-weighted sequence which is added to a dedicated brain tumor protocol.MRI images are independently reviewed by two board-certified radiologists from distinct institutions,who are blinded to the patients’ olfactory function status.Furthermore,quality of life data,neuropsychological testing,and psychosomatic screening are performed at specific intervals throughout the study.Also,we examine next-generation-sequencing results to investigate potential genetic associations with hyposmia in glioblastoma patients. RESULTS The first participant was enrolled in May 2023.Currently,16 patients and three controls are already enrolled(May 2024).Plans are underway to open a second study site in 2024,with the aim to complete recruitment by December 2025.Follow-up assessments will continue until December 2027.We anticipate that the final results of the study will be available in 2028. CONCLUSIONS In the process,this study is the first prospective study which investigates the olfactory function systematically as prognostic factor in glioblastoma patients.

S100A9, as a potential predictor of prognosis and immunotherapy response for GBM, promotes the malignant progression of GBM cells and migration of M2 macrophages.

In the past decades, the therapeutic effect of glioblastoma (GBM) has not been significantly improved. Generous evidence indicates that S100A9 has a wide range of functions in tumors, but its exploration in GBM is less. The purpose of this study is to conduct a comprehensive bioinformatics analysis and cytological experiment on S100A9 in GBM. The expression data and clinical data of GBM samples were downloaded from the public database, and comprehensive bioinformatics analysis was performed on S100A9 in GBM using R software. Wound healing assay and transwell assay were used to detect the migration activity of cells, and colony formation assay, EdU staining, and CCK-8 assay were used to detect the proliferation activity of cells. The effect of S100A9 on the migration activity of M2 macrophages was verified by the cell co-culture method. The protein expression was detected by western blotting and immunohistochemical staining. S100A9 is an independent prognostic factor in GBM patients and is related to poor prognosis. It can be used as an effective tool to predict the response of GBM patients to immune checkpoint inhibitors (ICIs). In addition, S100A9 can promote the malignant progression of GBM and the migration of M2 macrophages. On the whole, our study highlights the potential value of S100A9 in predicting prognosis and immunotherapeutic response in GBM patients. More importantly, S100A9 may promote the malignant progress of GBM by involving in some carcinogenic pathways and remodeling the tumor microenvironment (TME).

Sequential Evaluation of Hematology Markers as a Prognostic Factor in Glioblastoma Patients.

In our study, we investigated the prognostic significance of hematological markers-NLR (Neutrophil-to-Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio), and RDW-CV (Red Blood Cell Distribution Width-Coefficient of Variation)-in 117 glioblastoma patients. The data collected from January 2016 to December 2018 included demographics, clinical scores, and treatment regimens. Unlike previous research, which often examined these markers solely before surgery, our unique approach analyzed them at multiple stages: preoperative, postoperative, and before adjuvant therapies. We correlated these markers with the overall survival (OS) and progression-free survival (PFS) using statistical tools, including ANOVA, Cox regression, and Kaplan-Meier survival analyses, employing SPSS version 29.0. Our findings revealed notable variations in the NLR, PLR, and RDW-CV across different treatment stages. The NLR and PLR decreased after surgery, with some stabilization post-STUPP phase (NLR: p = 0.007, η2p = 0.06; PLR: p = 0.001, η2p = 0.23), while the RDW-CV increased post-surgery and during subsequent treatments (RDW-CV: p < 0.001, η2p = 0.67). Importantly, we observed significant differences between the preoperative phase and other treatment phases. Additionally, a higher NLR and RDW-CV at the second-line treatment and disease progression were associated with an increased risk of death (NLR at 2nd line: HR = 1.03, p = 0.029; RDW-CV at progression: HR = 1.14, p = 0.004). We proposed specific marker cut-offs that demonstrated significant associations with survival outcomes when applied to Kaplan-Meier survival curves (NLR at 2nd line < 5: p < 0.017; RDW-CV at progression < 15: p = 0.007). An elevated NLR and RDW-CV at later treatment stages correlated with poorer OS and PFS. No significant preoperative differences were detected. These biomarkers may serve as non-invasive tools for glioblastoma management.

Expression of key unfolded protein response genes predicts patient survival and an immunosuppressive microenvironment in glioblastoma

Abstract Background Dysregulation of cellular processes related to protein folding and trafficking leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), triggering ER stress. Cells cope with ER stress by activating the unfolded protein response (UPR), a signaling pathway that has been implicated in a variety of diseases, including cancer. However, the role of the UPR in cancer initiation and progression is still unclear. Methods Here we used bulk and single cell RNA sequencing data to investigate ER stress-related gene expression in glioblastoma, as well as the impact key UPR genes have on patient survival. Results ER stress-related genes are highly expressed in both cancer cells and tumor-associated macrophages, with evidence of high intra- and inter-tumor heterogeneity. High expression of the UPR-related genes HSPA5, P4HB, and PDIA4 was identified as risk factors while high MAPK8 (JNK1) expression was identified as a protective factor in glioblastoma patients, indicating UPR genes have prognostic potential in this cancer type. Finally, expression of XBP1 and MAPK8, two key downstream targets of the ER sentinel IRE1α, correlates with the presence of immune cell types associated with immunosuppression and a worse patient outcome. This suggests that the expression of these genes is associated with an immunosuppressive tumor microenvironment and uncover a potential link between stress response pathways, tumor microenvironment and glioblastoma patient survival. Conclusions We performed a comprehensive transcriptional characterization of the unfolded protein response in glioblastoma patients and identified UPR-related genes associated with glioblastoma patient survival, providing potential prognostic and predictive biomarkers as well as promising targets for developing new therapeutic interventions in glioblastoma treatment.

The global immune-nutrition-inflammation index (GINI) as a robust prognostic factor in glioblastoma patients treated with the standard stupp protocol.

Systemic inflammation can significantly impact gliomas' onset, progression, and prognosis. Glioblastoma multiforme (GBM) represents the glioma subtype characterized by the most profound inflammatory and immunosuppressive states. Consequently, various blood-borne biomarkers have been scrutinized concerning their prognostic value in GBM patients. We sought to investigate whether the recently introduced Global Immune-Nutrition-Inflammation Index (GINI) holds prognostic significance for GBM patients treated with the standard Stupp protocol. We retrospectively analyzed the data from a cohort of newly diagnosed GBM patients receiving the standard Stupp regimen using the propensity score-matching methodology. The GINI was computed using the original formula: GINI = [(C-reactive protein × Monocytes × Platelets × Neutrophils) ÷ (Albumin × Lymphocytes)]. We employed receiver operating characteristic (ROC) curve analysis to identify the optimal cutoff values for GINI, which could help distinguish between different survival outcomes. The primary and secondary objectives were the differences in overall survival (OS) and progression-free survival (PFS) between the GINI groups. The optimal GINI cutoff value was 1350. Out of 294 eligible patients, 211 were PSM-matched: GINI<1350 (N = 95) and GINI≥1350 (N = 116). Comparative Kaplan-Meier estimates indicated that the GINI≥1350 patients had substantially worse median PFS (8.0 vs 16.8months; p < .001) and OS (14.3 vs 22.9months; p < .001) durations than their GINI<1350 counterparts. High pretreatment GINI values are robustly and independently associated with inferior PFS and OS outcomes in selected GBM patients who receive standard Stupp protocol. These findings suggest that if further confirmed, the novel GINI could serve as a valuable biological marker for the prognostic stratification of GBM patients.

Effect of antibiotic drug use on outcome and therapy-related toxicity in patients with glioblastoma-A retrospective cohort study.

Glioblastoma (GB) is the most frequent malignant brain tumor and has a dismal prognosis. In other cancers, antibiotic use has been associated with severity of chemotherapy-induced toxicity and outcome. We investigated if these mechanisms are also involved in GB. We selected a cohort of 78 GB patients who received combined radiochemotherapy. We investigated if exposure to prediagnostic antibiotic use is associated with clinical side effects and laboratory changes during adjuvant therapy as well as overall survival (OS) and progression-free survival (PFS) using chi-square test, binary logistic regression, Kaplan-Meyer analysis, and multivariable Cox regression. Seventeen patients (21.8%) received at least one course of prediagnostic antibiotics and 61 (78.2%) received no antibiotics. We found a higher incidence of loss of appetite (23.5% vs. 4.9%; P = .018) and myelosuppression (41.2% vs. 18.0%; P = .045) in the antibiotic group. Multivariable logistic regression analysis revealed antibiotics to be a predictor for nausea (OR = 6.94, 95% CI: 1.09-44.30; P = .041) and myelosuppression (OR = 9.75, 95% CI: 1.55-61.18; P = .015). Furthermore, lymphocytopenia was more frequent in the antibiotic group (90.0% vs. 56.1%, P = .033). There were no significant differences in OS (P = .404) and PFS (P = .844). Multivariable Cox regression showed a trend toward shorter survival time (P = .089) in the antibiotic group. Our study suggests that antibiotic use affects symptoms and lab values in GB patients. Larger prospective studies are required to investigate if prediagnostic antibiotic use could be a prognostic factor in GB patients.

Potential Prognostic Value of GATA4 Depends on the p53 Expression in Primary Glioblastoma Patients.

Primary glioblastoma is characterized by an extremely poor prognosis. The promoter methylation of GATA4 leads to the loss of its expression in many cancer types. The formation of high-grade astrocytomas can be promoted by the concurrent loss of TP53 and GATA4 in normal human astrocytes. Nevertheless, the impact of GATA4 alterations with linkage to TP53 changes in gliomagenesis is poorly understood. This study aimed to evaluate GATA4 protein expression, GATA4 promoter methylation, p53 expression, TP53 promoter methylation, and mutation status in patients with primary glioblastoma and to assess the possible prognostic impact of these alterations on overall survival. Thirty-one patients with primary glioblastoma were included. GATA4 and p53 expressions were determined immunohistochemically, and GATA4 and TP53 promoter methylations were analyzed via methylation-specific PCR. TP53 mutations were investigated via Sanger sequencing. The prognostic value of GATA4 depends on p53 expression. Patients without GATA4 protein expression were more frequently negative for TP53 mutations and had better prognoses than the GATA4 positive patients. In patients positive for GATA4 protein expression, p53 expression was associated with the worst outcome. However, in patients positive for p53 expression, the loss of GATA4 protein expression seemed to be associated with improved prognosis. GATA4 promoter methylation was not associated with a lack of GATA4 protein expression. Our data indicate that there is a possibility that GATA4 could function as a prognostic factor in glioblastoma patients, but in connection with p53 expression. A lack of GATA4 expression is not dependent on GATA4 promoter methylation. GATA4 alone has no influence on survival time in glioblastoma patients.

Co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia predict prognosis and immunotherapy response in glioblastoma

Objectives Anesthetic drugs had been reported may impact the bio-behavior of the tumor. Propofol and sevoflurane are common anesthetics in the operation for glioblastoma (GBM). This study aims to establish a co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia to predict prognosis and immunotherapy response in GBM. Method GPM tissues with different anesthetics gene expression profiles (GSE179004) were obtained from the Gene Expression Omnibus (GEO) database. Core modules and central genes associated with propofol and sevoflurane anesthesia were identified by weighted gene coexpression network analysis (WGCNA) and establish a risk score prognostic model. Immune cell signature analysis in TCGA datasets was predicted via CIBERSORT. At last, serum methylation level of O6-methylguanine-DNA methyltransferase (MGMT) promoter was detected in GPM patient in different time during perioperative period. Results The burlywood1 group screened was significantly associated with sevoflurane-treated GBM tissue. 22 independent prognostic differential genes were construct a prognostic-related genes risk score in GBM, and showed good predictive ability. The risk score was strongly correlated with the age of the patients, but not with the sex of the patients. In addition, the differential responses to immunotherapy in high and low risk groups were analyzed, indicating that sevoflurane signature genes were consistent in the classification of gliomas. High-risk patients have high T-cell damage score and are less sensitive to immunotherapy. At last, serum methylation level of MGMT promoter was decreased in GBM patients during propofol and sevoflurane anesthesia. Conclusions Propofol and sevoflurane anesthesia associated impact on the gene expression of GBM, included the methylation level of MGMT promoter. Propofol and sevoflurane anesthesia-based risk score prognostic model, which has good prognostic power and is an independent prognostic factor in GBM patients. Therefore, this model can be used as a new biomarker for judging the prognosis of GBM patients. KEY MESSAGES Propofol and sevoflurane anesthesia-based risk score prognostic model has good prognostic power and is an independent prognostic factor in GBM patients. High Propofol and sevoflurane anesthesia-based risk score GBM patients have high T-cell damage scores and are less sensitive to immunotherapy. Serum methylation level of MGMT promoter decrease during propofol and sevoflurane anesthesia in GBM patients.

The Assessment of Clinical Outcomes and Prognostic Factors in Glioblastoma Patients.

To assess the outcomes of glioblastoma patients treated in our clinic over the last 10 years using a multimodality approach and cutting-edge techniques. In our study, we included 169 glioblastoma patients who were admitted to our clinic between 2009 and 2019 and received concurrent radiotherapy (RT) + temozolomide (TMZ) after surgery. Patients were collected retrospectively and analyzed using appropriate statistical methods. The average follow-up period was 19 months. The average overall survival (OS) was 20.5 months. PFS and PPS were found to be 10.8 and 8.9 months, respectively. In the multivariate analysis for prognostic factors on OS, the Karnofsky Performance Score (KPS), the extent of resection (EOR), and the use of adjuvant TMZ were significant. PFS was significantly predicted by KPS, EOR, adjuvant TMZ, and planning target volume (PTV). Acute severe lymphopenia (ASL) following RT reduced the OS and PFS. There was no statistical difference in OS, PFS, recurrence patterns, or ASL incidence between the RTOG and EORTC regimens and RT techniques (IMRT vs. 3D-CRT). The association between dose-volume parameters (V3, V5, V10, V15, and V20 and V25, V30, V40, and V60 Gy) and post-treatment ASL frequency was studied. For each parameter, threshold levels were discovered. Furthermore, patients with recurrent glioblastoma who received salvage therapies had better outcomes. A multidisciplinary, and intensive treatment approach using modern techniques improved the OS of glioblastoma patients. Furthermore, in glioblastoma patients, larger RT fields were not associated with better outcomes. As a result, lymphocytesparing RT may be more beneficial in increasing patients' compliance to adjuvant TMZ, which is an important prognostic factor of OS.

Comparison of Prognostic Factors in Glioblastoma Patients with Short- and Long-term Survival

Comparison of Prognostic Factors in Glioblastoma Patients with Short- and Long-term Survival

CSNK1D is associated with stemness and invasiveness in glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor. It has a poor 5-year survival rate, a high recurrence rate, and few therapeutic options. Exploring the molecular processes underlying the formation and progression of GBM, as well as identifying novel therapeutic targets, is critical for improving GBM therapy and prognosis. We extracted primary GSCs (glioblastoma stem cells) from patient-derived samples. Different levels of CSNK1D were evaluated through immunohistochemistry, western blot and real-time PCR assays. A Transwell assay was used to detect invasive ability of cell lines. Tumorsphere formation assay was performed to detect cancer stemness properties. Orthotopic xenograft models were used to evaluate the effect of CSNK1D on GSC tumorigenesis. We found the expression levels of CSNK1D was elevated in GBM tissues compared with normal brain. CSNK1D expression had an increased tendency among WHO grades (G2-G4), and was higher in IDH wildtype group than in mutation group. The prognosis of the CSNK1D high expression group was significantly worse than that of the low expression group. Cox multivariate analysis showed that CSNK1D was also an independent prognostic factor in GBM patients. In primary GBM cells, we observed increased levels of CSNK1D in GSCs compared to non-stem tumor cells (NSTCs). In addition, the change of stemness markers expression and proliferation of GSCs were in coordinate with CSNK1D overexpression or knockdown. Furthermore, CSNK1D could affect the epithelial-mesenchymal transition (EMT) markers and MMPs expression in GSCs. Finally, disruption of CSNK1D expression impairs GSC survival and GBM tumor propagation in orthotopic xenograft models. Our results suggest that CSNK1D correlated with GBM prognosis and might influence the stemness and invasiveness of GSCs, which represented a potential therapeutic target in GBM patients.

BIOM-07. LOW EXPRESSION OF HLA-A AS A NOVEL PROGNOSTIC FACTOR IN GLIOBLASTOMA TREATED WITH TUMOR FUSED DENDRITIC CELL VACCINES

Abstract Although immunotherapy has become an attractive approach to cancer treatment in patients with broad types of aggressive tumors, phase III clinical trials of immunotherapy for glioblastoma (GBM) have not achieved extended survival of patients. Dendritic cells perform an essential role in the immune system as antigen-presenting cells and tumor fused dendritic cells (TFDCs) can induce tumor-specific cytotoxic T cells as a cancer vaccine. We have previously described the safety and mechanisms of TFDCs therapy, as well as immunological and clinical responses of patients with GBM, however, there were little known about predictive and prognostic biomarkers specific to TFDCs therapy. In the present study, we investigated the whole transcriptome sequencing of tumor cells, and novel prognostic factors were identified through molecular profiling GBM treated with TFDCs immunotherapy. Fifty-three patients were eligible in this study and 28 samples from patients with newly diagnosed GBM IDH wild-type were included. Of these 28 samples, 15 high-quality RNA samples successfully extracted from tumors were analysed. The samples were divided into two groups based on the median patient's overall survival. Differential expression analyses and enrichment analysis between the two groups were carried out using CLC Genomics Workbench (QIAGEN), and Gene Ontologies (GO) were assigned. A total of 473 differentially expressed genes were detected including 327 enriched GO terms. Fifteen GO terms out of 327 GO terms represented the highest enrichment scores, revealed that five GO terms were associated with the major histocompatibility complex (MHC). The relationship among the MHC, immune-related genes, and clinical outcomes was investigated using the Cox regression model and Kaplan–Meier log-rank test. Low expression of HLA-A in the tumors turned out to be a significantly favorable prognostic impact (p = 0.01). The decreased expression of HLA-A might be a novel prognostic factor in GBM patients treated with TFDCs immunotherapy.

Functional In Vitro Assessment of VEGFA/NOTCH2 Signaling Pathway and pRB Proteasomal Degradation and the Clinical Relevance of Mucolipin TRPML2 Overexpression in Glioblastoma Patients.

Glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high vascularization and its growth depends on the formation of new blood vessels. We have previously demonstrated that TRPML2 mucolipin channel expression increases with the glioma pathological grade. Herein by ddPCR and Western blot we found that the silencing of TRPML2 inhibits expression of the VEGFA/Notch2 angiogenic pathway. Moreover, the VEGFA/Notch2 expression increased in T98 and U251 cells stimulated with the TRPML2 agonist, ML2-SA1, or by enforced-TRPML2 levels. In addition, changes in TRPML2 expression or ML2-SA1-induced stimulation, affected Notch2 activation and VEGFA release. An increased invasion capability, associated with a reduced VEGF/VEGFR2 expression and increased vimentin and CD44 epithelial-mesenchymal transition markers in siTRPML2, but not in enforced-TRPML2 or ML2-SA1-stimulated glioma cells, was demonstrated. Furthermore, an increased sensitivity to Doxorubicin cytotoxicity was demonstrated in siTRPML2, whereas ML2-SA1-treated GBM cells were more resistant. The role of proteasome in Cathepsin B-dependent and -independent pRB degradation in siTRPML2 compared with siGLO cells was studied. Finally, through Kaplan-Meier analysis, we found that high TRPML2 mRNA expression strongly correlates with short survival in GBM patients, supporting TRPML2 as a negative prognostic factor in GBM patients.

Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli.

Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

P14.90 Survival outcomes and prognostic factors in glioblastoma patients treated with radiotherapy plus concomitant and adjuvant temozolomide - real-world study

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults. The current standard of care for newly diagnosed GBM is maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ). This study aimed to evaluate the survival outcomes and identify predictors of survival among these patients. MATERIAL AND METHODS We performed a single-centre retrospective analysis of GBM patients treated with radiotherapy plus concomitant and adjuvant TMZ from 2013 to 2020. The analyses of progression-free survival (PFS) and overall survival (OS), each one evaluated starting from initial diagnosis, were performed. Survival curves were estimated with the Kaplan- Meier method and compared using the log-rank test. RESULTS Fifty-eight patients were identified. The median age was 61 years (range 18- 80), 51 (88%) patients were in ECOG-PS 0–1, 6 (10%) patients had isocitrate dehydrogenase (IDH) mutation and 53 (91%) of patients had undergone debulking surgery. At a median follow-up of 21 months, median OS was 12.8 months (95% confidence interval [CI] 9.7–15.9), whereas median PFS was 9.5 months (95% CI 8.5–10.5). The 1-year survival rate was 42% and the 2-year survival rate was 10%. Grade 3 or 4 hematologic toxicity occurred in 11 (19%) patients. Twenty-five (42%) patients completed at least 6 cycles of TMZ monotherapy with statistically significant differences between this sub-group and those who weren’t able to continue TMZ monotherapy [median OS 19.3 months (95% CI 14.4–24.2) vs 10.6 months (95% CI 7.8–13.4) p&amp;lt;0.001]. ECOG-PS = 0 [median OS 16.7 months (95% CI 13.4–20.0, p=0.001)] and patients under 65 years of age [median OS 15.6 months (95% CI 12.3–18.9, p=0.02) were associated with significantly better median OS. CONCLUSION The current standard of care treatment for GBM remains poor. An important factor predictor of survival is the completion of the 6 maintenance cycles of TMZ. At baseline, ECOG PS and the patient’s age could be used to define patient prognosis.

The Multifunctional Role of EMP3 in the Regulation of Membrane Receptors Associated with IDH-Wild-Type Glioblastoma.

Epithelial membrane protein 3 (EMP3) is a tetraspan membrane protein overexpressed in isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma (GBM). Several studies reported high EMP3 levels as a poor prognostic factor in GBM patients. Experimental findings based on glioma and non-glioma models have demonstrated the role of EMP3 in the regulation of several membrane proteins known to drive IDH-wt GBM. In this review, we summarize what is currently known about EMP3 biology. We discuss the regulatory effects that EMP3 exerts on a variety of oncogenic receptors and discuss how these mechanisms may relate to IDH-wt GBM. Lastly, we enumerate the open questions towards EMP3 function in IDH-wt GBM.

What is the role of CRP in glioblastoma?

BackgroundGlioblastoma is the most common primary malignant brain tumor in adults. Previous studies have suggested that CRP (C-reactive protein) could serve as a biomarker candidate as well as a prognostic factor in glioblastoma patients, and we here further investigate its potential role. Materials and methodsPublicly available datasets were used to compare gene expression between brain samples from glioblastoma patients and non-tumor tissue. The structure of CRP was compared between humans and rats. Glioblastoma cells from humans and rats were stained with anti-CRP. Fischer 344 rats were inoculated with syngeneic glioblastoma cells pre-coated with anti-CRP, and survival was monitored. CRP concentration in rats carrying glioblastoma was followed. ResultsCRP was upregulated on one locus on gene level in glioblastoma tissue as compared to non-tumor brain tissue, but not in glioma stem cells as compared to neural stem cells. The structure of the CRP protein was a characteristic pentamer in both humans and rats. Both human and rat glioblastoma cells were clearly positive for anti-CRP staining. Pre-coating of glioblastoma cells with anti-CRP antibodies did not affect survival in rats with intracranial tumors. Serum levels of CRP increased during tumor progression but did not reach significantly different levels. ConclusionsBoth human and rat glioblastoma cells could be stained with anti-CRP antibodies in vitro. In a syngeneic glioblastoma rat model we could see an increase in serum CRP during tumor progression, but coating glioblastoma cells with anti-CRP antibodies did not provide any survival change for the animals.

Ki-67 Proliferative Activity in the Tumor Margins as a Robust Prognosis Factor in Glioblastoma Patients.

The infiltrative margin of glioblastomas (GBM) contains proliferative tumor cells difficult to estimate radiologically as they are included in the hyperintense signal of T2 sequences and they remain in the cavity margin after tumor resection. The amount of these cells could determine overall survival (OS) of these patients. From October 2007 to January 2010, patients whose MRI were suggestive of newly diagnosed, resectable high-grade glioma were operated using fluorescence-guided surgery (FGS). Separate samples were selectively taken from nonfluorescent white matter areas just adjacent to the border of the pale fluorescence and staining was made for Ki-67. OS was analyzed with Kaplan-Meier and Cox regression. Multivariate analysis included the following prognosis variables: age, extent of resection (EOR), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and performance status index. Sample included 65 patients, comprising 37 men and 28 women, with a median Karnofsky Performance Score (KPS) of 80 (40-100) and mean age of 60 (34-78) years. Mean preoperative tumor volume was 35.8 mL. EOR was 100% in 52 patients (80%), with the lower EOR being 88%. For Ki-67, 39 patients had <5% and 26 had ≥5%. OS was 26.8 months (95% confidence interval [CI]: 18.9-28.2) for the Ki-67 low group versus 15.8 months (95% CI: 7.7-18.2) for the Ki-67 high group (p = 0.002). Proliferative activity in the normal-looking brain around the resection cavity measured with Ki-67 immunostaining is an important independent prognostic factor for GBM cases with complete resection of enhancing tumor. When complete resection is not reached, this factor is not relevant for prognosis.

GENE-07. INFLUENCE OF EPIGENETIC MODULATION OF THE T-CELL REGULATORS EXPRESSION ON GLIOBLASTOMAS BY HISTONE 3 LYSINE METHYLTRANSFERASE OR DEMETHYLASE ON THE PROGNOSIS OF THE GLIOBLASTOMA PATIENTS

Abstract PURPOSE The primary aim of this study is to investigate the expression of the T cell stimulators and inhibitors as well as histone modifying enzymes in the glioblastoma cells. Based on the expression of these proteins, authors estimate the prognostic role in glioblastoma patients and also validate the known prognostic factors. MATERIALS AND METHODS Using 84 FFPE samples of glioblastoma in the pathologic archives at our institute, immunohistochemical staining for T cell stimulators (CD 27, CD 28, CD 137, OX40, ICOS), inhibitors (CTLA-4, PD-1, PD-L1, TIM3, CD200R), histone 3 lysine methyltransferase (MLL4, RIZ, EZH1, NSD2), and histone 3 lysine demethylase (KDM5c, JMJD1a, UTX, JMJD5). RESULTS Median values of the immunohistochemical staining for T cell stimulators and inhibitors were 16.3% of CD27, 10.4% of CD28, 47.5% of CD137, 52.9% of ICOS, 32.2% of OX40, 31.4% of CTLA-4, 7.2% of PD-1, 55.5% of PD-L1, 62.2% of TIM3, and 42.8% of CD200R. In multivariate analysis, increased expression of CD28 (p=0.042), CD137 (p=0.009), EZH1 (p=0.040), and decreased expression of CTLA-4 (p=0.003), PDL-1 (p=0.020) in glioblastoma cells were independently associated with longer OS as well as known prognostic factors such as young age, high KPS, wide extent of resection, PRA class, and methylated MGMT promoter. Interestingly, 42 of 43 samples (97.7%) with decreased PDL1 expression had the increased EZH1 expression, 31 of 33 samples (93.9%) with decreased CTLA4 expression had the increased RIZ expression, 25 of 26 samples (96.2%) with increased CD137 expression had the increased UTX expression, and 36 of 39 samples (92.3%) with increased CD28 expression had the increased JMJD1a expression, respectively. CONCLUSION The result of presenting study suggest that the regulators of T cell can be considered as independent prognostic factors in glioblastoma patients and the expression of these regulators can be controlled by unique histone 3 lysine methylation enzymes.